Coagulopathies Evangelina Berrios- Colon, Pharmd, MPH, BCPS, CACP • Julie Anne Billedo, Pharmd, BCACP

Home , Dysfibrinogenemia, Factor V Leiden, Factor XIII deficiency, Hemarthrosis, Protein C deficiency, Thrombocytopenia

CHAPTER33 Coagulopathies Evangelina Berrios- Colon, PharmD, MPH, BCPS, CACP • Julie Anne Billedo, PharmD, BCACP

Coagulopathies include hemorrhage, thrombosis, and Activated protein C (APC) inhibition is catalyzed by protein embolism, and represent common clinical manifestations of S, another vitamin K–dependent plasma protein, and also hematological disease. Normally, bleeding is controlled by requires the presence of platelet phospholipid and calcium. a fi brin clot formation, which results from the interaction Antithrombin III (AT III) primarily inhibits the activity of of platelets, plasma proteins, and the vessel wall. The fi brin thrombin and Factor X by binding to the factors and block- clot is ultimately dissolved through fi brinolysis. A derange- ing their activity. This inhibition is greatly enhanced by hep- ment of any of these components may result in a bleeding arin. Loss of function and/or decreased concentrations of or thrombotic disorder. In this chapter, individual disease these proteins result in uninhibited coagulation and hence a states are examined under the broad headings of coagulation predisposition to spontaneous thrombosis otherwise known factor defi ciencies, disorders of platelets, mixed disorders, as a hypercoagulable state. acquired thrombophilias, and inherited thrombophilias. Fibrinolysis is a mechanism for dissolving fi brin clots. Plasmin, the activated form of plasminogen, cleaves fi brin to produce soluble fragments. Fibrinolytics, such as tissue n ANATOMY, PHYSIOLOGY, AND PATHOLOGY plasminogen activator, streptokinase, and urokinase, activate plasminogen, resulting in dissolution of a fi brin clot.

Coagulation is initiated after blood vessels are damaged, enabling the interaction of blood with tissue factor, a pro- n CLASSES OF BLEEDING DISORDERS tein present beneath the endothelium ( Figure 33.1). Small amounts of Factor VII present in plasma bind to tissue factor, and this tissue factor–Factor VII complex activates Vascular defects usually cause bleeding only into the skin Factor X. Activated Factor X, in the presence of Factor V, and mucous membranes. Congenital causes include Osler– activates prothrombin ( II) to thrombin ( Ila), which subse- Weber– Rendu syndrome and Ehlers– Danlos disease. quently cleaves fi brinogen to fi brin. The fi brin polymer- Acquired causes of vascular purpura include infections, izes into an insoluble gel. This is stabilized by the action of drugs, uremia, connective tissue disorders, and dysprotein- Factor XIII. This process constitutes the extrinsic pathway. emias. Treatment is directed to the primary illness. Coagulation is consolidated by the intrinsic pathway. Factor XI is activated (possibly by thrombin generated in Inherited Coagulation Disorders the extrinsic pathway), resulting in the activation of Factor IX, which then activates Factor X in the presence of Factor Hereditary bleeding disorders are extremely rare. The most VIII. Activated Factor X produces a fi brin clot, as outlined common bleeding disorders include hemophilia A, hemo- in the description of the extrinsic pathway. Decreased lev- philia B, and von Willenbrand disease ( vWD). The world- els of clotting factors may be caused by defective synthesis, wide incidence of hemophilia A is 1 case per 5,000 live male excessive use, circulating inhibitors of clotting factors, or births. Hemophilia B occurs at an even lower rate, with 1 excessive proteolysis by the fi brinolytic system. case per 50,000 live male births (Soucie, Evatt, & Jackson, The coagulation pathway is controlled by a number 1998). vWD is the most common of the three bleeding dis- of endogenous anticoagulants. Protein C is a plasma pro- orders across all ethnic groups, affecting 1% of the popu- tein that is vitamin K dependent. It requires activation by a lation. Up to 80% of affected patients have Type I vWD complex of thrombin and thrombomodulin, an endothelial ( Zimmerman & Valentino, 2013). cell protein, to inhibit activated Factors V and VIII, thus Defi ciencies of any of the known coagulation factors inhibiting the activation of Factors IX and X, respectively. could be present from birth. Defi ciencies may be inherited

INTRINSIC PATHWAY INTRINSIC PATHWAY

(Coagulation initiated by events (Coagulation initiated by events within the bloodstream) within the bloodstream)

Factor XII Factor VII (Hageman Factor) (Proconvertin)

Factor XI + (Plasma Thromboplastin Antecedent) Calcium (Ca++) (Factor IV) + Ca++ + Tissue Thromboplastin Factor IX (Factor III) (Plasma Thromboplastin Component)

+ Ca++

+ Platelet Factor 3 (PF3)

Factor VIII (Antihemophilic Factor)

Factor X (Stuart-Power Factor)

++ Ca PF3 FIGURE 33.1 T he coagulation cascade Factor V (Proacceletin) i s initiated by the extrinsic pathway and consolidated Factor II Thrombin by the intrinsic pathway. (Prothrombin) Coagulation is controlled by Factor I Fibrin the inhibition of Factor VIII (Fibrinogen) and Factor V by activated XII Stable clot protein C (APC), and by anti- (Fibrin Stabilizing Factor) thrombin III (AT III) inhibition o f Factors II and X.

or result from a spontaneous disruption in the associated moderate disease (factor level: 1%–4%) or mild hemophilia coagulation factor genes. The more common defi ciencies of (factor level: 5%–25%) are at a reduced risk of spontaneous Factors VIII and IX, as well as vWD, are discussed in this hemorrhage, but may bleed excessively after trauma or sur- chapter (Table 33.1). gery (Wagenman, Townsend, Mathew, & Crookston, 2009).

