5 and Clotting Disorders Vivienne J. Halpern and Frank C.T. Smith

Bleeding and clotting disorders have major a history of myeloproliferative, myelodysplastic, implications for the effective management of and lymphoproliferative disorders may also vascular patients. Such disorders can influence have increased bleeding through several mech- disease progression, perioperative complica- anisms, which may not appear in routine pre- tions, graft patency, limb salvage, and wound operative testing. Renal failure predisposes to healing. Most of these disorders are relatively bleeding tendencies based on dysfunc- rare, and diagnosis requires an index of clinical tion, whereas, for instance, recent suspicion combined with a need to obtain a may induce predisposing to relevant medical history and appropriate abnormal clotting. An abnormal history of clot- specialized investigations. Correct and timely ting, such as multiple episodes of deep venous treatment may help prevent some of the com- (DVT), may warrant screening for plications associated with these disorders. This . chapter reviews the presentation, diagnosis, Medications can influence both bleeding and management of some of the more common and clotting. Commonly used drugs such as disorders. Medications frequently associated aspirin and other nonsteroidal antiinflamma- with abnormal bleeding or clotting are also tory drugs (NSAIDs) affect platelet function, as discussed. do Aggrenox and Plavix. Herbal remedies and various vitamin combinations may also increase bleeding risks (Table 5.2). Furthermore, malnu- History, Physical and trition and vitamin deficiencies, such as vitamin C deficiency, may contribute to abnormal bleed- Laboratory Evaluation ing tendencies. Estrogen or estrogen-like med- ications including phytoestrogens predispose Recognition of a patient with a bleeding or to thrombotic episodes. PC-SPES is an herbal clotting disorder involves taking an adequate preparation with several components used for history. A screening questionnaire, such as that treatment of prostate carcinoma. It contains provided in Table 5.1 is useful and may help to phytoestrogens, which may induce thrombosis. direct further investigation. Obtaining a history However, it also contains Baikal skull cap of mucosal bleeding involving epistaxis, gum (Scutellaria baicalensis georgi), which is a bleeding, or menorrhagia may be more consis- coumarin (a naturally occurring group of tent with platelet disorders (, substances, structurally similar to warfarin). , etc.) than, for instance, These examples illustrate the importance of bleeding into a joint or muscle, which occurs querying the use of herbal medications as well more commonly with hemophilia. Patients with as more conventional pharmacotherapies when

39 40

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Table 5.1. Screening survey for abnormal bleeding or clotting Do you suffer from a bleeding disorder? Do you have bleeding from the gums or from the nose? Have you ever coughed up or vomited blood? Do you notice easy or spontaneous bruising or does it take you a long time to stop bleeding when cut? Do you have excessive bleeding with menstrual cycles? Have you had any blood in the urine or with stools? Have you had any bleeding into muscles or joints? Have you had a tooth extraction or any other procedure after which bleeding has taken a long time to stop? Have you needed to receive any blood products, plasma, or vitamin K to help stop bleeding? Do you have any problems with your liver or kidneys? Has anyone in your family had any of the above problems? Have you or anyone in your family had a history of clots in the blood vessels, either artery or veins? Do you take oral contraceptives? Do you take aspirin or any medications for pain or arthritis? Do you take any steroid medications? Do you take any herbal medications or vitamins? Do you take Coumadin or other blood thinners? Do you take any medications to prevent stroke or heart attacks? Do you have any blood diseases?

