Blood and endocrine system diseases in children. Lesson 3. Topics: Hemorrhagic disease in children. Hemophilia, thrombocytopenia and thrombocytopathies children. Etiology Pathogenesis. Classification. Diagnostics. Differential diagnosis with other hemorrhagic conditions in children. Treatment. Emergency treatment of bleeding and hemorrhagic conditions requiring treatment.

International Guidelines: Clinacal Practice guidelines: Henoch-Schonlein purpura http://www.rch.org.au/clinicalguide/guideline_index/HenochSchonlein_Purpura/

The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia http://www.bloodjournal.org/content/bloodjournal/117/16/4190.full.pdf GUIDELINES FOR THE MANAGEMENT OF HEMOPHILIA http://www.hemoacademy.cz/dokumenty/guidelines_mng.pdf

Introduction: All hemorrhagic diatheses are divided into 3 groups, depending on the type and cause of hemorrhagic syndrome: vasopathies, thrombopathias, coagulopathies.

IMMUNE THROMBOCYTOPENIC PURPURA (ITP)  Autoantibodies against platelet surface  Clinical presentation o Typically 1–4 weeks after a nonspecific viral infection o Most 1–4 years of age → sudden onset of petechiae and purpura with or without mucous membrane bleeding o Most resolve within 6 months o <1% with intracranial hemorrhage o 10–20% develop chronic ITP  Labs o Platelets <20,000/mm3 o Platelet size normal to increased o Other cell lines normal o Bone marrow—normal to increased megakaryocytes Treatment o Transfusion contraindicated unless life-threatening bleeding (platelet antibodies will bind to transfused platelets as well) o No specific treatment if platelets >20,000 and no ongoing bleeding o If very low platelets, ongoing bleeding that is difficult to stop or life- threatening: Intravenous immunoglobulin for 1–2 days o If inadequate response, then prednisone o Splenectomy reserved for older child with severe disease

Immune Thrombocytopenic Purpura (idiopathic thrombocytopenic purpura, autoimmune thrombocytopenic purpura, primary thrombocytopenic purpura) Background: Immune thrombocytopenic purpura (ITP) is a clinical syndrome in which a decreased number of circulating platelets (thrombocytopenia) present as a bleeding tendency, easy bruising (purpura), or extravasation of blood from capillaries into skin and mucous membranes (petechiae). Pathophysiology: An abnormal autoantibody, usually immunoglobulin G (IgG) with specificity for one or more platelet membrane glycoproteins, binds to circulating platelet membranes. Immunoglobulin-coated platelets induce receptor–mediated phagocytosis by mononuclear macrophages, primarily but not exclusively in the spleen. The spleen is the key organ in the pathophysiology of ITP, not only because platelet autoantibodies are formed in the white pulp, but also because the immunoglobulin-coated platelets are destroyed by mononuclear macrophages in the red pulp. If bone marrow megakaryocytes are not able to increase production and maintain a normal number of circulating platelets, thrombocytopenia and purpura develop. Frequency: The annual incidence of chronic ITP has been estimated to be 1 in 10,000 Mortality/Morbidity: The most frequent cause of death in ITP is spontaneous or accidental, trauma-induced intracranial bleeding in patients whose platelet counts are less than 10,000 per µL. This situation occurs in 1-2% of cases. Sex: In children, the incidence is the same among males and females. Age: Children may be affected at any age, but the peak incidence occurs in children aged 3-5 years. Causes: 1. Postviral illness. In children, most cases of ITP are acute, and onset seems to occur within a few weeks of recovery from a viral illness. Thrombocytopenia is a recognized complication following Ebstein-Barr virus infection; varicella virus; cytomegalovirus; rubella virus; hepatitis A, B or C; or more typically, a vaguely defined, viral, upper respiratory infection or gastroenteritis. Transient thrombocytopenia often follows recent immunization with attenuated live-virus vaccines. 2. Human immunodeficiency virus (HIV). Thrombocytopenia may occur during the acute retroviral syndrome coincident with fever, rash, and sore throat. 3. Drug-induced thrombocytopenia. Persons who have been sensitized (by prior exposure) to quinidine or quinine may develop immune-mediated drug purpura within hours to days of subsequent exposure. ther drugs that have been associated with drug purpura include antibiotics (eg, cephalothins, rifampicin), gold salts, analgesics, neuroleptics, diuretics, antihypertensives, eptifibatide (Integrilin), and, more recently, abciximab (ReoPro), a chimeric monoclonal fragment antigen binding (Fab) antibody fragment directed against the platelet GPIIb/IIIa receptor. CLINICAL Physical: 1. Skin and mucous membranes. The presence of widespread petechiae and ecchymoses, oozing from a venepuncture site, gingival bleeding, or hemorrhagic bullae indicates that the patient is at risk for a serious bleeding complication (Fig. 1). If the patient's blood pressure was taken recently, petechiae may be observed under and distal to the area where the cuff was placed and inflated (Fig. 2). Similarly, suction-type ECG leads may induce petechiae. 2. Abdomen. The spleen is palpable in less than 10% of children with ITP. In children with acute ITP, the presence of a readily palpable spleen is not typical.

Fig. 1. Haemorrhagic rush in idiopathic thrombocytopenic purpura.

Fig. 2. “Cuff” symptrom in thrombocytopenic purpura.

Fig. 3. Petechiae and purpura from immune thrombocytopenic purpura

Lab Studies: Complete blood count. The hallmark of ITP is isolated thrombocytopenia. Peripheral blood smear 1. The morphology of red cells and leukocytes is normal. 2. The morphology of platelets is typically normal, with varying numbers of large platelets. 3. Clumps of platelets on a peripheral smear prepared from ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood are evidence of pseudothrombocytopenia. Antiplatelet antibody. Assays for platelet antigen-specific antibodies, platelet-associated immunoglobulin, or other antiplatelet antibodies are available in some medical centers and certain mail-in reference laboratories. Imaging Studies: Computer-assisted tomographic (CT) scanning or magnetic resonance imaging (MRI) Use them promptly when the medical history or physical examination suggests serious internal bleeding. Procedures: The primary diagnostic evaluation is the bone marrow aspirate and biopsy. In ITP, a normal-to-increased number of megakaryocytes exist in the absence of other significant abnormalities. Spleen. No specific findings exist in the spleen. Medical Care: 1. The goal of medical care is to increase the platelet count to a safe level, permitting patients with ITP to live normal lives while awaiting spontaneous or treatment-induced remission. After 6 months, if the platelet count cannot be maintained at a safe level or it cannot be maintained at a safe level with medication without serious treatment-related toxicity, consider splenectomy. 2. Corticosteroids (oral prednisone, IV methylprednisolone) are the drugs of choice for initial management of ITP. 3. Intravenous immune globulin (IVIG) has been the drug of second choice for many years. However, recent studies indicate that for patients who are Rh(D) positive with ITP, intravenous Rho immune globulin (RhIG) offers comparable efficacy, less toxicity, greater ease of administration, and a lower cost than IVIG. 4. The limitation of using IV RhIG is the lack of efficacy in patients who are Rh(D) negative or splenectomized. Also, IV RhIG induces immune hemolysis in persons who are Rh(D) positive and should not be used when the hemoglobin concentration is less than 8.0 g/dL. Medical care in children

1. The initial treatment of ITP depends on whether the risk of severe hemorrhage, such as intracranial bleeding, is estimated to be low, moderate, or high.

2. Children whose platelet count is greater than 30,000/ L typically only have mild purpura, and the risk of a severe hemorrhage is low. They may be managed as outpatients without specific treatment.

3. Children whose platelet count is less than 20,000/ L may have more significant purpura and mucosal bleeding. Oral prednisone is conservative treatment, and the addition of IV RhIG for patients who are Rh(D) positive or IVIG for patients who are Rh(D) negative is a more aggressive treatment.

4. Children whose platelet count is less than 10,000/ L are likely to have a significant bleeding tendency and a high risk of serious hemorrhage. Initial treatment with IV methylprednisolone and either IV RhIG or IVIG is appropriate.

5. Platelet transfusions may be required for overt bleeding but are not recommended for prophylaxis. Chronic or treatment-resistant ITP

1. For those patients whose platelet counts do not or no longer respond to treatment with tolerable doses of corticosteroids, IV RhIG, IVIG, or splenectomy, other treatments are available.

2. Data supporting these options are based on relatively few case studies and response rates are comparatively lower.

3. Before concluding that a patient has failed both medical management and splenectomy, necessitating treatment with alternative options, perform an imaging study to ensure that the problem is not associated with the presence of an accessory spleen.

4. Among the medical treatment options in these circumstances are cyclophosphamide, azathioprine, and danazol.

5. Interventions of uncertain efficacy include vinblastine, vincristine, ascorbic acid, colchicine, or interferon-alpha, for which conflicting reports of efficacy in the medical literature exist. Surgical Care: In acute ITP, splenectomy usually results in a rapid, complete, and lifelong clinical remission. In chronic ITP, the results of splenectomy typically are less predictable. Platelet counts may not revert to fully normal values, and relapses are not uncommon. Splenectomy results in a lifelong increased risk of sepsis from infection by encapsulated bacteria. In children, the risk of bacterial sepsis after splenectomy is estimated to be 1-2%. Many pediatricians recommend delaying splenectomy until children are aged 5 years. MEDICATION Prednisone 4-8 mg/kg/d PO; however, a reduced dose of 1.5-2.0 mg/kg/d may be adequate for management of nonurgent situations or when risk of adverse effects is high because of predisposing factor, such as diabetes or psychiatric illness Methylprednisolone (Solu-Medrol) 30 mg/kg/d IV for initial management of a severe bleeding tendency in ITP. IV methylprednisolone recommended when most rapid and reliable treatment of ITP is required. In this situation, combine methylprednisolone with IV RhIG in qualified patients who are Rh(D) positive or IVIG in patients who are Rh(D) negative or unqualified patients who are Rh(D) positive. Intravenous Rho immune globulin (WinRho SDF) -- Specialized immunoglobulin product manufactured from pools of plasma from persons who are Rh(D) negative and have been alloimmunized to the D blood group antigen. A single infusion of 50 µg/kg, followed by a second dose, if required, of 20-40 µg/kg, is recommended; an off-label dose of 75 µg/kg in patients whose hemoglobin concentration is at least 8.0 g/dL may increase efficacy without adverse effect Not recommended for persons whose Rh blood type is Rh(D)- negative or who have had a splenectomy; IV RhIG should not be used for persons whose hemoglobin concentration is <8.0g/dL; persons with known IgA deficiency and anti-IgA are at risk of an anaphylactic/anaphylactoid reaction to all plasma- containing biologicals, including IV RhIG Immune globulin intravenous (IVIG, Gamimune, Gammagard, Sandoglobulin) Begin with 1.0 g/kg infused IV at starting rate of 0.5 mL/kg/h (5% solution) to a maximum rate of 4.0 mL/kg/h; repeat dose at 3-4 wk intervals when indicated by decreasing platelet count Immunosuppressive antimetabolite -- Used in patients with ITP to reduce production of abnormal autoantibody. Azathioprine (Imuran) -- May be effective in some patients with ITP who do not or no longer respond to corticosteroids, IV RhIG, or IVIG. May be used in conjunction with prednisone to reduce dose of prednisone, or it may be used as another oral medication to delay splenectomy. Adult Dose 2 mg/kg/d PO/IV Pediatric Dose 50mg/daily Synthetic antineoplastic drugs (chemically related to nitrogen mustards) -- Inhibit cell growth and proliferation. Cyclophosphamide (Cytoxan) -- May be useful in some patients who do not or no longer respond to corticosteroids, IV RhIG, IVIG, or splenectomy. Induces less of a decrease in platelet count compared to other immunosuppressive alkylating agents. 2 mg/kg/d PO or 1.0-1.5 g/m2 q2-4mo as a bolus IV infusion; occasionally, patients require more frequent dosing Prognosis: More than 80% of children with untreated ITP had a spontaneous recovery with completely normal platelet counts in 2-8 weeks. Fatal bleeding occurred in 0.9% on initial presentation. Fatal intracerebral hemorrhage occurs rarely in children who have been treated with prednisone and IV RhIG or IVIG for at least 2 days.

Thrombasthenia Glanzmann thromboasthenia, Glanzmann disease, constitutional thrombopathy, hereditary hemorrhagic thrombopathy Background: Glanzmann initially described thrombasthenia in 1918 when he noted purpuric bleeding in patients with platelet counts within the reference range. Glanzmann thrombasthenia is one of several inherited disorders of platelet function. athophysiology: Glanzmann thrombasthenia is an autosomal recessive trait whereby the production and assembly of the platelet membrane glycoprotein (GP) IIb-IIIa is altered, preventing the aggregation of platelets and subsequent clot formation. Mortality/Morbidity: The probability of death following bleeding is estimated at approximately 5%. ] Age: Patients with Glanzmann thrombasthenia are typically diagnosed in infancy; all individuals with the disorder are recognized by age 5 years. Physical: Most patients with thrombasthenia present with signs of purpura or bleeding. The diagnosis is made in patients with refractory hemorrhage and appropriate findings on the diagnostic laboratory studies Causes: Trauma and pressure remain the most frequent causes of bleeding in persons with thrombasthenia. Lab Studies:

1. A history of prolonged bleeding, a prolonged bleeding time, and failure of platelets to aggregate in response to any of the usual agonists are diagnostic of thrombasthenia.