HEMOPHILIA VON WILLEBRAND DISEASE Hemophilia is an X-linked recessive disorder associated with von Willebrand factor ( vWF) is a plasma protein that is a congenital defi ciency of Factor VIII or Factor IX. Factor required for the adhesion of platelets to sites of vascular VIII defi ciency is known as hemophilia A and Factor IX damage. In persons with von Willebrand disease, defi ciency defi ciency is known as hemophilia B. Hemophilia B was of vWF is called Type I; qualitative abnormality of vWF is fi rst diagnosed by Steven Christmas and thus is also called called Type II. vWD is an autosomally inherited hemostatic Christmas disease. Hemophilia is suspected in any male who disorder of variable severity, characterized by mucosal and has excessive bleeding after trauma, or spontaneous bleeding cutaneous bleeding, similar to patients with platelet disor- into joints or soft tissues (Table 33.1). Patients with severe ders (see Table 33.2). Patients may have a prolonged pro- hemophilia (factor level: <1%) are at risk for spontaneous thrombin time ( PT) and activated partial thromboplastin hemarthrosis and soft-tissue bleeding. Patients who have time ( aPTT).

TABLE 33.1 Overview of Coagulopathies BLEEDING DISORDER FACTOR FREQUENCY CLINICAL PRESENTATION LAB TESTING

Hemophilia A VIII 1 in 5,000 live Eccymosis Prolonged aPTT male births Hemathrosis Decreased Factor VIII Muscle hemorrhage Decreased Factor IX Wound bleeding

Hemophilia B IX 1 in 50,000 live Eccymosis Prolonged aPTT male births Hemathrosis Decreased Factor IX Muscle hemorrhage Wound bleeding

von Willebrand disease vWF 1% Minor bleeding Decreased von Willebrand factor- Epistaxsis antigen (vWF:Ag), Factor VIII Increased postoperative bleeding

CLOTTING DISORDER FACTOR FREQUENCY CLINICAL PRESENTATION LAB TESTING

Factor V Leiden V 5% Thromboembolism Positive genotypic assay APC resistance

Prothrombin G20210A II 3% Thromboembolism Positive genotypic assay

Protein C deficiency Protein C <1% Thromboembolism Decreased protein C activity

Protein S deficiency Protein S <1% Thromboembolism Decreased protein S activity

Antithrombin III ATIII <1% Thromboembolism Decreased AT III activity deficiency

APC, activated protein C; aPTT, activated partial thromboplastin time; AT III, antithrombin III.

Mixed Coagulation Disorders VITAMIN K DEFICIENCY Factors II, VII, IX, and X are vitamin K–dependent coagu- Mixed coagulation disorders are a group of acquired dis- lation factors that are synthesized in the liver. Vitamin K is eases. They usually involve multiple elements of the hemo- naturally synthesized by intestinal bacteria. Vitamin K is a static system and are often associated with a particular lipid-soluble vitamin, which is absorbed only in the presence disease or clinical syndrome. of bile salts. Depletion of vitamin K–dependent factors may occur in patients receiving certain antibiotics; in obstruc- tive jaundice, malabsorptive states, or hepatic parenchymal DISSEMINATED INTRAVASCULAR COAGULATION disease; and in patients receiving warfarin therapy. Patients Disseminated intravascular coagulation (DIC) can be have an elevated PT resulting in an increased international caused by the activation of either the coagulation or fibri- normalized ratio (INR). nolytic system, resulting in excessive bleeding or thrombosis. Conditions associated with DIC include gram-negative Platelet Disorders sepsis infections, meningococcemia, Rocky Mountain spot- ted fever, typhoid fever, obstetric complications (abruptio Platelet disorders include thrombocytopenia, which may be placentae, eclampsia, retained dead fetus), massive trauma, caused by diminished platelet production, enhanced plate- surgery, shock, and certain malignancies. let destruction, or sequestration of platelets (Table 33.2). Qualitative platelet disorders are more commonly acquired, but could be congenital. Congenital disorders affect platelet LIVER DISEASE adhesion, aggregation, or secretion, and are rare. Acquired Coagulation disorders are common in patients with acute qualitative platelet disorders are secondary to uremia, myelo- and chronic hepatic diseases. These may arise from malab- proliferative disorders, drugs, and dysproteinemias. sorption of vitamin K, decreased synthesis of clotting proteins, abnormal synthesis of clotting proteins, or decreased clearance of activated factors. Fibrin degradation products IMMUNE THROMBOCYTOPENIC PURPURA may be elevated because of poor hepatic clearance, resulting Immune thrombocytopenic purpura (ITP), the autoim- in impaired coagulation resembling DIC. Liver disease asso- mune destruction of platelets, usually presents as bruising, ciated with hypersplenism may result in thrombocytopenia. petechiae, or bleeding. The differential diagnosis includes

Heparin-induced thrombocytopenia is associated with TABLE 33.2 Causes of Thrombocytopenia an early nonimmune clinical syndrome and a later immune- Diminished platelet production mediated thrombocytopenia that occurs 5 to 7 days after Marrow infiltration with tumor, fibrosis, infection the initiation of heparin. This type of thrombocytopenia Aplastic/hypoplastic anemia may be associated with paradoxical thrombosis instead of Exposure to environmental toxins (arsenic, pesticides) bleeding. Ionizing radiation In all cases, the offending drug should be discontinued Nutritional deficiencies (B12, folate) and switched to an alternative if possible. Viral infections Drugs (thiazides, alcohol, myelosuppressive agents) Paroxysmal nocturnal hemoglobinemia THROMBOTIC THROMBOCYTOPENIC PURPURA Splenic sequestration Thrombotic thrombocytopenic purpura (TTP) is a complex Lymphoproliferative disorders clinical syndrome characterized by a formation of blood Portal hypertension Myeloproliferative disorders clots under the skin. Patients may present with headaches, Infections (bacterial, viral, parasitic) blurred vision, seizures, profound coma, purpura, and pete- Increased platelet destruction chiae from thrombocytopenia, jaundice, hemolytic ane- Nonimmune mia, fever, or renal dysfunction. TTP may be acquired or Vascular prosthesis DIC congenital. The causes of TTP are unknown, although this Sepsis/infection disease has been associated with certain drugs, pregnancy, TTP malignancy, and HIV infection. Immune Laboratory findings include anemia, thrombocytopenia, Drug-induced antibodies fragmented red blood cells seen on peripheral smear, ele- ITP vated blood urea nitrogen and creatinine levels, proteinuria,

DIC, disseminated intravascular coagulation; ITP, immune thrombocytopenic hematuria, and an elevated level of lactic dehydrogenase. purpura; TTP, thrombotic thrombocytopenic purpura. The PT/INR and aPTT are usually normal.

nnCLASSES OF THROMBOTIC DISORDERS aplastic anemia, sepsis, DIC, acute leukemia, drug-induced thrombocytopenia, and infiltrative bone marrow disorders. The diagnosis is made by excluding other causes of throm- Acquired Thrombophilias bocytopenia, after a careful history, physical examination, and peripheral smear. An HIV test should be performed in Thrombophilia refers to a tendency to have venous throm- those patients with risk factors. Bone marrow aspiration boembolisms (VTEs) and to be at risk for recurrent epi- may be indicated in elderly patients or patients with atypical sodes. Acquired causes of thrombosis include malignancy, findings. myeloproliferative disorders, use of certain drugs, surgery, ITP may be acute (short term) or chronic. Acute ITP trauma, prolonged immobilization, pregnancy, antiphos- occurs primarily in children and usually lasts <6 months. pholipid antibodies with or without systemic lupus ery- Chronic ITP usually occurs in adults and lasts for >6 thematosus, and hyperhomocysteinemia (see discussion on months, with a 3:1 ratio of females to males. It is common Virchow’s triad in Chapter 74 for additional information). in patients between the ages of 20 and 50 years. ITP may also be associated with HIV infection, systemic lupus ery- thematosus, lymphoproliferative disorders, ulcerative coli- ANTIPHOSPHOLIPID ANTIBODIES tis, and carcinoma. The thrombocytopenia is often chronic The antiphospholipid antibodies—anticardiolipin anti- and unremitting, requiring definitive therapy. body, lupus anticoagulant, and antib2-glycoportein 1— are directed against different phospholipids. The lupus anticoagulant is an antibody against the phospholipid DRUG-INDUCED THROMBOCYTOPENIA moiety of prothrombin activator complex, which inter- Drug-induced thrombocytopenia is diagnosed after feres with and prolongs the aPTT and less commonly excluding other causes, and by noting a temporal rela- increases the INR. Despite the prolonged aPTT, this tion between the onset of thrombocytopenia and the disorder is not associated with bleeding, but it may be administration of the drug, as well as resolution upon associated with thrombosis. The lupus anticoagulant discontinuation of the drug. Although many drugs can be most highly predicts thrombosis. Antiphospholipid anti- implicated, alcohol, thiazide diuretics, quinine, quinidine, body syndrome is a term used for patients with persis- penicillins, gold, sulfa, and heparin are the most common. tent antiphospholipid antibodies who experience at least Myelosuppressive drugs used to treat malignancies and one clinical manifestation, such as a vascular thrombosis other disorders can produce thrombocytopenia by sup- and/or pregnancy morbidity (Ruiz-Irastorza, Crowther, pressing platelet production. Branch, & Khamashta, 2010).