2. A CBC may also suggest the degree of bleeding. Patients who are thrombasthenic have platelet counts within the reference range and, on blood smear, normal platelet morphology.

3. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are within reference ranges.

4. A urinalysis may demonstrate proteinuria and microscopic hematuria.

5. The diagnosis is confirmed by documenting the absence of GP IIb- IIIa via sodium dodecyl sulfate-polyacrylamide gel electrophoresis of radiolabeled platelet proteins. Medical Care:

1. Refractory bleeding in individuals with thrombasthenia requires the transfusion of normal platelets.

2. E-aminocaproic acid may be useful in controlling bleeding after dental extraction.

3. Corticosteroids are not helpful in persons with acute bleeding.

4. Other more rare therapies cited were bone marrow transplants and recombinant factor VIIa. Surgical Care: Patients with severe menorrhagia may require hysterectomy. Vasculitis and Thrombophlebitis Vasculitis is a descriptive term associated with a heterogeneous group of diseases that results in inflammation of blood vessels. Arteries and veins of any size in any organ may be affected, leading to ischemic damage to organs. The pattern of vessel involvement is highly variable, leading to innumerable clinical presentations. The most common vasculitides of childhood are Henoch-Schцnlein purpura and Kawasaki disease. See articles on Kawasaki Disease, Infantile Polyarteritis Nodosa, Polyarteritis Nodosa, and Takayasu Arteritis. For the clinician, diagnosing the cause of vasculitis is a difficult task that involves distinguishing disease entities with possibly overlapping clinical presentations. Classification criteria have been established for a number of distinct clinical syndromes, but these are less useful in making a diagnosis in patients who do not meet all the criteria of any one disease. While groups of patients with unifying features can be identified, a patient with vasculitis often presents initially with nonspecific constitutional findings. Various classification schemes for vasculitis have been proposed, most recently by an international consensus conference in Chapel Hill, North Carolina in 1994. This classification is as follows: Large-sized vessel vasculitis

1. Temporal arteritis - Granulomatous arteritis of the aorta and major branches, especially the extracranial branches of the carotid artery that usually occurs in patients older than 50 years

2. Takayasu arteritis - Granulomatous arteritis of the aorta and major branches that usually occurs in patients younger than 50 years Medium-sized vessel vasculitis

1. Polyarteritis nodosa - Necrotizing vasculitis of medium- or small- sized arteries without involvement of large arteries, veins, or venules; renal involvement without glomerulonephritis

2. Kawasaki disease - Medium- and small-sized arteritis of childhood associated with mucocutaneous lymph node syndrome; most commonly affects coronary arteries, although veins and aorta may be involved (Lesions of the aorta have been found on autopsy.) Small-sized vessel vasculitis

1. Wegener granulomatosis - Granulomatous inflammation of small- to medium-sized vessels involving the respiratory tract; necrotizing glomerulonephritis common

2. Churg-Strauss syndrome - Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis of small- to medium-sized vessels; associated with asthma and eosinophilia (Under the classification of the American College of Rheumatology and traditional classifications, Wegener granulomatosis and Churg-Strauss syndrome are grouped together with polyarteritis nodosa under medium-sized vessel vasculitis.)

3. Microscopic polyangiitis (MPA) - Pauci-immune necrotizing vasculitis involving small- and medium-sized vessels; necrotizing glomerulonephritis common; pulmonary capillaritis frequent

4. Schönlein-Henoch disease: Small-vessel vasculitis with immunoglobulin A (IgA) immune accumulation; involvement of skin, gut, and glomeruli typical; associated with arthritis or arthralgia

5. Essential cryoglobulinemic vasculitis - Vasculitis with cryoglobulin immune accumulation affecting arterioles and venules; associated with serum cryoglobulins; skin and glomeruli often involved

6. Cutaneous leukocytoclastic vasculitis - Isolated cutaneous vasculitis without systemic vasculitis or glomerulonephritis

7. Possible thrombophlebitis, or superficial venous thrombosis - Resulting from vasculitic lesions with endothelial activation; in children, more often due to hypercoagulable states or catheter instrumentation

Background Idiopathic thrombocytopenic purpura (ITP), also known as primary immune thrombocytopenic purpura and autoimmune thrombocytopenic purpura, is defined as isolated thrombocytopenia with normal bone marrow and the absence of other causes of thrombocytopenia. The 2 distinct clinical syndromes manifest as an acute condition in children and a chronic condition in adults. ITP is a decrease in the number of circulating platelets in the absence of toxic exposure or a disease associated with a low platelet count. Pathophysiology ITP is primarily a disease of increased peripheral platelet destruction, with most patients having antibodies to specific platelet membrane glycoproteins. Relative marrow failure may contribute to this condition, since studies show that most patients have either normal or diminished platelet production. Acute ITP often follows an acute infection and has a spontaneous resolution within 2 months. Chronic ITP persists longer than 6 months without a specific cause. Epidemiology Frequency United States The incidence of ITP in adults is approximately 66 cases per 1,000,000 per year. An average estimate of the incidence in children is 50 cases per 1,000,000 per year. New cases of chronic refractory ITP comprise approximately 10 cases per 1,000,000 per year. International According to studies in Denmark and England, childhood ITP occurs in approximately 10-40 cases per 1,000,000 per year. A study in Kuwait reported a higher incidence of 125 cases per 1,000,000 per year. Mortality/Morbidity

 Hemorrhage represents the most serious complication; intracranial hemorrhage is the most significant. The mortality rate from hemorrhage is approximately 1% in children and 5% in adults. In patients with severe thrombocytopenia, predicted 5- year mortality rates from bleeding are significantly raised in patients older than 60 years versus patients younger than 40 years, 47.8% versus 2.2%, respectively.  Older age and previous history of hemorrhage increase the risk of severe bleeding in adult ITP.

 Spontaneous remission occurs in more than 80% of cases in children but is uncommon in adults. Sex

 In chronic ITP (adults), the female-to-male ratio is 2.6:1. More than 72% of patients older than 10 years are female.

 In acute ITP (children), distribution is equal between males (52%) and females (48%). Age

 Peak prevalence occurs in adults aged 20-50 years.

 Peak prevalence occurs in children aged 2-4 years.

 Approximately 40% of all patients are younger than 10 years. History

 Focus on the symptoms of bleeding (eg, type, severity, duration) and on symptoms that may exclude other causes of thrombocytopenia.

 Elicit risk factors for HIV and systemic symptoms linked to other illnesses or to medications (eg, heparin, alcohol, quinidine/quinine, sulfonamides) that may cause thrombocytopenia. Medications can be a common etiology for inducing thrombocytopenia, and patients should have their medications carefully reviewed. One study used 3 distinct methods to document drugs that may be associated with drug-induced immune thrombocytopenia (DITP).[1, 2] Approximately 1500 drugs are associated with thrombocytopenia, but, using this analysis, 24 drugs had evidence of causing thrombocytopenia by all 3 methods.

 Address risk factors for increased bleeding, such as GI disease, CNS disease, urologic disease, or active lifestyle, as these may determine the aggressiveness of management.

 Common signs, symptoms, and precipitating factors include the following: o Abrupt onset (childhood ITP) o Gradual onset (adult ITP) o Purpura o Menorrhagia o Epistaxis o Gingival bleeding o Recent live virus immunization (childhood ITP) o Recent viral illness (childhood ITP) o Bruising tendency

 Limited data are available on the recurrent form of the disease. One study showed a 6% prevalence of recurrent ITP with most patients (69%) having only one recurrence. Though one third of patients had their recurrent episode within 3 months of their initial one, the remainder of patients had at least a 3-month interval between episodes. Physical Evaluate the type and the severity of bleeding and try to exclude other causes of bleeding. Seek evidence of liver disease, thrombosis, autoimmune diseases (eg, nephritis, cutaneous vasculitis, arthritis), and infection, particularly HIV. Common physical findings include the following:

 Nonpalpable petechiae, which mostly occur in dependent regions

 Hemorrhagic bullae on mucous membranes

 Purpura

 Gingival bleeding

 Signs of GI bleeding

 Menometrorrhagia, menorrhagia

 Retinal hemorrhages

 Evidence of intracranial hemorrhage, with possible neurologic symptoms

 Nonpalpable spleen: The prevalence of palpable spleen in patients with ITP is approximately the same as that in the non-ITP population (ie, 3% in adults, 12% in children). 3  Spontaneous bleeding when platelet count is less than 20,000/mm . Causes

 Immunoglobulin G (IgG) autoantibodies on the platelet surface Differential Diagnoses

 Disseminated Intravascular Coagulation

 HIV Infection and AIDS

 Thrombocytopenic Purpura Laboratory Studies

 CBC o Isolated thrombocytopenia is the key finding regarding laboratory evaluation. o Truly giant platelets on peripheral smear suggest congenital thrombocytopenia. o The WBC count and hemoglobin typically are normal, unless severe hemorrhage has occurred.

 Coagulation studies are normal, and a bleeding time is not useful. Imaging Studies A CT scan of the head is warranted if concern exists regarding intracranial hemorrhage. Prehospital Care

 Prehospital care focuses on the ABCs, which include providing oxygen, controlling severe hemorrhage, and initiating intravenous (IV) fluids to maintain hemodynamic stability.

 Prehospital airway control may be necessary for a large intracranial hemorrhage.

 EMS providers should be aware of the potential for serious bleeding complications in patients with idiopathic thrombocytopenic purpura (ITP). Emergency Department Care

 Life-threatening bleeding requires conventional critical care interventions.

 In the patient with known ITP, high-dose parenteral glucocorticoids and IV immunoglobulin (IVIg), with or without platelet transfusions, are appropriate.

 Platelet transfusion is indicated for controlling severe hemorrhage. Send a blood specimen to the lab for type and screen in case platelet transfusion is necessary.  Platelet survival is increased if the platelets are transfused immediately after IVIg infusion.

 A consultation with a hematologist may be required to make a decision regarding the transfusion of platelets.

 Guidelines for transfusion dosage o 6-8 U of platelet concentrate, or 1 U/10 kg 3 o 1 U of platelets to increase count of a 70-kg adult by 5-10,000/mm and an 18-kg child by 20,000/mm3

 Splenectomy is reserved for patients in whom medical therapy fails. Emergent splenectomy is indicated in patients with life-threatening bleeding in whom medical therapy fails.

 In patients without life-threatening complications, focus ED care on confirming the diagnosis, if possible, and initiating therapy as needed.

 Most patients with undiagnosed thrombocytopenia and purpura will need admission for further evaluation and treatment, since ITP is a diagnosis of exclusion. Consultations

 Consult a hematologist for assistance in confirming the diagnosis or, in the patient with known ITP, arranging disposition and follow-up care, if appropriate.