HYPERHOMOCYSTeINEMIA PROTHROMBIN G20210A MUTATION A high level of homocysteine, an amino acid produced Prothrombin G20210A mutation is a single base pair muta- from methionine metabolism, causes an increased risk of tion on the 3'-untranslated region of the prothrombin gene. venous and arterial thrombosis when it undergoes auto- At position 20210 in this region, guanine is substituted with oxidation. Normal metabolism of homocysteine relies on adenine. This substitution leads to increased production of adequate stores of folic acid and vitamins B6 and B12. Thus, prothrombin and thus thrombin. Both heterozygote and hyperhomocysteinemia is not a coagulation cascade issue homozygote carriers have elevated levels of prothrombin. but a defect in metabolism and/or increase in production. Heterozygote carriers of prothrombin G20210A mutation Hyperhomocysteinemia can be precipitated by acquired are at a threefold increased risk for a first-time VTE com- medical conditions, including vitamin deficiencies, or by pared to the general population (Lijfering et al., 2010). genetic defects.

ANTITHROMBIN DEFICIENCY Inherited Thrombophilias Lack of antithrombin activity enables the coagulation cascade to continue uninterrupted. Antithrombin deficiency Inherited thrombophilias should be considered in patients results from a quantitative or qualitative defect and is who have a VTE and who are <45 years old, have a fam- divided into two different types depending on its origin. ily history of VTEs, have had recurrent spontaneous episodes Type I antithrombin deficiency is quantitative and occurs of VTEs, have had thrombosis in an unusual site (e.g., mes- when production of normally functioning antithrombin is enteric vein, cerebral vein), and/or have had recurrent fetal decreased. Type II antithrombin deficiency is qualitative and losses and acquired causes have been excluded. All of the occurs when dysfunctional antithrombin molecules are pro- inherited thrombophilias discussed here are transmitted as an duced. Certain conditions can induce a state of antithrom- autosomal dominant trait, meaning that carriers, or heterozy- bin deficiency. Such conditions associated with acquired gotes, are affected. antithrombin deficiency include heparin therapy, liver and/ The prevalence of inherited thrombophilias in the gen- or renal disease, and DIC (Seligsohn & Lubetsky, 2001). eral population is relatively low. The two most common thrombophilias are Factor V Leiden (FVL) and prothrombin G20210A mutation. Both of these are more prevalent PROTEIN C DEFICIENCY in Caucasians, with a prevalence of about 5% for Factor Protein C deficiency results from either a quantitative or V Leiden and 3% for prothrombin G20210A mutation. A a qualitative defect and is divided into two different types majority of those with either disease are heterozygote car- depending on its origin. Type I protein C deficiency is quan- riers. Being a carrier for both Factor V Leiden and pro- titative and occurs when production of normally functioning thrombin mutation is rare, with a prevalence of about 0.1% protein C molecule is decreased. Type II is qualitative and (Lijfering et al., 2010). Deficiencies of the natural anticoag- occurs when defective protein C molecules are produced, ulants have a prevalence of <1% in the general population. leading to low activity of protein C. Type I defect predomi- The least common is antithrombin deficiency (Seligsohn & nates in protein C deficiency. Certain conditions can cause Lubetsky, 2001). People can be carriers of multiple throm- protein C deficiency and/or induce further deficiency. Such bophilia disorders, each of which further increases a per- conditions associated with acquired protein C deficiency son’s lifetime risk for a VTE. include liver disease, vitamin K deficiency, use of vitamin K antagonists (VKAs), and DIC (Seligsohn & Lubetsky, 2001). FACTOR V LEIDEN A mutation of a single DNA base pair found on the PROTEIN S DEFICIENCY Factor V gene causes the production of defective Factor As with the other deficiencies, protein S deficiency results V proteins. This single base change, where guanine is from a quantitative or qualitative defect; Type I and Type II, substituted with adenine, leads to the replacement of respectively. However, protein S deficiency has another cate- arginine by guanine at position 506, creating Factor V gory, Type III. Type III protein S deficiency is due to decreased Leiden. These defective Factor V proteins resist APC. In amounts of free protein S molecules. Approximately 60% of other words, this mutation causes resistance of Factor V protein S is bound to C4b-binding protein, an acute phase to the endogenous anticoagulation effects of protein C reactant, and the remaining free portion of protein S has the and causes an imbalance of the clotting cascade favor- ability to be the cofactor that helps activate protein C. Free ing thrombosis. The Factor V Leiden mutation was dis- protein S can be decreased due to increased C4b-binding covered by researches in Leiden, Netherlands, and is the proteins or due to a divergence between protein S and C4b- most commonly diagnosed thrombophilia. Heterozygote binding protein to complex. Types I and III predominate in carriers of Factor V Leiden are at a five-fold increased protein S deficiency. As with the other deficiencies, certain risk for a first-time VTE, and homozygote carriers are at situations can cause protein S deficiency. Situations associ- an 18-fold increased risk, compared to the general popu- ated with acquired protein S deficiency include pregnancy, lation (Lijfering et al., 2010). oral contraceptive therapy, inflammatory conditions, liver

© Springer Publishing Company, LLC. 512 Unit ViI: Hematologic Conditions disease, vitamin K deficiency, use of VKAs, and DIC (Marlar kininogen, and Factors XII, XI, IX, VIII, X, V, II, I); and & Gausman, 2011; Seligsohn & Lubetsky, 2001). the thrombin time, which tests for deficiencies or inhibitors of thrombin and fibrinogen. A complete blood count will determine if there is a quantitative platelet deficiency. nnHISTORY AND PHYSICAL EXAMINATION nnDIAGNOSTIC TESTS Bleeding Disorders

Any recurrent bleeding, especially if it begins in early child- If a patient with a bleeding history has an increased PT/INR or hood or includes a family history of bleeding, is suggestive of a prolonged aPTT, then a mixing study should be performed an inherited bleeding disorder. Spontaneous hemarthroses or using a 50:50 mix of patient plasma and control plasma hematomas are associated with severe hemophilia A or B but (Figure 33.2). The PT/INR or aPTT would correct to normal may be observed with other severe coagulopathies. Abnormal with a coagulation factor deficiency, whereas plasma with an bruising and mucosal bleeding, including epistaxis, gingival inhibitory antibody would not correct in mixing studies. bleeding, and menorrhagia, are typical of abnormalities of In a patient with a bleeding history and normal screening platelets or vascular endothelium. Neonatal umbilical cord tests, one should suspect vWD. Repeated determinations of bleeding and defective wound healing may indicate Factor the bleeding time and activity of vWF may be necessary to XIII deficiency, afibrinogenemia, or rarely dysfibrinogenemia. establish the diagnosis. The laboratory workup may include A patient of European Jewish descent with postsurgical the functional ristocetin cofactor assay to determine the and mucosal bleeding may have a deficiency of Factor XI, plasma level of vWF, and characterization of the multimeric which occurs predominantly in this population. Deficiencies structure of the vWF molecule by gel electrophoresis. of the intrinsic contact factors (Factor XII, prekallikrein, or If these tests are normal in a patient with a bleeding his- high-molecular-weight kininogen) do not produce abnor- tory, testing for Factor XIII should be performed by testing for mal bleeding. increased solubility of the fibrin clot in urea. Further testing A detailed drug history (notably aspirin, nonsteroidal should rule out deficiencies of plasminogen activator inhibi- anti-inflammatories, anticoagulants, and antibiotics) and an tor, or α2 antiplasmin. These latter tests are seldom necessary evaluation for underlying medical conditions such as liver unless a positive history of bleeding and negative screening disease, cancer, uremia, or collagen vascular disorders are laboratory tests indicate a high probability of such disorders. essential. A careful history of every previous surgical, den- Platelet function can be evaluated in vitro by platelet tal, or traumatic event should be taken, noting the amount aggregation studies, in which light transmission through of blood loss and measures needed to control the bleeding. turbid platelet-rich plasma increases as platelets aggregate after the addition of an agonist. Laboratory findings in DIC Thrombotic Disorders include thrombocytopenia, an increased INR, prolonged aPTT and thrombin time, increased levels of fibrin degrada- The primary clinical manifestations of thrombophilias are tion products, and hypofibrinogenemia. thromboembolisms, especially in the deep venous system of Laboratory abnormalities in hemophilia include a vari- the lower extremities; in other words, deep venous thrombosis able prolongation of the aPTT and reduced Factor VIII (DVT) with or without pulmonary embolisms (PEs). Other activity (Wagenman et al., 2009). Inhibitory antibodies are locations of thrombosis that have been associated with throm- present in about 10% of patients with hemophilia A and bophilias include cerebral veins and arteries, mesenteric veins, 2% of patients with hemophilia B. Inhibitory antibodies in hepatic veins, and renal veins. Following a DVT, patients can hemophiliacs should be suspected when mixing studies with present with post-thrombotic syndrome (PTS). PTS occurs normal plasma fail to normalize the factor level in vitro. due to damaged valves in the venous system and causes discol- Patients who demonstrate thrombophilia should be oration, ulceration, swelling, and chronic pain. See Chapter evaluated for all of the different inherited thrombophilias. 74 on venous thromboembolisms for further discussion. Genotypic assays are used to diagnose Factor V Leiden and prothrombin G20210A mutation. For Factor V Leiden, an APC resistance assay is also helpful in diagnosis. Factor V nnDIAGNOSTIC CRITERIA Leiden accounts for 90% to 95% of cases of APC resistance. In a plasma sample from a person with Factor V Leiden, the addition of APC will cause a slight increase in Basic tests to diagnose a bleeding disorder include a bleed- aPTT. In comparison, a sample of plasma from a control or ing time, which tests quantitative and qualitative platelet a person without this mutation, the addition of APC will disorders; an INR, which examines the extrinsic pathway cause a prolonged aPTT because Factors V and VIII do not of the coagulation cascade (i.e., a deficiency or inhibition resist the anticoagulant effects of protein C. Evaluating the of Factors VII, X, V, II, I); an aPTT, which examines the concentrations of protein C, protein S, and antithrombin intrinsic pathway of the coagulation cascade (i.e., a defi- helps to diagnose these defciencies. The concentrations of ciency or inhibition of prekallikrein, high-molecular-weight these proteins are expressed as percentages. When assessing

A Elevated INR

50:50 mix

Correction Prolonged INR of INR

Deficiency: Inhibitor (rare) liver disease, warfarin, Factor VII (rare)

B Elevated INR

50:50 mix

Correction Prolonged PTT of PTT

Deficiency: Inhibitor: Factors VIII, IX, XI Specific: Factor VIII, IX inhibitor Nonspecific: lupus anticoagulant, heparin

C Elevated PT/PTT

50:50 mix

Correction Prolonged INR of INR/PTT

Deficiency: Inhibitor: Single: Factor X, V, II, I Nonspecific: lupus Multiple: liver disease, anticoagulant DIC, coumadin F IGURE 33.2 An algorit hm for the ev aluation of a D Normal INR/PTT blee din g patient.