 Consult a neurosurgeon for intracranial hemorrhage. Consultation by other surgical specialists may be required for extensive hemorrhage at other sites. Medication Summary Glucocorticoids and IVIg are the mainstays of medical therapy. Indications for use, dosage, and route of administration are based on the patient's clinical condition, the absolute platelet count, and the degree of symptoms. Consultation with a hematologist may be needed prior to starting therapy. Children who have platelet counts >30,000/mm3 and are asymptomatic or have only minor purpura do not require routine treatment. Children who have platelet counts < 20,000/mm3 and significant mucous membrane bleeding and those who have platelet counts < 10,000/mm3 and minor purpura should receive specific treatment. Adults with platelet counts >50,000/mm3 do not require treatment. Treatment is indicated for adults with counts < 50,000/mm3 with significant mucous membrane bleeding. Treatment also is indicated for those adults with risk factors for bleeding (eg, hypertension, peptic ulcer disease, vigorous lifestyle) and in patients with a platelet count < 20,000-30,000/mm3. IV anti-(Rh)D, also known as IV Rh immune globulin (IG), was not recommended by the 1996 American Society of Hematology practice guidelines. However, recent studies using higher dosages of IV RhIG in acute ITP in children and adults show platelet count increases at 24 hours faster than medicating with steroids and at 72 hours similar to IVIg. Although generally less toxic than IV steroids, IV RhIG is more expensive than IV steroids. Studies in children with chronic ITP show that escalating or elevated doses of IV RhIG have comparable responses to those of high-dose IVIg therapy in children. This therapy is not appropriate for patients who have undergone splenectomy. Acute intravascular hemolysis after infusing IV RhIG has been reported, with an estimated incidence of 1 in 1115 patients. Steroid use and immunosuppressives and splenectomy may be undesirable because of their associated complications. For long-term steroid use, this includes osteoporosis, glaucoma, cataracts, loss of muscle mass, and an increased risk of infection. For immunosuppressive therapy and splenectomy, risks include worsening immunosuppression and infection or sepsis. Studies of the use of multiagent therapies in refractory patients are ongoing. Some small studies have shown limited success. According to one study, using a combination of weekly vincristine, weekly methylprednisolone, both until platelet counts reached 50,000/mm3, and cyclosporine orally twice daily until the platelet count is normal for 3-6 months seems promising, though larger prospective studies are needed. Other therapies, such as cyclophosphamide, danazol, dapsone, interferon alfa, azathioprine, vinca alkaloids, accessory splenectomy, and splenic radiation have been studied. Many case series discussing these treatments are too small to show sufficient evidence of a clinically significant reduction in bleeding or mortality rate; however, they serve as additional therapeutic measures in ITP refractory-to- primary therapy (eg, glucocorticoids, IVIg immunoglobulin, splenectomy). Newer studies on rituximab suggest that this agent is an effective treatment option in splenectomized refractory or relapsed ITP patients. Clinical trials have shown promise for agents that directly stimulate platelet production, such as thrombopoietin (TPO) receptor-binding agents. Two new agents, eltrombopag and romiplostim, are available to patients with chronic ITP who have failed other therapies. Both of these agents require registration in a database. While they show promise for raising platelet counts, there are potential safety concerns such as thrombocytosis and rebound thrombocytopenia. It is unlikely that emergency physicians should be prescribing these agents without being under the recommendation of a hematologist. Glucocorticoids Class Summary These agents are used to treat idiopathic and acquired autoimmune disorders. They have been shown to increase platelet count in ITP.

Prednisone (Deltasone, Orasone, Sterapred) Useful in treating inflammatory and allergic reactions; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. DOC for all adult patients with platelet counts < 50,000/mm3. Asymptomatic patients with platelet counts >20,000/mm3, or patients with counts 30,000-50,000/mm3 with only minor purpura, may not need therapy; withholding medical therapy may be appropriate for asymptomatic patients, regardless of count.

Methylprednisolone (Solu-Medrol, Depo-Medrol) Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased permeability. Used as alternative glucocorticoid of choice for all patients with severe, life-threatening bleeding or children with platelet counts < 30,000/mm3. Careful observation without medical treatment may be appropriate in some asymptomatic children. Blood products Class Summary Administration of IVIg may temporarily increase platelet counts in some children and adults with ITP. Consider IVIg if the situation requires a rapid, temporary rise in platelet count.

Intravenous immune globulin (IVIg) DOC for severe, life-threatening bleeding or for children with platelet counts < 20,000/mm3 with minor purpura; can be used alone or in addition to glucocorticoid therapy. Thrombopoietic Agent Class Summary These agents directly stimulates bone marrow platelet production.

Eltrombopag (Promacta) Oral thrombopoietin (TPO) receptor agonist. Interacts with transmembrane domain of human TPO receptor and induces megakaryocyte proliferation and differentiation from bone marrow progenitor cells. Indicated for thrombocytopenia associated with chronic idiopathic thrombocytopenic purpura in patients experiencing inadequate response to corticosteroids, immunoglobulins, or splenectomy. Not for use to normalize platelet counts but used when clinical condition increases bleeding risk. Prescribers must enroll in Promacta Cares program. Only available through restricted distribution program. Program phone number is (877) 9-PROMACTA (877-977-6622).

Romiplostim (Nplate) An Fc-peptide fusion protein (peptibody) that increases platelet production through binding and activation of the thrombopoietin (TPO) receptor, a mechanism similar to endogenous TPO. Indicated for chronic immune (idiopathic) thrombocytopenic purpura in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Only available through the Nplate NEXUS (Network of Experts Understanding and Supporting Nplate) program, a program designed to promote informed risk- benefit decisions before initiating treatment. Further Inpatient Care

 Rule out other potential causes of thrombocytopenia.

 Emergency splenectomy may be necessary if severe bleeding complications due to thrombocytopenia do not respond to medical therapy.

 Observe for life-threatening bleeding.

 Consult with a hematologist, as further treatments (eg, steroids, IVIg, platelet transfusion) may be indicated. Further Outpatient Care

 Close follow-up care with a hematologist is required.

 Elective splenectomy may be necessary if medical therapy fails. Transfer Transfer may be necessary under the following conditions:

 A hematologist is not available.

 Blood bank support is insufficient.

 A higher level of intensive care is needed. Complications Complications of idiopathic thrombocytopenic purpura may include the following:

 Intracranial or other major hemorrhage

 Severe blood loss

 Adverse effects of corticosteroids  Pneumococcal infections if the patient must have a splenectomy Prognosis

 Children o Approximately 83% of children have a spontaneous remission, and 89% of children eventually recover. o More than 50% of patients recover within 4-8 weeks. o Approximately 2% of patients die.

 Adults o Only 2% of adults have a spontaneous recovery; however, approximately 64% of adults eventually recover. o Approximately 30% of patients have chronic disease, and 5% of patients die from hemorrhage. Patient Education

 Instruct patients to return for follow-up in order to assess for a potentially reduced platelet count.

 Emphasize close outpatient follow-up care.

 Because of the increased risk of bleeding, instruct patients to avoid aspirin products.

HEMORRHAGIC VASCULITIS (SCHÖNLEIN-HENOCH DISEASE). Most common vasculitis among children in United States; leukocytoclastic vasculitis (vascular damage from nuclear debris of infiltrating neutrophils) + IgA deposition in small vessels (arterioles and venules) of skin, joints, GI tract and kidney. Worldwide distribution, all ethnic groups; slightly greater in males; almost all age 3-10 years; occurs mostly in fall, winter and spring, many after an URI Infectious trigger is suspected, mediated by IgA and IgA-immune complexes Genetic component suggested by occasional family clusters Skin biopsy shows vasculitis of dermal capillaries and postcapillary venules with infiltrates of neutrophils and monocytes; in all tissues, immunofluorescence shows IgA deposition in walls of small vessels and smaller amounts of C3, fibrin and IgM Clinical presentation: Nonspecific constitutional findings Rash: palpable purpura, start as pink macules and then become petechial and then purpuric or ecchymotic; usually symmetric and in gravity-dependent areas (legs and back of arms) and pressure points (buttocks); lesions evolve in crops over 3-10 days and may recur up to 4 months. Usually there is some amount of subcutaneous edema Arthralgia/arthritis: oligoarticular, self-limited and in lower extremities; resolves in about 2 weeks, but may recur GI: in up to 80%: pain, vomiting, diarrhea, ileus, melena, intussusception, mesenteric ischemia or perforation (purpura in GI tract) Renal: up to 50%: hematuria, proteinuria, hypertension, nephritis, nephrosis, acute or chronic renal failure Neurological: due to hypertension or CNS vasculitis, possible intracranial hemorrhage, seizures, headaches and behavioral changes Less common: orchitis, carditis, inflammatory eye disease, testicular torsion and pulmonary hemorrhage American College of Rheumatology diagnosis: need 2 of the following:  palpable purpura age of onset <10 years  bowel angina = postprandial pain, bloody diarrhea  biopsy showing intramural granulocytes in small arterioles and venules

Labs (none are diagnostic): increased WBCs, platelets, mild anemia, increased ESR, CRP; stool + for occult blood; increased serum IgA. Must assess and follow BP, UA, serum Cr; GI ultrasound: bowel wall edema, rarely intussusception; skin and renal biopsies would be diagnostic but are rarely performed (only for severe or questionable cases) Treatment: supportive and corticosteroids (with significant GI involvement or life-threatening complications only), although steroids will not alter course/overall prognosis or prevent renal disease. For chronic renal disease – azathioprine, cyclophosphamide, mycophenolate mofetil. Outcome: Most significant acute complications affecting morbidity and mortality = serious GI involvement; renal complications are major long-term and can develop up to 6 months after initial diagnosis, but rarely if initial UA and BP are normal. Monitor all patients for 6months with BP and UA. Overall prognosis is excellent; most have an acute, self-limited disease; about 30% have >1 recurrence, especially in 4-6 months, but with each relapse symptoms are less. If more severe at presentation, higher risk for relapses. 1-2% with chronic renal disease and 8% ESRD.

Frequency: Henoch-Schцnlein purpura occurs in 10,000 children per year, with an estimated incidence of 13.5 cases per 100,000 children. Sex: Schönlein-Henoch disease - Male-to-female ratio of 1.5:1 Age: Schönlein-Henoch disease: Peak age of onset is 5-15 years. Etiology: Schönlein-Henoch disease is an immunocomplex disease. Suspected though not proved inciting agents (antigens) include: group A β- hemolytic streptococci and other bacteria, viruses, drugs, foods, insect bites. Pathogenesis: antigen influence → immunoglobulin G, M, A hyperproduction → antigen-antibody-complement complex in the blood → skin, kidney, intestine, joints precipitation → lesion → new autoantigens production → autoimmune damage of small vessels. CLINICAL Schönlein-Henoch disease: Up to 50% of patients may report a history of preceding upper respiratory tract infection or pharyngitis. The triad of abdominal pain, palpable purpura, and periarticular inflammation, swelling, or both may be incomplete at presentation Clinical Findings 1. The skin rash is often urticarial initially and progresses to a macular- papular appearance, which transforms into a diagnostic symmetric purpuric rash distributed on the ankles, buttocks, elbows (Fig. 3, Fig. 4). Purpuric areas of a few millimeters in diameter may progress to larger hemorrhages. The rash usually begins on the lower extremities, but the entire body may be involved. New lesions can continue to appear for 2–4 weeks. 2. Approximately two-thirds of patients develop migratory polyarthralgia and polyarthritis, primarily of the ankles and knees. 3. Edema of the hands, feet, scalp and periorbital region may occur. 4. Abdominal colic – due to hemorrhage and edema primarily of the small intestine – occurs in about 50% of those affected. Abdominal symptoms include severe colicky abdominal pain, nausea, vomiting, and hematochezia or diarrhea. 5. 25–50% of those affected develop renal involvement, with hematuria, proteinuria or nephrotic syndrome. Renal symptoms manifest in the second to third week of illness. Nephritis is a late finding, but if present initially, it portends a worse renal outcome. 6. Testicular torsion may occur. 7. Neurologic symptoms are possible.

Fig. 3. Purpuric rash on the ankles.

Fig. 4. Purpuric rash on the buttocks and legs.

Laboratory findings:

1. CBC reveals normochromic normocytic anemia of chronic disease; leukocytosis and thrombocytosis are associated with inflammatory process.

2. The Westergren sedimentation rate is elevated.

3. The platelet count, platelet function test, and bleeding time are usually normal.

4. Blood coagulation studies are normal.

5. Urinalysis frequency reveals hematuria, proteinuria, but casts are uncommon.

6. The ASO (antistreptolizin-O) titer is frequently elevated and the throat culture positive for group A beta-hemolytic Streptococci.

7. Serum Ig A may be elevated. Histologic Findings: Leukocytoclastic vasculitis observed in Henoch- Schцnlein purpura, is characterized by focal segmental necrotizing full-thickness lesions of varying stages in small vessels. Fibrinoid necrosis is present. The cellular infiltrate is predominantly polymorphonuclear neutrophils. Lymphocytes and eosinophils may be present. Henoch-Schцnlein purpura reveals a leukocytoclastic vasculitis with IgA immune deposits. Medical Care: Treatment goals are to decrease acute inflammation of blood vessels and to maintain adequate perfusion of skin and vital organs, while limiting the side effects of potentially toxic therapies. Individualize treatment based on the organs affected and the overall condition of the patient. In general, corticosteroids are administered to control acute symptoms and laboratory evidence of systemic inflammation. After control is achieved, attempts may be made to taper over a month. Treatment: 1. Corticosteroids therapy may provide symptomatic relief for severe gastrointestinal or joint manifestations, but doesn’t alter skin or renal manifestations. 2. Aspirin is useful for the pain associated with arthritis. 3. If culture for group A beta-hemolytic Streptococci is positive or if the ASO titer is elevated, penicillin should be given in full therapeutic doses for 10 days. 4. Heparin should be administrated to treat Henoch-Schönlein purpura in case of: large, repeated rush with ulcerating; renal syndrome; abdominal syndrome. Heparin Pediatric Dose Initial dose: 50-100 U/kg IV Maintenance infusion: 15-25 U/kg/h IV; increase dose by 2-4 U/kg/h q6-8h prn using aPTT results

Background

Henoch-Schönlein purpura (HSP) is an inflammatory disorder characterized by a generalized vasculitis involving the small vessels of the skin, GI tract, kidneys, joints, and, rarely, the lungs and CNS. It is the most common vasculitis in children.

The syndrome takes its name from 2 German physicians. In 1837, Johan Schönlein first described several cases of peliosis rheumatica or purpura associated with arthritis. Thirty years later, Edouard Henoch described the GI manifestations, including vomiting, abdominal pain, and melena. Henoch-Schönlein purpura has also been referred to as rheumatica purpura, leukocytoclastic vasculitis, and allergic vasculitis. See the images below.

Pathophysiology The etiology of Henoch-Schönlein purpura is unclear. It is thought to be multifactorial with genetic, environmental, and antigenic components. More than 75% of patients report antecedent upper-respiratory, pharyngeal, or GI infections. Multiple bacterial and viral infectious agents have been associated with the development of Henoch-Schönlein purpura, and cases of Henoch-Schönlein purpura also have been reported after drug ingestions and vaccinations. Henoch-Schönlein purpura is thought to be an immunoglobulin A (IgA)–mediated autoimmune phenomenon. An unknown antigenic stimulant has been postulated to cause a rise in IgA. The antigen-antibody complexes deposit locally throughout the body and activate pathways leading to necrotizing vasculitis. Genetic research may reveal the potential role of cytokines, endothelia and nitric oxide metabolism in Henoch-Schönlein purpura. Henoch-Schönlein purpura can involve nearly any organ system. Hallmarks of Henoch-Schönlein purpura include a characteristic rash, migratory polyarthritis, renal involvement, and GI involvement. The clinical manifestations of Henoch- Schönlein purpura are the result of antigen-antibody complexes depositing throughout the body, which cause migratory arthralgias, abdominal cramping, the petechial and/or vasculitic rash, and hematuria. Epidemiology Frequency United States The rate is 14 cases per 100,000 population. Mortality/Morbidity Henoch-Schönlein purpura generally resolves without permanent complications. However, serious GI and renal complications may occur. GI complications include intussusception (usually ileoileal), bowel infarction, bowel perforation, hydrops of the gallbladder, pancreatitis, or massive GI bleeding. Approximately 20% of patients have renal manifestations, and 5% develop end- stage renal disease (ESRD). Patients with only hematuria do not develop ESRD. About 15% of patients with hematuria and proteinuria develop ESRD. Approximately 50% of patients with nephritic or nephrotic syndrome develop ESRD. The long-term morbidity is predominantly attributed to renal involvement. Sex In children, the male-to-female ratio is 2:1. In adults, the male-to-female ratio is approximately 1:1. Age Henoch-Schönlein purpura primarily affects children. Adults are rarely affected. Approximately 75% of cases occur in children aged 2-11 years. The median age is 5 years. Older age at disease onset is associated with development of chronic renal disease. History The following may be noted in the history of patients with Henoch-Schönlein purpura (HSP):

 The prodrome is associated with the following: o Headache o Anorexia o Fever

 After the prodrome, a rash, abdominal pain, peripheral edema, vomiting and/or arthritis develop. o The rash appears in 100% of patients and is the presenting feature in 50%. o The distribution usually depends on parts of the body, including the lower trunk, lower extremities, buttocks and perineum. o The rash typically appears in crops with new crops appearing in waves. o Eruptions usually last an average of 3 weeks. o As many as 85% of patients will have GI symptoms, including abdominal pain, nausea, and vomiting. o The most common symptom is colicky abdominal pain. o Joint involvement is present in 75% of reported patients with Henoch-Schönlein purpura and the presenting sign in approximately 25%. o The large joints (eg, knees and ankles) are most commonly involved, with pain and edema being the only symptoms. The arthritis resolves completely over several days without permanent articular damage. o Renal involvement is present in 30-50% of patients and may persist as long as 6 months after the onset of the rash. o Renal involvement manifests in a range from mild hematuria or proteinuria to oliguria and renal failure. o Permanent renal impairment is seen in 20% of patients who have nephrotic or nephritic syndrome; however, this turns out to be less than 0.1 % of all patients diagnosed with Henoch-Schönlein purpura. Physical

 Skin o Lesions consist of erythematous macules, urticarial papules, pruritic papules, and plaques. Skin lesions tend to appear in crops in the dependent portions of the body (eg, lower extremities, lower abdomen, buttocks). o Children younger than 2 years also may have involvement of the upper extremity, head, and trunk. o The rash typically appears as red macules and papules, which later become purple and then rust-colored. o Various stages of eruption are usually present simultaneously. The lesions may blanch initially, but they progress to palpable purpura as they mature.

 Abdomen o Heme-positive stool is the primary finding on GI examination. o Findings on abdominal examination are generally unremarkable. o On occasion, the abdomen is tender. o Signs of an acute abdomen are rarely present.

 Joints o The knees, ankles, and (less commonly) wrists are involved. o Tenderness and edema are periarticular. Warmth, erythema, and effusions are not typically associated with Henoch-Schönlein purpura.

 Other o Case reports describe patients with Henoch-Schönlein purpura presenting with protein-losing enteropathy without liver or kidney dysfunction. o The rash may appear late in the course, simplifying the diagnosis. Causes The current understanding of the etiology of Henoch-Schönlein purpura suggests the involvement of toxins, viruses, idiopathic causes, and drugs. No single etiology has been clearly identified; however, most cases are preceded by a recent upper airway infection.

 Infectious agents associated with Henoch-Schönlein purpura o Streptococcus species (especially group A) o Yersinia species o Legionella species o Parvovirus o Adenovirus o Mycoplasma species o Epstein-Barr virus o Varicella

 Drugs associated with Henoch-Schönlein purpura o Penicillin o Ampicillin o Erythromycin o Quinidine o Quinine

 Vaccines associated with Henoch-Schönlein purpura o Typhoid and paratyphoid A and B o Measles o Yellow fever o Cholera Differential Diagnoses

 Arthritis, Rheumatoid

 Disseminated Intravascular Coagulation

 Glomerulonephritis, Acute

 Idiopathic Thrombocytopenic Purpura

 Inflammatory Bowel Disease

 Meningitis

 Mononucleosis

 Orchitis

 Pediatrics, Chicken Pox or Varicella

 Pediatrics, Child Abuse

 Pediatrics, Gastroenteritis

 Pediatrics, Gastrointestinal Bleeding

 Pediatrics, Hand-Foot-and-Mouth Disease

 Pediatrics, Intussusception

 Pediatrics, Kawasaki Disease  Pediatrics, Meningitis and Encephalitis

 Renal Failure, Acute

 Shock, Septic

 Systemic Lupus Erythematosus

 Testicular Torsion

 Thrombocytopenic Purpura

 Tick-Borne Diseases, Rocky Mountain Spotted Fever Laboratory Studies Electrolyte values in patients with Henoch-Schönlein purpura (HSP) are generally in the reference range, but excessive vomiting can affect the values. BUN and creatinine levels may be increased in the presence of renal involvement. Amylase and lipase levels may be elevated in patients with pancreatitis. A CBC count usually reveals a leukocytosis with a left shift, possibly eosinophilia, and a normal or increased platelet count. Hemoglobin and/or hematocrit values may be normal or decreased secondary to bleeding. Urinalysis usually shows hematuria, proteinuria, and occasional red cell casts. Additional laboratory tests that can be helpful in narrowing the differential diagnosis include the following:

 Assessment of antistreptolysin-O (ASO) titer

 Monospot test

 Antinuclear antibody (ANA) test

 Rheumatoid factor (RF) test

 Determination of C3/C4 levels

 Measurement of the prothrombin time (PT)

 Measurement of the activated partial thromboplastin time (aPTT)

 Blood cultures

Imaging Studies Imaging studies are necessary only as the clinical picture dictates. CT scanning may aid in the exclusion of other causes of abdominal pain. Barium enema study or endoscopy might be needed to evaluate epigastric pain, hematemesis, and melena. Ultrasonography may be helpful for evaluating intussusception and to exclude appendicitis. A chest radiograph should be obtained after hemoptysis, and a head CT is necessary if neurologic symptoms or severe headache persist. Imaging of the scrotum by means of ultrasonography or a technetium radionuclide scanning may be necessary if scrotal edema is a presenting feature. Emergency Department Care ED treatment of Henoch-Schönlein purpura (HSP) is supportive, with frequent monitoring of vital signs. For minor complaints of arthritis, edema, fever or malaise, symptomatic treatment is advised, including use of acetaminophen, elevation of swollen extremities, eating a bland diet, and adequate hydration. Most patients with self-limited cases can be safely discharged home with close follow-up by their primary physician. Whether or not to admit the patient to the hospital depends on the practice of the admitting pediatrician and his or her preference. Admission to the hospital is recommended for control of abdominal pain or vomiting, monitoring of renal function, confirming a doubted diagnosis, and observation and monitoring. One study examined the prevention and treatment of renal disease in patients with Henoch-Schönlein purpura. Meta-analyses of 4 trials revealed no significant difference in the risk of persistent kidney disease at 6 months and 12 months in children given prednisone for 14-28 days upon presentation, compared with placebo or supportive treatment. Also, no significant difference was noted in the risk of persistent renal disease in children given cyclophosphamide compared with supportive treatment and with cyclosporin compared with methylprednisolone. However, data from randomized trials for any intervention used to improve renal outcome in children with Henoch-Schönlein purpura are sparse. All unnecessary drugs should be discontinued if the etiology is suspected to be drug related. Patients with renal involvement require close attention in regard to their fluid balance, electrolyte status, and use of antihypertensives (if indicated).

 Use of immunosuppressive and cytotoxic drugs is gaining favor based on research and case studies.

 Dapsone has been used to treat associated purpura and arthralgias.

 Factor VIII concentrate has been used to relieve abdominal pain when corticosteroids are contraindicated.

 Plasmapheresis is currently under investigation.

 Kidney transplantation may be indicated in patients with severe renal disease that is resistant to medical therapy. Surgery may be undertaken to treat severe bowel ischemia. Consultations If the patient has renal involvement, a nephrologist should be consulted for assistance in determining if dialysis is indicated. Because 1 in 20 patients with Henoch-Schönlein purpura develop renal failure, early consultation is desirable. Medication Summary Treatment of Henoch-Schönlein purpura (HSP) is largely supportive. Analgesia with nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen may reduce joint and soft tissue discomfort. The evidence does not clearly demonstrate that corticosteroid administration prevents the development of nephritis in patients with Henoch-Schönlein purpura, although its use in the treatment of intestinal and neurologic complications is gaining acceptance. If used, prednisone 1-2 mg/kg/d PO for 7 days is recommended. Antihypertensives may be indicated with renal involvement; for more information, see the pediatric topic Hypertension. Other drugs are currently under investigation (see Emergency Department Care). For more information on long-term medication management, see the pediatric general medicine topic Henoch-Schönlein Purpura. Analgesic agents Class Summary Pain control is essential for quality patient care. Some analgesics (eg, acetaminophen, ibuprofen) are also effective for treating fever.

Ibuprofen (Advil, Motrin) Effective for treating fever or mild-to-moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Acetaminophen (Feverall, Tempra, Tylenol) Inhibits action of endogenous pyrogens on heat-regulating centers; reduces fever by a direct action on the hypothalamic heat-regulating centers, which, in turn, increase the dissipation of body heat via sweating and vasodilation. Effective for treating fever and relieving mild-to-moderate pain. Glucocorticoids Class Summary Short-term use may be considered to decrease inflammation during neurologic or intestinal complications.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred) Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocyte and antibody production. Further Inpatient Care Patients with Henoch-Schönlein purpura (HSP) have the potential for severe complications, which may occur precipitously (eg, acute abdomen, acute scrotum, renal failure). Whether or not to admit the patient to the hospital for observation and monitoring depends on the practice of the admitting pediatrician and his or her preference. Further Outpatient Care In all patients, urinalysis and blood pressure monitoring to evaluate for renal involvement should be continued for up to 6 months after presentation, even if initial urinalysis results are normal. Complications Henoch-Schönlein purpura can involve nearly every organ system. GI complications include hydrops of the gallbladder, pancreatitis, and GI bleeding. Surgical complications include intussusception, bowel infarction, and perforation. Overall, 5% of patients develop end-stage renal disease (ESRD). Other potential complications include the following:

 Coronary artery vasculitis resulting in myocardial infarction (MI)

 Headache

 Irritability

 Fever

 Pulmonary hemorrhage

 CNS bleeding

 Scrotal edema

 Pain Prognosis Most patients have complete resolution of symptoms within 8 weeks. Up to half of all affected patients will have at least 1 recurrence. Younger patients usually have a better prognosis than older patients. As many as 15% of patients may have long-term renal insufficiency, but less than 1% will have end-stage renal disease. Patients with a normal urinalysis at 6 months and without prior renal involvement have not gone on to develop kidney problems.[4] Pregnant women who had HSP during childhood appear to be at increased risk of developing hypertension and proteinuria during pregnancy.