Consider vWD, Factor XIII deficiency, vascular disorder, INR, Internation al Normali zation Ratio; PTT, partial thromboplastin time; vWD, von platelet disorder, dysfibrinogenemia, α2 antiplasmin deficiency Willebrand disease. these laboratory results, factors that can lead to decreased Patients should also be evaluated for the evidence of concentrations must be considered. hyperhomocysteinemia and antiphospholipid antibodies. The diagnosis of ant iphospholipid antibodies is confi rmed by performing the dilute Rus sell viper venom time a nd an Clinical Pearls ant icardiolipin antibody assay. n Because protein C and protein S are vitamin K– d ependent factors, assays of these factors as well as APC resistance should be performed when the n TRE ATMENT OPTIONS, EXP ECTED patient has not been receiving war farin for at OUTCOMES, AND COMPREHENSIVE least two weeks. Similarly, pat ients who are receiving heparin may have dec reased levels of AT III . MANAGEMENT

n During an acute VTE , the concentrations of these proteins are also dec reased. However, if a result Hemophilia is normal and obtained during a scenario associated with dec reased concentration and/or activity, In pat ients with mild hemophilia A, des mopressin (DDA VP), the defi ciency can be ruled out. If the result is which stimulates the release of both Factor VII I and vWF , can low, repeat testing should be performed prior to diagnosing a patient with one of the defi ciencies. be used for the control of bleeding and as prophylaxis before The different subtypes of these defi ciencies are some surgical procedures (Bol ton-Mag gs & Pas i, 2003). determined by functional assays. DDAVP should not be used as therapy in patients with life- threatening bleeding or in patients with severe defi ciencies of

Factor VII I. DDA VP is administered as an int ravenous infusion DDA VP, administered at 0.3 mg/kg by int ravenous infu- (0.3 mg/kg) and can be repeated every 8 to 12 hours. Prolonged sion, can elevate vWF activity for 6 to 8 hours in most cases administration of DDA VP may result in tac hyphylaxis. of Typ e I vWD . The response to DDA VP in Typ e II vWD is variable and in some cases potentially harmful. Some Von Willebrand Disease authorities recommend testing certain Typ e II vWD pat ients with DDA VP well in advance of surgery to assess if they will The two primary treatments for vWD are DDA VP and respond. The concomitant use of antifi brinolytics, such as transfusion therapy. Replacement therapy with cryopre- tranexamic and aminocaproic acids, is recommended, par- cipitate or intermediate-purity Factor VIII concentrates ticularly for dental procedures and minor mucosal bleeding. containing functional vWF have been used. These therapies are reserved for pat ients with severe Type I disease and the Dis seminated Intravascular Coagulation majority of Typ e II vWD pat ients. The tre atment of DIC is aimed primarily at the underlying disease process and secondarily at the coagulopathy that Clinical Pearls results in the thr ombotic or hemorrhagic manifestation. In pat ients with severe bleeding, fre sh-frozen plasma (FFP ), n In patients undergoing dental procedures, oral cryoprecipitate, or platelets can be used. In pat ients with ant ifi brinolytic mouthwashes may be used to con- thrombosis, heparin may be useful, usually at lower-than- trol bleeding. Tra nexamic acid and ami nocaproic normal doses, to reduce the risk of bleeding (e.g., 500 units/ acid mouthwashes have been compounded and hr intravenous infusion). However, unless the thrombotic administered for hemophilia pat ients undergoing or hemorrhagic complications are serious, specifi c therapy dental procedures. Additionally eps ilonamino- for DIC is probably of no benefi t. caproic acid (EAC A), an inhibitor of fi b rinolysis, can be used to control bleeding. One regimen is to administer EAC A on the day before the dental Liver Disease procedure and for 5 to 7 days afterward, along with a single 50% factor replacement dose imme- Patients with liver disease and a prolonged INR should diately before the procedure. empirically be given vitamin K 10 mg/d subcutaneously for n Severe hemophilia A is treated with Factor VII I con- 3 days, although only a minority of pat ients will respond. centrates (Man nucci, 2008). Hemophilia B is usually Patients who are actively bleeding may be given FFP, which treated with hig h-purity Factor IX concentrate. Minor may temporarily replace the defi cient coagulation factors. cuts and abrasions for all types usually require no Usually 2 to 4 units of FFP are administered every 4 to 6 therapy. Recombinant Factor VII has also been used hours. Care must be taken to avoid fl uid overload with this for the tre atment of hemophilia for pat ients who therapy. Recombinant Factor VII and pro thrombin complex have developed inhibitors to replacement coagula- concentrate (PCC) have also been used to control bleeding tion factors (Man nucci, 2005). in pat ients with liver disease. n Unc omplicated hem arthrosis and symptomatic hem atomas in non critical locations can be man- aged by administering Factor VII I or IX intrave- Vitamin K Defi ciency nously to achieve levels of about 50% of normal for 2 to 4 days. A single dose administered by the Intravenous administration of vitamin K (1 mg/d) results in patient at home at the onset of symptoms is often faster normalization of a prolonged PT than oral administra- suffi cient therapy for a hem arthrosis. Prompt tion (5–10 mg/d). Parenteral vitamin K should be adminis- initiation of therapy can minimize bleeding and tered slowly due to the risk of anaphylaxis. In pat ients with subsequent joint deformity. Immobilization of the severe hemorrhage, immediate replacement of coagulation joint for 2 to 3 days is important. Needle aspira- factors can be achieved by the administration of FFP , 2 to 4 tion of blood from the joint space is performed units every 4 to 6 hours. only if severe pain and swelling are present. Lif e- threatening hemorrhage, hem atomas in critical locations, and major surgery require achievement Thrombocytopenia of factor levels of 100% and longer courses of therapy. Therapy is monitored by assaying Factor In general, patients who are bleeding with thrombocytope- VII I or IX activity after a replacement dose. nia associated with platelet counts of <50,000/mL should be treated with platelet transfusions. A dose of platelets is n With replacement therapy, the average life expec- 0.1 units/kg and is expected to raise the platelet count by tancy now exceeds 60 years. Unfortunately, 70% to 90% of pat ients treated with factor concen- 30,000 to 50,000/mL. Asymptomatic patients with a plate- trates before 1985 were infected with the HIV and let count <10,000/mL should receive similar prophylaxis. hepatitis viruses. Heat and other treatments are Patients with thrombocytopenia from platelet destruc- now used to inactivate these viruses. tion rarely benefi t from platelet transfusions, and tre atment is directed at the cause of the thr ombocytopenia. Pat ients