VON WILLEBRAND DISEASE (VWD)  Most common hereditary bleeding disorder; autosomal dominant, but more females affected  Normal situation—vWF adheres to subendothelial matrix, and platelets then adhere to this and become activated; also serves as carrier protein for factor VIII  Clinical presentation—mucocutaneous bleeding (excessive bruising, epistaxis, menorrhagia, postoperative bleeding)  Labs—increased bleeding time and PTT  Quantitative assay for vWFAg, vWF activity (ristocetin cofactor activity), plasma factor VIII, determination of vWF structure and platelet count  Treatment—need to increase the level of vWF and factor VIII o Most with type 1 DDAVP induces release of vWF o For types 2 or 3 need replacement → plasma-derived vWF-containing concentrates with factor VIII Von Willebrand Disease Although referred to as a single disease, von Willebrand disease (vWD) is in fact a family of bleeding disorders caused by an abnormality of the von Willebrand factor (vWF). vWD is the most common hereditary bleeding disorder. First described by Erik Adolf von Willebrand in 1926, vWD is characterized by a lifelong tendency toward easy bruising, frequent epistaxis, and menorrhagia. Pathophysiology: vWD is due to an abnormality, either quantitative or qualitative, of the vWF, which is a large multimeric glycoprotein that functions as the carrier protein for factor VIII (FVIII). vWF also is required for normal platelet adhesion. As such, vWF functions in both primary (involving platelet adhesion) and secondary (involving FVIII) hemostasis. vWD can be classified into 3 main types, of which 70-80% are considered to be type 1.

1. Type 1 vWD is characterized by a partial quantitative decrease of qualitatively normal vWF and FVIII. 2. vWD type 2 is a variant of the disease with primarily qualitative defects of vWF.

3. type 3 vWD is characterized by marked deficiencies of both vWF and FVIIIc in the plasma, the absence of vWF from both platelets and endothelial cells, and a lack of the secondary transfusion response and the response to DDAVP Frequency: Prevalence worldwide is estimated at 0.9-1.3%. Sex: vWD affects males and females in equal numbers. History: Many children with vWD are asymptomatic and are diagnosed as a result of a positive family history or during routine preoperative screening (eg, prolonged bleeding time). Importantly, remember that a wide variation in clinical manifestations exists, even for members of the same family. The history may reveal the following:  Increased or easy bruising  Recurrent epistaxis  Menorrhagia  Postoperative bleeding (particularly after tonsillectomy or dental extractions)  Family history of a bleeding diathesis  Bleeding from wounds  Gingival bleeding  Postpartum bleeding Medical Care: Minor bleeding problems, such as bruising or a brief nosebleed, may not require specific treatment. For more serious bleeding, medications that can raise the vWF level and, thereby, limit bleeding are available. The goal of therapy is to correct the defect in platelet adhesiveness (by raising the level of effective vWF) and the defect in blood coagulation (by raising the FVIII level). In recent years, desmopressin (1-deamine-8-D-arginine vasopressin, DDAVP) has become a mainstay of therapy for most patients with mild vWD. For patients with vWF who do not respond to desmopressin, and for individuals with the rare types 2B or 3 vWD, plasma-derived Factor VIII (FVIII) concentrates that contain vWF in high molecular weight can be used. Pediatric Dose 20-50 U/kg; base the dose on the weight of the patient, the baseline FVIII level, and the severity of the bleeding. HEMOPHILIA. HEMOPHILIA A (VIII) AND B (IX) 85% are A and 15% B; no racial or ethnic predisposition X-linked Clot formation is delayed and not robust → slowing of rate of clot formation  With crawling and walking—easy bruising  Hallmark is hemarthroses—earliest in ankles; in older child, knees and elbows  Large-volume blood loss into iliopsoas muscle (inability to extend hip)— vague groin pain and hypovolemic shock  Vital structure bleeding—life-threatening Labs  2× to 3× increase in PTT (all others normal)  Correction with mixing studies  Specific assay confirms: o Ratio of VIII:vWF sometimes used to diagnose carrier state o Normal platelets, PT, bleeding time, and vW Factor Treatment  Replace specific factor  Prophylaxis now recommended for young children with severe bleeding (intravenous via a central line every 2–3 days); prevents chronic joint disease  For mild bleed—patient’s endogenous factor can be released with desmopressin (may use intranasal form)  Avoid antiplatelet and aspirin medications  DDAVP increases factor VIII levels in mild disease. Hemophilia A and B are inherited bleeding disorders caused by deficiencies of clotting factor VIII (F VIII) and factor IX (F IX), respectively. They account for 90-95% of severe congenital coagulation deficiencies. The 2 disorders are considered together because of their similar clinical pictures and similar patterns of inheritance. Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century. The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937 when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF). A bioassay of FVIII was introduced in 1950. Pathophysiology: F VIII and F IX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of either of these factors may significantly alter clot formation and clinical bleeding. Frequency: Hemophilia has a worldwide distribution. Sex: Both Hemophilia A and B are X-linked recessive disorders; therefore, they affect males almost exclusively. Physical: Only 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. At birth, other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area. After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers. When trauma-related soft-tissue hemorrhage occurs, young children may have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations often is troublesome because the oozing of blood may continue for a long time despite local measures. As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.

Hemophilia is classified according to the clinical severity as mild, moderate, or severe. Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% FVIII activity and bleed only after significant trauma or surgery. Lab Studies: Usually, the activated partial thromboplastin time (aPTT) is prolonged. Bleeding times, prothrombin times, and platelet counts are normal. The diagnosis is based on functional assay results for FVIII and FIX. It is usual to also measure von Willebrand factor which, when combined with low factor VIII, may indicate vWF deficiency as the primary diagnosis. TREATMENT Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability. For most mild hemorrhages, dose calculations are directed toward achieving an FVIII activity level of 30-40% or FIX activity levels of 30% and clotting factor activity of at least 50% in severe bleeds (eg, major dental surgery, major surgery or trauma), and 80-100% activity in life-threatening hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds; retroperitoneal hemorrhage; and hemorrhage related to head injury, surgery, or dental work. Patients are treated with prophylaxis or intermittent therapy (demand) for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints. In most countries with access to recombinant product, prophylaxis is primary recommended beginning as early as 1 year of age and continuing into adolescence. A cost benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity. In situations in which this is not feasible, secondary prophylaxis, ie, therapy after a target joint has been established to prevent worsening of the joint, is instituted for a defined period. Dosing is designed to maintain levels greater than 2% at the trough. This requires thrice weekly factor VIII or twice weekly factor IX to achieve. The treatment of hemophilia may involve the management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, and treatment of patients with factor inhibitors. Management of hemostasis Hemostasis is achieved with replacement therapy aimed at correcting the coagulation factor deficiency. Management of bleeding episodes Musculoskeletal bleeding Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain. Early infusion upon the recognition of pain often may eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days. Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Infusion must be aimed at maintaining a normal level of FVIII or FIX. Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression. Oral bleeding Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of the saliva. Combine adequate replacement therapy with an antifibrinolytic agent (e- aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity. GI bleeding Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FVIII coagulant or FIX. Intracranial bleeding If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established. FVIII products A variety of products are available for replacement therapy. Fresh frozen plasma and cryoprecipitate no longer are used in hemophilia A and B because of the lack of safe viral elimination and concerns regarding volume overload. Many plasma-derived FVIII concentrates are commercially available. Many recombinant FVIII concentrates are now available. The advantage of such products is the elimination of viral contamination. The effectiveness of these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of the presence of inhibitor appear to be unwarranted. The indications for this approach include intracranial hemorrhage, vascular compromise, iliopsoas bleeding, and preparation for surgery. Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP) DDAVP is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia. It stimulates a transient increase in plasma FVIII levels and results in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures. It can be administered intravenously at a dose of 0.3 mcg per kilogram of body weight. Its peak effect is observed in 30-60 minutes. Several doses of DDAVP may need to be infused every 12-24 hours before tachyphylaxis is observed. Treatment in patients with factor inhibitors Inhibitors to FVIII develop in 25-35% of children with severe hemophilia A, and inhibitors to FIX develop in 1-3% in children with hemophilia B. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII. In the treatment of patients with low-titer FVIII inhibitors (<5 Bodansky units [BU]), bleeding can be controlled with human FVIII administered at standard or higher doses. In patients with high-titer inhibitors, immune tolerance induction (ITI) may be used to reduce or suppress the inhibitor. Therapeutic options include standard or activated prothrombin complex concentrate (PCC); recombinant factor VIIa (NovoSeven); and porcine FVIII (Hyate:C), if no cross- reacting antibodies are present. In patients with high-titer FIX inhibitors, ITI usually is less successful compared with that in patients with FVIII inhibitors. Therapeutic options are the same for these patients as for those with FVIII inhibitors, with the same doses. Patients with hemophilia B and inhibitors can have anaphylactic reactions to FIX infusions. Antihemophilic factor Dose 20-50 U/kg/dose IV q12-24h; higher doses may be used (eg, 50-75 U/kg with high inhibitor titers); individualize doses according to clinical situation; may administer more frequently in special circumstances FIX Complex Dose 20-50 U/kg IV; individualize doses according to clinical situation; may administered higher doses and qd or more frequently in special cases Patients with FVIII: 75-100 U/kg IV q6-12h Recombinant factor VII (NovoSeven, NiaStase) -- Indicated for the treatment for bleeding episodes in patients with hemophilia A or B and inhibitors. Dose 90 mcg/kg IV q2h until hemostasis is achieved or treatment is judged inadequate; for patients with or without inhibitors; may use 35-120 mcg/kg, depending on the severity of the clinical situation; duration of administration has not been well established Hemophilia C Hemophilia C can be distinguished from hemophilias A (deficiency of factor VIII) and B (deficiency of factor IX) by the absence of bleeding into joints and muscles and by its occurrence in individuals of either sex. Unlike hemophilias A and B in which the bleeding tendency clearly is related to factor level, the bleeding risk in hemophilia C is not always influenced by the severity of the deficiency, especially in individuals with partial deficiency. This unpredictable nature of the disease makes it more difficult to manage than hemophilia A or B. Causes: Congenital deficiency of factor XI clotting activity is caused by mutations in the factor XI gene. Pathophysiology: The severity of the deficiency is based on plasma factor XIC (clotting) activity. Frequency: Hemophilia C has a high prevalence among Ashkenazi Jews (in Israel, estimated at 8%). Sex: The inheritance of factor XI is autosomal, affecting males and females equally. History: Bleeding after surgery or after injury is the usual presenting symptom in individuals prone to bleeding. The following presentations have been reported:  Massive hemothorax  Cerebral hemorrhage  Subarachnoid hemorrhage  Spinal epidural hematoma with the Brown-Sequard syndrome  Hematuria and spontaneous hemarthrosis are rare.  In women, menorrhagia is an important finding. Physical: Physical examination usually is normal except when bleeding occurs. Bruising may occur at unusual sites. The patient may have signs of pallor, fatigue, and tachycardia with excessive bleeding. Lab Studies: Prothrombin time (PT), aPTT, and thrombin time (TT): The aPTT is prolonged in factor XI deficiency, whereas the PT and TT are normal. Genetic analysis for the mutation in factor XI is helpful in determining which mutation has caused the deficiency. Medical Care: The basic principle of management consists of altering the balance between bleeding and clotting. This would consist of replacing the deficient factor and using other measures, such as fibrin glue and antifibrinolytics. Soft tissue bleeding may not require treatment. When therapy is required, therapeutic products are available to treat patients with factor XI deficiency, including fresh frozen plasma (FFP), solvent-detergent–treated FFP, and factor XI concentrates (available in Europe, but not in the United States). Adjunctive measures include the use of fibrin glue, antifibrinolytic agents, and desmopressin (DDAVP). Fresh frozen plasma -- Product of choice when factor XI concentrates are not available. Dose 15-20 mL/kg IV loading dose, followed by 3-6 mL/kg q12h until hemostasis is achieved Factor XI concentrates. The typical dose of these products is up to 30 U/kg. Prognosis is excellent in patients with partial deficiency who do not have bleeding manifestations. In patients with bleeding tendencies, hemorrhage and bleeding into organs may be life threatening. Hemophilia A. Practice Essentials Hemophilia A is an X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII), which may be inherited or arise from spontaneous mutation. The development of inhibitory antibodies to FVIII can result in acquired hemophilia A or can complicate the treatment of genetic cases. Essential update: FDA approves turoctocog alpha for treating hemophilia A In October 2013, the FDA approved turoctocog alpha (NovoEight, Novo Nordisk), a recombinant coagulation factor VIII, for the treatment of hemophilia A in adults and children. Approval was based on studies demonstrating efficacy and no development of inhibitors in more than 210 patients with severe hemophilia A. Signs and symptoms Depending on the level of FVIII activity, patients with hemophilia may present with easy bruising, inadequate clotting of traumatic injury or—in the case of severe hemophilia—spontaneous hemorrhage. Signs of hemorrhage include the following:

 General: Weakness, orthostasis, tachycardia, tachypnea  Musculoskeletal (joints): Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)

 CNS: Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes

 Gastrointestinal: Hematemesis, melena, frank red blood per rectum, and abdominal pain

 Genitourinary: Hematuria, renal colic, and post circumcision bleeding

 Other: Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions; excessive bleeding with routine dental procedures Diagnosis Laboratory studies for suspected hemophilia include the following:

 Complete blood cell count

 Coagulation studies

 FVIII assay Expected laboratory values are as follows:

 Hemoglobin/hematocrit: Normal or low

 Platelet count: Normal

 Bleeding time and prothrombin time: Normal

 Activated partial thromboplastin time (aPTT): Significantly prolonged in severe hemophilia, but may be normal in mild or even moderate hemophilia Normal values for FVIII assays are 50-150%. Values in hemophilia are as follows:

 Mild: >5%

 Moderate: 1-5%

 Severe: < 1% Imaging studies for acute bleeds are chosen on the basis of clinical suspicion and anatomic location of involvement, as follows:

 Head computed tomography scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage  Magnetic resonance imaging scans of the head and spinal column are used for further assessment of spontaneous or traumatic hemorrhage

 MRI is also useful in the evaluation of the cartilage, synovium, and joint space

 Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions Testing for inhibitors is indicated when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode. Inhibitor concentration is titrated using the Bethesda method, as follows:

 Positive result: Over 0.6 Bethesda units (BU)

 Low-titer inhibitor: Up to 5 BU

 High-titer inhibitor: Over 5 BU Management The treatment of hemophilia may involve the following:

 Management of hemostasis

 Management of bleeding episodes

 Use of factor replacement products and medications

 Treatment of patients with factor inhibitors

 Treatment and rehabilitation of patients with hemophilia synovitis Disposition of treatment is as follows:

 Management ideally should be provided through a comprehensive hemophilia care center

 Home administration of treatment and infusions by the family or patient is customary

 FVIII treatment may be given prophylactically or on demand

 Hospitalization is reserved for severe or life-threatening bleeds For treatment of acute bleeds, target levels by hemorrhage severity are as follows:

 Mild hemorrhages (eg, early hemarthrosis, epistaxis, gingival bleeding): Maintain an FVIII level of 30%  Major hemorrhages (eg, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an FVIII level of at least 50%

 Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain an FVIII level of 80-100% To find the number of units of factor VIII needed to correct the factor VIII activity level, use the following formula: Units factor VIII = (weight in kg)(50 mL plasma/kg)(1 U factor VIII/mL plasma)(desired factor VIII level minus the native factor VIII level) FVIII regimens are as follows:

 The second dose should be administered 12 hours after the initial dose and is one half the initial calculated dose

 Minor hemorrhage requires 1-3 doses of FVIII

 Major hemorrhage requires many doses and continued FVIII activity monitoring with the goal of keeping the trough activity level at least 50%

 Continuous infusions of FVIII may be considered for major hemorrhage. The following types of FVIII concentrates are available:

 Plasma-based products: Undergo purification to inactivate viruses

 First-generation recombinant products: Produced in mammalian cell lines and have a small amount of human serum albumin added for stability

 Second-generation recombinant products: Manufactured without human albumin

 Third-generation products: Have no exposure to animal proteins Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), has the following attributes:

 Considered the treatment of choice for mild and moderate hemophilia A

 Not effective in the treatment of severe hemophilia

 Can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting

 Peak effect is observed in 30-60 minutes

 A concentrated DDAVP intranasal spray is available for outpatient use The following antifibrinolytics are used in addition to FVIII replacement for oral mucosal hemorrhage and prophylaxis:

 Epsilon aminocaproic acid (Amicar)

 Tranexamic acid (Cyklokapron) Treatments used in patients with inhibitors of FVIII are as follows:

 High doses of FVIII for low-titer inhibitors

 Anti-inhibitor coagulant complex (FEIBA VH)

 Porcine FVIII, which has low cross-reactivity with human FVIII antibody

 Activated prothrombin complex concentrate (PCC)

 Activated FVII

 Desensitization

 Immune tolerance induction (ITI) Background Hemophilia A is an inherited, X-linked, recessive disorder caused by deficiency of functional plasma clotting factor VIII (FVIII). Significant rates of spontaneous mutation and acquired immunologic processes can result in this disorder as well. Morbidity and death are primarily the result of hemorrhage, although infectious diseases (eg, HIV, hepatitis) became prominent, particularly in patients who received blood products prior to 1985. Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and a factor VIII (FVIII) assay (see Workup). The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis. Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center (see Treatment). Please see the following for more information:

 Acquired Hemophilia

 Hemophilia B  Hemophilia C Classification The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or on plasma procoagulant levels; the latter are the most widely used criteria. Persons with less than 1% normal factor (< 0.01 IU/mL) are considered to have severe hemophilia. Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (>0.05 to < 0.40 IU/mL) are considered to have mild hemophilia. Severe disease presents in children younger than 1 year and accounts for 43-70% of those with hemophilia A. Moderate disease presents in children aged 1-2 years and accounts for 15-26% of cases. Mild disease presents in children older than 2 years and accounts for 15-31% of cases. Clinical bleeding symptom criteria have been used because patients with FVIII levels of less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease. For discussion of factor IX deficiency, see Hemophilia B. Historical background Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century. The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937 when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF). A bioassay of FVIII was introduced in 1950. Although the intimate relationship between FVIII and von Willebrand factor (vWF) is now known, it was not appreciated at the time. In 1953, decreased factor FVIII in patients with vWF deficiency was first described. Further research by Nilson and coworkers indicated the interaction between these 2 clotting factors. In 1952, Christmas disease was described and named after the surname of the first patient who was examined in detail. This disease was distinct from hemophilia because mixing plasma from a patient with "true hemophilia" and with plasma from a patient with Christmas disease corrected the clotting time; thus, hemophilia A and B were differentiated. Hemophilia A makes up approximately 80% of hemophilia cases. In the early 1960s, cryoprecipitate was the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized intermediate-purity concentrates were obtained from a large pool of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport has dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care. Unfortunately, the large size of the donor pool—as many as 20,000 donors may contribute to a single lot of plasma-derived FVIII concentrate—heightened the risk of viral contamination of commercial FVIII concentrates. By the mid 1980s, most patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human immunodeficiency virus (HIV). Viricidal treatment of plasma-derived FVIII concentrates have been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and hepatitis C exposures. The introduction of recombinant FVIII concentrate, and the gradual elimination of albumin from the production process used for these products, has virtually eliminated the risk of viral exposure. Pathophysiology Factor VIII deficiency, dysfunctional factor VIII, or factor VIII inhibitors lead to the disruption of the normal intrinsic coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma. Hemorrhage sites include joints (eg, knee, elbow), muscles, CNS, GI system, genitourinary system, pulmonary system, and cardiovascular system. Intracranial hemorrhage is most common in patients younger than 18 years and can be fatal. The clotting cascade The role of the coagulation system, as depicted in the image below, is to produce a stable fibrin clot at sites of injury. The clotting mechanism has 2 pathways: intrinsic and extrinsic.

Fig. Coagulation system.

The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation. In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the cell surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipid. In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells. It is thought to be a lipoprotein complex that acts as a cell surface receptor for FVII, with its resultant activation. It also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII. In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin fragments 1 and 2. Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII. Fibrinopeptides A and B, the results of the cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands. Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only one in vivo pathway with different mechanisms of activation has been suggested. FVIII and FIX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of FVIII may significantly alter clot formation and, as a consequence, result in clinical bleeding. Genetics The gene for FVIII (ie, hemophilia A) is located on the long arm of chromosome X, within the Xq28 region. The gene (F8C) is unusually large, representing 186 kb of the X chromosome. It comprises 26 exons and 25 introns. Mature FVIII contains 2332 amino acids. Approximately 40% of cases of severe FVIII deficiency arise from a large inversion that disrupts the FVIII gene. Deletions, insertions, and point mutations account for the remaining 50-60% of hemophilia A defects. Low FVIII levels may arise from defects outside the FVIII gene, as in type IIN von Willebrand disease, in which the molecular defect resides in the FVIII-binding domain of von Willebrand factor. Hemorrhage into joints The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint, resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths. Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa (FXa) inhibition, which predisposes hemophilic joints to bleed. This effect may also account for the dramatic response of FVIIa infusions in patients with acute hemarthroses and FVIII inhibitors. Synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage progress, with subchondral bone-cyst formation. Bleeding into a joint may lead to synovial inflammation, which predisposes the joint to further bleeds. A joint that has had repeated bleeds (by one definition, at least 4 bleeds within a 6-month period) is termed a target joint. Commonly, this occurs in knees.

Inhibitors Approximately 30% of patients with severe hemophilia A develop alloantibody inhibitors that can neutralize FVIII. These inhibitors are typically immunoglobulin G (IgG), predominantly of the IgG4 subclass, that do not fix complement and do not result in the end-organ damage observed with circulating immune complexes. They neutralize the coagulant effects of replacement therapy. Inhibitors occur at a young age (about 50% by age 10 y), principally in patients with less than 1% FVIII. Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) are associated with a higher incidence of inhibitor development (FVIII and FIX). In addition, inhibitors are more likely to develop in black children. In addition, purified products (some no longer marketed) have been associated with increased inhibitor development. As for recombinant FVIII products, no new inhibitors have been known to develop in previously treated patients, and inhibitors develop in as many as 30% of previously untreated patients (PUPs). In PUPs, the titer of the inhibitors is low in half and transient in one third. In the United States, levels of FVIII inhibitors are most often measured by the Bethesda method. In this method, 1 Bethesda unit (BU) equals the amount of antibody that destroys one half of the FVIII in an equal mixture of normal and patient plasma in 2 hours at 37°C. Acquired hemophilia Acquired hemophilia is the development of FVIII inhibitors (autoantibodies) in persons without a history of FVIII deficiency. This condition can be idiopathic (occurring in people >50 y), it can be associated with collagen vascular disease or the peripartum period, or it may represent a drug reaction (eg, to penicillin). High titers of FVIII autoantibodies may be associated with lymphoproliferative malignancies. Etiology Hemophilia A is caused by an inherited or acquired genetic mutation or an acquired factor VIII inhibitor. The defect results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue- factor pathway inhibitor, creates an extraordinary tendency for spontaneous bleeding. This disorder is inherited in an X-linked recessive pattern. The gene for FVIII is located on the long arm of the X chromosome in band q28. The factor VIII gene is one of the largest genes; it is 186 kilobases (kb) long and has a 9-kb coding region that contains 26 exons. The mature protein contains 2332 amino acids and has a molecular weight of 300 kd. It includes 3 A domains, 1 B domain, and 2 C domains. Numerous mutations in the gene structure have been described. Genetic abnormalities include genetic deletions of variable size, abnormalities with stop codons, and frame-shift defects. Data suggest that 45% of severe hemophilia A cases result from an inversion mutation. Epidemiology Hemophilia A is the most common X-linked genetic disease and the second most common factor deficiency after von Willebrand disease (vWD). The worldwide incidence of hemophilia A is approximately 1 case per 5000 male individuals, with approximately one third of affected individuals not having a family history. The prevalence of hemophilia A varies with the reporting country, with a range of 5.4- 14.5 cases per 100,000 male individuals. In the United States, the prevalence of hemophilia A is 20.6 cases per 100,000 male individuals, with 60% of those having severe disease. An estimated 17,000 people were affected with hemophilia A in the United States in 2003. History For patients in whom hemophilia is suspected, ascertain the history of hemorrhage disproportionate to trauma, spontaneous hemorrhage, bleeding disorders in the family, concomitant illness (eg, chronic inflammatory disorders, autoimmune diseases, hematologic malignancies [acquired form], allergic drug reactions), and pregnancy. For individuals with documented hemophilia, ascertain the type of deficiency (eg, VIII, IX, von Willebrand), percent factor deficiency, known presence of inhibitors, and HIV/hepatitis status. For patients with mild-to-moderate disease, determine responsiveness to desmopressin acetate (DDAVP). Signs of hemorrhage include the following:

 General - Weakness and orthostasis

 Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)  CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes

 GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain

 Genitourinary - Hematuria, renal colic, and post circumcision bleeding

 Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions; excessive bleeding with routine dental procedures Signs of infectious disease include the following:

 HIV/AIDS-related symptoms

 Hepatitis-related symptoms Male patients with severe hemophilia present at circumcision. Easy bruising may occur at the start of ambulation or primary dentition. The patient may have a history of hemarthroses and prolonged bleeding with surgical procedures, trauma, dental extraction, and he or she may have spontaneous bleeding in soft tissues. A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is diagnosed. Factors that elevate factor VIII (FVIII) levels (eg, age, ABO blood type, stress, exercise) may mask mild hemophilia. The principal sites of bleeding in patients with hemophilia are as follows. Bleeds affect weight-bearing joints and other joints. The muscles most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve. In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia. Physical Examination Signs of hemorrhage include the following:

 Tachycardia

 Tachypnea  Hypotension

 Orthostasis Organ system–specific signs of hemorrhage include the following:

 Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, effusion, and warmth

 CNS - Abnormal neurologic exam findings, altered mental status, and meningismus

 GI - Can be painless; hepatic/splenic tenderness, and peritoneal signs

 Genitourinary - Bladder spasm/distension/pain and costovertebral angle pain

 Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome) Signs of infectious disease include the following:

 HIV/AIDS-related signs

 Hepatitis-related signs Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area. After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures. As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention. Petechiae usually do not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which is typically the result of vasculitis or abnormalities in the number or function of platelets. Hemophilia is classified according to the clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor VIII (FVIII) activity and bleed only after significant trauma or surgery.