© Springer Publishing Company, LLC. CHAPTER 33: Coagulopathies 515 with thr ombocytopenia from platelet sequestration may CLINICAL WARNING: require far greater quantities of platelets than normal. ! Occasionally, a splenectomy may be indicated to correct the Patients with thrombophilia should be counseled thr ombocytopenia. about the high risk of venous thrombosis associated Acquired qualitative platelet disorders are generally with oral contraceptive use. Because pregnancy and treated with platelet transfusions. Uremic bleeding associ- the 4 weeks after delivery are times associated with ated with qualitative platelet abnormalities can be treated high thrombotic risk, the administration of unfraction- with DDA VP or dialysis, however. ated heparin, 5,000 units three times a day, or a low- Treatment for chronic ITP includes prednisone, 1 to 2 molecular-weight heparin (LMWH) is recommended. mg/kg daily. Splenectomy should be considered for patients Before and after surgery, pat ients should receive who need an excessively high dose of prednisone to main- subcutaneous unfractionated heparin (UFH), 5,000 tain an adequate platelet count, or for patients whose dis- units three times a day, or LMW H. When the risk is ease does not respond to steroid tre atment. exceptionally high, as in certain orthopedic proce- Intravenous immune globulin, 400 mg/kg daily for 5 dures, transfusion of AT III or protein C concentrates days, usually increases the platelet count more rapidly than may be considered as additional therapy for pat ients steroids alone and can be used in actively bleeding patients. with AT III or protein C defi ciency, respectively. Transfused platelets are cleared rapidly and are therefore A patient with a documented fi rst episode of rarely benefi cial. Pat ients who suffer relapses after spl e- VTE and no previous venous thr ombosis with or nectomy may be treated with a variety of drugs, including without a history of thr ombophilia should receive cyc lophosphamide, aza thioprine, vin cristine, or dan azol, at least 3 months of anticoagulation therapy and with variable success. consider extended duration of therapy if the VTE Without appropriate tre atment, TTP is almost univer- was unprovoked and the patient’s risk of bleeding sally fatal. However, 70% of patients will survive with is low to mod erate (Kea ron et al., 2012). If tre at- expediently administered exchange transfusions with FFP ment with VKA is started in pat ients with protein C (3 to 4 L/d) and in some cases prednisone daily. Plasma or protein S defi ciency, pat ients should be bridged exchange is continued until the clinical status has improved with heparin or LMW H to prevent further defi - and the platelet count and level of lactic deh ydrogenase are ciency in proteins C and S. normal for several consecutive days. See Chapter 74 for further discussion on venous The cry osupernatant fraction of plasma may be used in thr omboembolism tre atment. pat ients whose disease does not initially respond to plasma exchange with FFP . Approximately, 20% of pat ients whose disease initially responds suffer a relapse and require ret reat- ment. Platelet transfusions should be withheld in pat ients Clinical Pearls with TTP, except for patients with severe hemorrhage. n Pat ients should use compression stockings with a 30 to 40 mmH g compression to help prevent PTS . Prevention n The true incidence of recurrence in pat ients with thr ombophilia who discontinue anticoagulant Pat ients with severe thr ombocytopenia should be warned therapy after a single episode of venous thr ombosis is against taking aspirin or nonsteroidal anti-infl ammatories, unknown. Thus, the risks and benefi ts of lifelong anti- which interfere with platelet function and could increase the coagulation should be individualized. Most authorities risk of bleeding. would offer lifelong anticoagulation to thr ombophilic Prenatal testing for both hemophilia A and B can be per- pat ients who have had more than one episode of venous thr ombosis. Usually, lifelong anticoagulant formed via cho rionic villous sampling on women who are therapy is not offered after the fi rst thr ombotic carriers of the gene and who are pregnant with a male fetus. episode, especially if it developed in association with As with any pos tconception screening, moral and emotional surgery, pregnancy, or other circumstances associated issues may make this diagnostic tool unacceptable for some with a high risk of thr ombosis. If the fi rst thr ombotic people. Excellent genetic counseling should be given to per- event was lif e-threatening or if there are multiple sons considering this test. inherited genetic defects, lifelong oral anticoagulant therapy may be considered. For such pat ients treated with VKAs, the recommended therapeutic INR range Thr ombophilias is 2 to 3 rather than lower, <2, or higher, >3 (Hol brook et al., 2012). In addition, for pat ients with hyp er- Lifelong prophylaxis should not be considered for asymp- homocysteinemia, administration of fol ate 1 mg/d, tomatic persons with inherited thrombophilia who are not pyridoxine 100 mg/d, and cob alamin 0.4 mg/d reduce exposed to thr ombotic risk factors. However, prophylactic the level of serum hom ocysteine; however, such measures should be implemented when the patient is exposed supplements do not reduce the risk of recurrent VTE to transient clinical risk factors (e.g., surgery, prolonged or cardiovascular events, in those with coronary artery immobilization, pregnancy, and the postpartum period). disease or stroke (And erson & Wei tz, 2011).

The care of patients with severe bleeding diatheses Patient and family education focuses on the particular should be supervised by a hematologist experienced features of the bleeding and/or thr ombotic disorder in in hemostatic disorders. Referrals should be made to a question. General guidelines for counseling include the hematologist for such patients before surgical procedures following: and in the event of signiﬁ cant hemorrhagic episodes. n Physical exercise that is safe and aerobic in nature Hemophiliacs with inhibitory antibodies are especially is strongly encouraged. Being in good physical con- difﬁ cult to treat and should be evaluated by a hematolo- dition can reduce the number and minimize the gist. Patients with thrombocytopenia should be evaluated damage of bleeding complications. The physical by a hematologist, especially if the cause is not imme- regimen should be planned to reduce the chance of diately evident, if the platelet count is <50,000/mL, or if potential bleeding from trauma; contact sports are the patient is actively bleeding. Management of patients discouraged. receiving VKA for treatment and secondary prophylaxis of n All patients should be taught to detect warning signs thrombosis should be under the care of an anticoagula- and to seek immediate treatment should those signs tion clinic. occur. This is especially important for the patient with thr ombocytopenia. Bruising, nosebleeds, oral bleeding, or petechiae may indicate danger. For pat ients with thr ombotic disorders, pain, swelling, warmth, and redness in the extremities may indicate n REFERENCES a DVT and shortness of breath, diffi culty breathing, and che st pain may indicate a PE. n Bleeding disorders can be treated with blood transfu- And erson, J. A., & Wei tz, J. I. (2011). Hyp ercoagulable states. Cri tical sions. Patients with bleeding disorders who have not Car e Clinics, 27( 4), 933–952. been exposed to hepatitis B should receive the hepati- Bolton-Mag gs, P. H., & Pasi, K. J. (2003). Haemophilias A and B. Lan cet, tis B vaccine series. 361 (9371), 1801–1809. n Genetic counseling is important for patients with Hol brook, A., Schulman, S., Witt, D. M., Van dvik, P. O., Fish, J., Kovacs, inherited diatheses. M. J., … Guy att, G. H.; American College of Che st Physicians. (2012). Evidence-based management of anticoagulant therapy: Antithrombotic n Pat ients with thr ombophilias and plans to travel for therapy and prevention of thr ombosis, 9th ed: Ame rican College of an extended period of time (e.g., fl ights 4 hours in Che st Physicians evidence-based clinical practice guidelines. Che st, duration or longer) should be counseled on wearing 141 (2 Sup pl), e15 2S–e184S. loose-fi tting clothing, getting up and walking around, Kearon, C., Akl, E. A., Comerota, A. J., Prandoni, P., Bounameaux, H., drinking lots of fl uids, stretching legs, and wearing Goldhaber, S. Z., … Kahn, S. R.; American College of Chest Physicians. compression stockings. (2012). Ant ithrombotic therapy for VTE disease: Ant ithrombotic therapy and prevention of thr ombosis, 9th ed: Ame rican College of Che st Physicians evidence-based clinical practice guidelines. Che st, 141 (2 Sup pl), e41 9S–e494S. n COMMUNITY RESOURCES Lijfering, W. M., Middeldorp, S., Veeger, N. J., Hamulyák, K., Prins, M. H., Büll er, H. R., & van der M eer, J. (2010). Risk of recurrent venous throm bosis in homozygous carriers and double heterozygous carriers n National Hemophilia Foundation: www.hemophilia of facto r V Lei de n and proth rombin G2021 0A. Circu lation, 121(1 5), .org/NHFWeb/Mai nPgs/Mai nNHF.asp?menuid=180 1706–1712. Mannucci, P. M. (2005). Hemophilia: Treatment options in the twenty-fi rst &contentid=45&ptname=ble eding century. 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