Table 1. Severity, Factor Activity, and Hemorrhage Type

Classification Factor Activity, % Cause of Hemorrhage Mild >5-40 Major trauma or surgery Moderate 1-5 Mild-to-moderate trauma Severe < 1 Spontaneous, hemarthrosis Direct the examination to identify signs related to spontaneous or, with minimal challenge, bleeding in the joints, muscles, and other soft tissues. Observe the patient's stature. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice, other signs of liver failure (eg, cirrhosis from viral infection), and signs of opportunistic infections in patients who are HIV seroconverted. Diagnostic Considerations Problems to be considered include vitamin K and other factor deficiencies. Other congenital bleeding disorders must be excluded. These may include the following:

 von Willebrand disease (autosomal dominant transmission)

 Platelet disorders (eg, Glanzmann thrombasthenia)

 Deficiency of other coagulation factors (ie, FV, FVII, FX, FXI, or fibrinogen) Differentiating between severe hemophilia A and hemophilia B is almost clinically impossible, but specific laboratory factor assays can help with the distinction. Conditions that can increase FVIII levels (eg, age, ABO blood type, stress, exercise) can obscure the diagnosis of hemophilia A. Please see the following for more information:

 Acquired Hemophilia  Hemophilia B

 Hemophilia C Differential Diagnoses

 Acquired Hemophilia

 Ehlers-Danlos Syndrome

 Factor XI Deficiency

 Glanzmann Thrombasthenia

 Hemophilia C

 Hemophilia, Type B

 Physical Child Abuse

 Platelet Disorders

 von Willebrand Disease Approach Considerations Laboratory studies for suspected hemophilia include a complete blood cell count, coagulation studies, and a factor VIII (FVIII) assay. Never delay indicated coagulation correction pending diagnostic testing. On the hemoglobin/hematocrit, expect normal or low values. Expect a normal platelet count. On coagulation studies, the bleeding time and prothrombin time (which assesses the extrinsic coagulation pathway) are normal. Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even moderate hemophilia because of the relative insensitivity of the test. The aPTT is significantly prolonged in severe hemophilia. For FVIII assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FVIII U/mL. Normal values are 50-150%. Values in hemophilia are as follows:

 Mild: >5%

 Moderate: 1-5%

 Severe: < 1% Spontaneous bleeding complications are severe in individuals with undetectable activity (< 0.01 U/mL), moderate in individuals with activity (2-5% normal), and mild in individuals with factor levels greater than 5%. Aging, pregnancy, oral contraceptive use, and estrogen replacement therapy are associated with increased levels. Because FVIII is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of cord blood. Differentiation of hemophilia A from von Willebrand disease is possible by observing normal or elevated levels of von Willebrand factor antigen and ristocetin cofactor activity. Bleeding time is prolonged in patients with von Willebrand disease but normal in patients with hemophilia. In patients with an established diagnosis of hemophilia, periodic laboratory evaluations include screening for the presence of FVIII inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV infection. Screening for infection may be less important in patients who receive only recombinant FVIII concentrate. Imaging studies for acute bleeds Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated. Imaging choices are guided by clinical suspicion and anatomic location of involvement. Head CT scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage. Perform magnetic resonance imaging on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. MRI is also useful in the evaluation of the cartilage, synovium, and joint space. Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated. Testing for Inhibitors Laboratory confirmation of a FVIII inhibitor is clinically important when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode. For the assay, the aPTT measurement is repeated after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Bethesda method. By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor. Less than 5 BU is considered a low titer of inhibitor, and more than 10 BU is a high titer. The distinction is clinically significant, as patients with low-titer inhibitors may respond to higher doses of FVIII concentrate. Radiography Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may be visible on radiographs in patients who are untreated or inadequately treated or in those with recurrent joint hemorrhages. In these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progresses with subchondral bone cyst formation. Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules. For discussion of the 5-stage Arnold-Hilgartner classification of hemophilic arthropathy. Approach Considerations The treatment of hemophilia may involve management of hemostasis, management of bleeding episodes, use of factor replacement products and medications, treatment of patients with factor inhibitors, and treatment and rehabilitation of patients with hemophilia synovitis. Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These centers follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Patients treated at comprehensive care clinics have been shown to have better access to care, less morbidity, and better overall outcome. Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability. Dose calculations are directed toward achieving a factor VIII (FVIII) activity level of 30-40% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or prophylaxis of major dental surgery or major surgery, and 80-100% in life-threatening hemorrhage. Hospitalization is reserved for severe or life- threatening bleeds, such as large-soft tissue bleeds; retroperitoneal hemorrhage; and hemorrhage related to head injury, surgery, or dental work. Patients are treated with prophylaxis or intermittent, on-demand therapy for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints. According to a review of 6 randomized controlled trials, preventative therapy started early in childhood, as compared to on-demand treatment, is able to reduce total bleeds and bleeding into joints resulting in a decrease in overall joint deterioration and an improvement in patient quality of life. In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity. In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has developed, to prevent worsening of the joint) is instituted for a defined period. Dosing is designed to maintain trough levels greater than 2%. This usually requires the administration of FVIII 3 times per week. Individualized therapy (ie, tailored prophylaxis) has been also used with success; the best approach has yet to be determined. Hospitalizing patients with internal bleeding, with uncontrollable bleeding, and before elective surgery or other invasive procedures is advised. Prehospital Care Rapid transport to definitive care is the mainstay of prehospital care. Prehospital care providers should do the following:

 Apply aggressive hemostatic techniques

 Assist patients capable of self-administered factor therapy

 Gather focused historical data if the patient is unable to communicate Emergency Department Care Before a patient with hemophilia is treated, the following information should be obtained:

 The type and severity of factor deficiency

 The nature of the hemorrhage or the planned procedure

 The patient's previous treatments with blood products

 Whether inhibitors are present and if so, their probable titer

 Any previous history of desmopressin acetate (DDAVP) use (mild hemophilia A only), with the degree of response and clinical outcome. Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays. If admission is indicated, disposition (ICU vs floor) should be based on severity of hemorrhage and potential for morbidity and death. Choose attending service based on etiology of hemorrhage. Hematology/ blood bank/pathology consultation is mandatory. Patients whose condition and bleeding are stabilized should be transferred to a specialized center for further treatment and monitoring because a multidisciplinary approach by specialists experienced in hemophilia may be required. Further outpatient care for patients with minor hemorrhage (not life threatening) consists of continued hemostatic measures (eg, brief joint immobilization, bandage). Hematologist or primary care physician follow-up care is indicated. The patient should continue factor replacement and monitoring. If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic, monitor the patient's CD4 count, observe the patient for adverse effects of anti-HIV treatment, and monitor for and treat possible opportunistic infections. Factor VIII Concentrates Various FVIII concentrates are now available to treat hemophilia A. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload. Various purification techniques are used in plasma-based FVIII concentrates to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a potential problem. Many recombinant FVIII concentrates are now available. The advantage of such products is the elimination of viral contamination. Third-generation products without any exposure to animal proteins are now available to further decrease this risk. The effectiveness of these products appears comparable to that of plasma- derived concentrates. Concerns regarding higher incidences of the presence of inhibitor appear to be unwarranted. With wider availability of improved products (ie, better stability, purity), use of continuous infusion of factors has incrementally increased. Continuous administration of antihemophilic factors prevents the peaks and valleys in factor concentrations that occur with intermittent infusion; this benefit is particularly important when treatment is required for prolonged periods. Besides improved hemostasis, continuous infusions decreases the amount of factor used, which can result in significant savings. The indications for this approach include intracranial hemorrhage, vascular compromise, iliopsoas bleeding, and preparation for surgery. In most minor-to-moderate bleeding episodes, intermittent boluses are adequate. Intermittent boluses can also be used prophylactically, especially in the treatment of recurrent bleeding in target joints. Doses of FVIII concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The reaction half-time is 8-12 hours. Target levels by hemorrhage severity are as follows:

 Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain an FVIII level of 30%

 Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain an FVIII level of 50%

 Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis): Maintain an FVIII level of 80-90%. Plasma levels are maintained above 40-50% for a minimum of 7-10 days.

Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia

FVIII Factor level Indication or Site of Bleeding Dose, Comment Desired, % IU/kg* Severe epistaxis; mouth, lip, 20-50 10-25 Consider aminocaproic acid tongue, or dental work (Amicar), 1-2 d Joint (hip or groin) 40 20 Repeat transfusion in 24-48 h Soft tissue or muscle 20-40 10-20 No therapy if site small and not enlarging (transfuse if enlarging) Muscle (calf and forearm) 30-40 15-20 None Muscle deep (thigh, hip, iliopsoas) 40-60 20-30 Transfuse, repeat at 24 h, then as needed Neck or throat 50-80 25-40 None Hematuria 40 20 Transfuse to 40% then rest and hydration Laceration 40 20 Transfuse until wound healed GI or retroperitoneal bleeding 60-80 30-40 None Head trauma (no evidence of CNS 50 25 None bleeding) Head trauma (probable or definite 100 50 Maintain peak and trough factor CNS bleeding, eg, headache, levels at 100% and 50% for 14 d if vomiting, neurologic signs) CNS bleeding documented† Trauma with bleeding, surgery† 80-100 50 10-14 d Variations in responses related to patient or product parameters make determinations of factor levels important. These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels. Obtain factor assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration. Desmopressin Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia. DDAVP stimulates a transient increase in plasma FVIII levels and results in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures. Other possible mechanisms of action are noted. A test dose should be performed. It can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting. Its peak effect is observed in 30-60 minutes. A concentrated DDAVP intranasal spray is available for outpatient use. Its effectiveness is similar to that of the intravenous preparation, although its peak effect is observed later, at 60-90 minutes after administration. Patients should be advised to limit water intake during treatment and to avoid 3 consecutive daily doses to a prevent hyponatremia. Several doses of DDAVP may need to be infused every 12-24 hours before tachyphylaxis is observed. The major adverse effects of DDAVP include asymptomatic facial flushing and hyponatremia. Management of Bleeding Episodes by Site Musculoskeletal bleeding The most common sites of clinically significant bleeding are joint spaces. Weight- bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint. Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain. Early infusion upon the recognition of pain may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days. Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply. Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. Administer adequate replacement therapy for at least 3 days. Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely replacement therapy is important to prevent such disabilities. Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals normal hip rotation but significant limitation of extension. Ultrasonography in the involved region may reveal a hematoma in the iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature. Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These occur in the upper arm, forearm, wrist, and palm of the hand. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level of FVIII. Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression. Oral bleeding Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of the saliva. Combine adequate replacement therapy with an antifibrinolytic agent (epsilon- aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity. Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used. Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery. Administer prophylactic factor infusion therapy before an oral surgical procedure to prevent the need for further treatment. Gastrointestinal bleeding GI bleeds are unusual compared with those associated with von Willebrand disease and, therefore, require an evaluation for an underlying cause. Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FVIII. Intracranial bleeding Intracranial hemorrhage is often trauma induced; spontaneous intracranial hemorrhages are rare. If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established. All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI. If the patient is not hospitalized, instruct the patient and his or her family regarding the neurologic signs and symptoms of CNS bleeding so that the patient can know when to return for reinfusion. Treatment of Patients with Inhibitors Inhibitors are antibodies that neutralize factor VIII and can render replacement therapy ineffective. They are found more commonly in patients with moderate to severe hemophilia (up to 30% of those with severe disease) who have received significant amounts of replacement therapy. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII. Rarely, inhibitors can develop in individuals without hemophilia (eg, elderly persons, pregnant women); these occasionally are responsive to immunosuppressive therapy (eg, prednisone). In a 2013 study of 574 consecutive patients with severe hemophilia A (FVIII activity, < 0.01 IU/mL), 177 of whom developed inhibitors, the risks of inhibitor development were found to be similar with recombinant and plasma-derived factor VIII products, and there was no association identified between the development of inhibitory antibodies and the von Willebrand factor content of products; switching from a plasma-derived product to a recombinant product; or switching among brands of factor VIII products. However, unexpectedly, there was a higher likelihood of inhibitor development with second-generation full-length recombinant products than with third-generation products. The treatment of patients with inhibitors of FVIII is difficult. Assuming no anamnestic response, low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII. There is no established treatment for bleeding episodes in patients with high-titer inhibitors. A study of 26 patients over 2 years of age with severe hemophilia A tested the prophylactic use of anti-inhibitor coagulant complex (AICC) for preventing bleeding. Results show treatment 3 times per week on nonconsecutive days for 6 months led to a 62% reduction in all bleeding episodes as compared with on- demand therapy. Other bleeding events including hemarthroses and target-joint bleeding were also reduced; 61% and 72%, respectively. Other approaches to treating patients with FVIII inhibitors include the following:

 Porcine FVIII, which has low cross-reactivity with human factor VIII antibody

 Activated prothrombin complex concentrate (PCC)

 Activated FVII

 Desensitization

 Immune tolerance induction (ITI) Recombinant activated FVIIa Recombinant activated FVIIa (Eptacog Alfa or Novo Seven) has become the first choice of bypassing agents. Recombinant FVIIa is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa. It is manufactured by using DNA biotechnology. Intravenous recombinant FVIIa has been studied for treating bleeding episodes and for providing hemostasis during surgery in patients with a particular bleeding diathesis. Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann thrombasthenia. To date, recombinant activated FVIIa has proven to be relatively free of the risk of antigenicity, thrombogenicity, and viral transmission. However, the cost of this product has precluded its use as prophylaxis in patients with inhibitors for FVIII; when recombinant activated FVIIa has been used for this indication, select patients have had severe complications related to bleeding. In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of patients subjectively classified as responders. Clinical context and pH values before administration were independently associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients. Desensitization Desensitization in nonemergency situations also may be feasible. This therapy includes large doses of FVIII along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-threatening bleeding, methods to quickly remove the inhibiting antibody have been tried. Examples include vigorous plasmapheresis in conjunction with immunosuppression and infusion of FVIII with or without antifibrinolytic therapy. Immune tolerance induction In immune tolerance induction (ITI), a person is rendered tolerant to FVIII by means of daily exposure to FVIII over several months to years. The overall likelihood of success with ITI is 70% ± 10%. First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FVIII and with or without immunosuppressive therapy (eg, cyclophosphamide, prednisone). Most of the recent protocols that use FVIII alone have avoided use of immunosuppression because of the toxicity risk. This technique is well established in acquired hemophilia but not in congenital hemophilia. Rituximab, a chimeric human-mouse monoclonal antibody against CD20, has been used with success in ITI. Reports describe durable complete responses with a brief courses of rituximab and prednisone with or without cyclophosphamide in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU. Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia. Attenuation of B-cells essential to the development of an acquired immune response, or autoimmunization seen in patients with refractory FVIII inhibitors, with a 4-week course of weekly rituximab has shown durable and complete responses in several small trials. The addition of prednisone with or without cyclophosphamide has increased response rates. An international immune tolerance study was started in 2002 to compare the efficiency, morbidity, and cost-effectiveness of low- versus high-dose ITI. Prophylactic Factor Infusions Most of the care for children with severe forms of hemophilia now takes place at home, in the community, and at school, allowing children with hemophilia to participate in normal activities that are otherwise impossible. This resulted from the development of prophylactic regimens of factor concentrate infusions that are administered at home, usually by a parent. The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilia arthropathy that results from recurrent or target joint bleeding can be prevented by this method. Prophylaxis is not universally accepted, with only about half the children with hemophilia A receiving this treatment modality in the United States. Reasons cited for the lack of acceptance include need for venous access, factor availability, repeated venipunctures, cost, and others. Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule. Tools have now been developed to assess long-treatment effects. Assessing adherence to prophylaxis The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent questionnaire that uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log entries). Pain Management Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be extremely painful. This requires immediate analgesic relief. Hemophilic chronic arthropathy is associated with pain. Narcotic agents have been used, but frequent use of these drugs may result in addiction. Nonsteroidal anti- inflammatory drugs may be used instead because their effects on platelet function are reversible and because these drugs can be effective in managing acute and chronic arthritic pain. Avoid aspirin because of its irreversible effect on platelet function. Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs. Complications HIV-associated immune thrombocytic purpura is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to less than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces transient remissions. Anti-HIV medications and splenectomies may result in long- term improvement of thrombocytopenia. Allergic reactions are occasionally reported with the use of cryoprecipitate, fresh- frozen plasma (FFP), and factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem. Deterrence/Prevention Do not circumcise male infants born to mothers who are known or thought to be carriers of hemophilia until disease in the infant has been excluded with appropriate laboratory testing. Perform blood assays of FVIII with cord blood. When a cord blood sample is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites. Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella [MMR] vaccines) may be given by means of a deep subcutaneous route (rather than deep intramuscular route) with a fine-gauge needle. Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia. Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum. In severe hemophilia, consider prophylactic or scheduled factor VIII. Prophylactic replacement of FVIII is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis. This goal is achieved by administering factor 2-3 times a week. The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1- 2 years. Carrier testing Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because a cesarean delivery may be planned or replacement therapy can be scheduled for the perinatal period. Phenotypic and genotypic (ie, restriction fragment–length polymorphism) methods have advantages and disadvantages. Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases. The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. This technique circumvents pregnancy termination. Activity Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improving psychosocial functioning. Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed spontaneously. Any physical activity may trigger bleeding in soft tissues. Prophylactic factor replacement early in life may help prevent bleeding during activity, as well as helping to prevent chronic arthritic and muscular damage and deformity. Gene Therapy With the cloning of FVIII and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was conceived. Substantial progress has been made in the development of gene therapy for hemophilia A and hemophilia B. This advancement reflects technical improvements of existing vector systems and the development of new delivery methods. Preclinical studies in mice and dogs with hemophilia have resulted in long-term correction of the bleeding disorders and, in some cases, a permanent cure. The induction of neutralizing antibodies often precludes stable phenotypic correction. Certain promoters are prone to transcriptional inactivation in vivo, resulting in failure of long-term FVIII expression. Several phase I trials of gene therapy are ongoing in patients with severe hemophilia. Some individuals report fewer bleeding episodes than before, and low levels of clotting factor activity are occasionally detected. Consultations Consultations may be indicated with a hematologist, blood bank, pathologist, or others as indicated by hemorrhagic complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is recommended. A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy. Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and healing period. Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis in relatively neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic replacement of factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the affected joint. Management should be provided in coordination with a comprehensive hemophilia care center.

KAWASAKI DISEASE Etiology  Many factors point to an infective cause but no specific organism has been found  Genetic susceptibility: highest in Asians irrespective of location and in children and sibs of those with KD  KD-associated antigen in cytoplasmic inclusion bodies of ciliated bronchial epithelial cells, consistent with viral protein aggregates; suggests respiratory portal of entry  Seems to require an environmental trigger Epidemiology  Asians and Pacific Islanders at highest risk  80% present at age <5 years (median is 2.5 years) but may occur in adolescence  Poor outcome predictors with respect to coronary artery disease: very young age, male, neutrophilia, decreased platelets, increased liver enzymes, decreased albumin, hyponatremia, increased CRP, prolonged fever Pathology  Medium size vasculitis, especially coronary arteries  Loss of structural integrity weakens the vessel wall and results in ectasia or saccular or fusiform aneurysms; thrombi may decrease flow with time and can become progressively fibrotic, leading to stenosis Diagnosis Absolute requirement: fever ≥5 days (≥101˚ F), unremitting and unresponsive; would last 1−2 weeks without treatment plus any 4 of the following:  Eyes: bilateral bulbar conjunctivitis, non-exudative  Oral: diffuse oral and pharyngeal erythema, strawberry tongue, cracked lips  Extremities: edema and erythema of palms and soles, hands and feet acutely; subacute (may have periungual desquamation of fingers and toes and may progress to entire hand)  Rash: polymorphic exanthema (maculopapular, erythema multiforme or scarlatiniform with accentuation in the groin); perineal desquamation common in acute phase  Cervical lymphadenopathy: usually unilateral and >1.5 cm, nonsuppurative Associated symptoms: GI (vomiting, diarrhea, pain); respiratory (interstitial infiltrates, effusions); significant irritability (likely secondary to aseptic meningitis); liver (mild hepatitis, hydrops of gallbladder); GU (sterile pyuria, urethritis, meatitis); joints (arthralgias/arthritis— small or large joints and may persist for several weeks) Cardiac findings  Coronary aneurysms: up to 25% without treatment in week 2-3; approximately 2−4% with early diagnosis and treatment; giant aneurysms (>8 mm) pose greatest threat for rupture, thrombosis, stenosis and MI; best detected by 2D echocardiogram  Myocarditis: in most in the acute phase; tachycardia out of proportion to the fever and decreased LV systolic function; occasional cardiogenic shock; pericarditis with small effusions. About 25% with mitral regurgitation, mild and improves over time; best detected by 2D echocardiogram plus EKG  Other arteries may have aneurysms (local pulsating mass) Clinical phases  Acute febrile: 1-2 weeks (or longer without treatment), diagnostic and associated findings and lab abnormalities; WBC increased (granulocytes), normocytic / normochromic anemia, normal platelets in first 1-2 weeks; ESR and CRP must be increased (usually significantly for the ESR); sterile pyuria, mild increase in liver enzymes and bilirubin; mild CNS pleocytosis. Most important tests at admission are platelet count, ESR, EKG, and baseline 2D-echocardiogram.  Subacute: next 2 weeks; acute symptoms resolving or resolved; extremity desquamation, significant increase in platelet count beyond upper limits of normal (rapid increase in weeks 2-3, often greater than a million); coronary aneurysm, if present, this is the time of highest risk of sudden death. Follow platelets, ESR and obtain 2nd echocardiogram.  Convalescent: next 2-4 weeks; when all clinical signs of disease have disappeared and continues until ESR normalizes; follow platelet, ESR and if no evidence of aneurysm, obtain 3rd echocardiogram; repeat echo and lipids at 1 year. If abnormalities were seen with previous echo, more frequent studies are needed, and cardiology follow-up and echocardiograms are tailored to their individual status. Treatment  Acute: (at admission): (a) IVIG over 10-12 hours (mechanism unknown but results in rapid defervescence and resolution of clinical symptoms in 85- 90%); the IVIG gives the large drop in incidence of aneurysms. If continued fever after 36 hours, then increased risk of aneurysm; give 2nd infusion. (b) oral high dose aspirin (anti-inflammatory dosing) until afebrile 48 hours o If winter, give heat-killed influenza vaccine if not yet received (Reye syndrome); cannot give varicella vaccine acutely (live, attenuated vaccine and concurrent IVIG would decrease its effectiveness, so must delay any MMR and varicella vaccine until 11 months post- IVIG.  Subacute (convalescent): change ASA to low dose (minimum dose for antithrombotic effects as a single daily dose until ESR has normalized at 6-8 weeks and then discontinue if echocardiogram is normal; if abnormalities, continue indefinitely Complications and prognosis  Small solitary aneurysms: continue ASA indefinitely; giant or numerous aneurysms need individualized therapy, including thrombolytic  Long-term follow-up with aneurysms: periodic echo and stress test and perhaps angiography; if giant, catheter intervention and percutaneous transluminal coronary artery ablation, direct atherectomy and stent placement (and even bypass surgery)  Overall- 50% of aneurysms regress over 1-2 years but continue to have vessel wall anomalies; giant aneurysms are unlikely to resolve  Vast majority have normal health  Acute KD recurs in 1-3%  Fatality rate <1%; all should maintain a heart-healthy diet with adequate exercise, no tobacco and should have intermittent lipid checks.

LITERATURE: 1. USMLE STEP 2. Lecture notes 2019. Pediatrics. P. 458-467. 2. www.kaptest.com/usmlebookresources 3. Nelson Textbook of Pediatrics, 21th Edition. - Expert Consult Premium Edition - Enhanced Online Features and Print / by Robert M. Kliegman, MD, Bonita M.D. Stanton, MD, Joseph St. Geme, Nina Schor, MD, PhD and Richard E. Behrman, MD. - 2020. - 2680 p. 4. Manual of Pediatric Hematology and Oncology, Fifth Edition. Edited by: Philip Lanzkowsky. Academic Press, 2016. - 1027p. 5. Hastings CA, Torkildson JC, Agrawal AK. Handbook of Pediatric Hematology and Oncology: Children's Hospital and Research Center Oakland, second edition. Oxford, John Wiley & Sons, 2012. – 378p.