Table 5.2. Common medications, herbs, and vitamins associated with increased bleeding Medication Mechanism of action When to stop preoperatively Medications that may increase bleeding Aspirin Inhibits platelet aggregation via 5–7 days before major surgery thromboxane B2 3–4 days before minor surgery Persantine Inhibits phosphodiesterase to increase Omit dose before surgery cyclic AMP Aggrenox Combined Persantine and aspirin: increased As aspirin effects of aspirin Plavix Irreversible binding to platelet inhibits ADP Stop 7–10 days before surgery binding to platelet NSAIDs Various mechanisms 24 hours prior to surgery Herbs/vitamins that may increase bleeding Feverfew Used for migraines, ? inhibits platelet Stop at least 1 week before surgery aggregation via thromboxane B2, may be irreversible Garlic Inhibits platelet function by inhibiting Stop at least 7–10 days before surgery thromboxane synthesis; may be irreversible Gingko Inhibition of platelet activating factor Stop at least 36 hours prior to surgery Ginseng Inhibits platelet aggregation; prolongs PT Minimum of 24 hours prior to surgery and PTT; may be irreversible Vitamin E May decrease platelet adhesiveness; may Unclear; should stop around effect vascular endothelium 5 days before surgery Willow bark Salicylate precursors Stop 7–10 days before surgery, similar to aspirin Oil of wintergreen Affects platelet function Meadowsweet flower

ADP,adenosine diphosphate; AMP,adenosine monophosphate; NSAID, nonsteroidal antiinflammatory drug; PT, prothrombin time; PTT, partial thromboplastin time. 41

BLEEDING AND CLOTTING DISORDERS assessing the patient with a bleeding or clotting Table 5.3. Thrombophilia screen disorder. Protein C levels Protein S levels Antithrombin III Investigations Activated protein C Standard preoperative investigations for most Lupus anticoagulant vascular surgery patients include prothrombin Anticardiolipin antibody time (PT),international normalized ratio (INR), Antiphospholipid antibody Homocysteine levels activated partial thromboplastin time (aPTT), Prothrombin 20210A mutation platelet count, and activated clotting time Factor VIII and XI levels (ACT). A platelet count of 50,000/mL should ensure adequate hemostasis, whereas a count of 10,000/mL or less may result in spontaneous bleeding. The aPTT evaluates the intrinsic and contact activation pathways of Bleeding Disorders with the exception of factors VII and XIII. This investigation is used to monitor the effects of Bleeding disorders may be secondary to abnor- treatment with heparin. The extrinsic pathway malities of plasma clotting factors, blood (factors II, V, VII, and X, and fibrinogen) is vessels, or . Some hemostatic defects evaluated with the PT and INR. These tests involve more than one of these systems. are employed to check the effectiveness of oral anticoagulation with warfarin. Additional tests should be directed by the history and clinical picture. Table 5.4. Protocol for further investigation of abnormal preoperative blood tests The prevalence of inherited bleeding and clotting disorders is relatively rare. Patients with Repeat abnormal PT/INR, aPTT with 50:50 mix with a recurrent, familial, or juvenile history of DVT; normal plasma (mixing study) arterial thrombosis at a young age or without If then normal, undertake the following investigations: Normal PT/INR, increased aPTT: evidence of atherosclerosis; or thrombosis in an Test for factor deficiency: usually isolated XI, IX,VIII unusual location, such as mesenteric or cerebral Increased PT/INR, normal aPTT: veins, should be assessed for a hypercoagulable Test for factor deficiency: isolated VII or can be state.Recurrent graft failure whether in a bypass multiple or an arteriovenous fistula, when not explained Test for liver abnormalities by the presence of an anatomical lesion, may Look for vitamin K deficiency (malnourished patient, also imply a prothrombotic state. Components patient on prolonged antibiotics) of a thrombophilia screen include those listed in Increased PT/INR and aPTT: Table 5.3 (Donaldson et al., 1990). Test for factor deficiency: isolated X,V,prothrombin, Patients with a history of abnormal bleeding, fibrinogen, or can be multiple If abnormal mixing study, undertake the following but not requiring medication, should undergo investigations: routine preoperative investigations as above. Normal PT/INR, increased aPTT: Excessive or prolonged bleeding during surgical Test for inhibitor activity, especially for XI, IX,VIII procedures where routine preoperative testing Test for nonspecific inhibitors, e.g., antiphospholipid of PT,aPTT,and platelet counts was normal may antibodies represent a platelet functional abnormality, a Increased PT/INR, normal aPTT: dysfibrinogenemia, factor XIII deficiency, vas- Test for factor VII inhibitor cular endothelial disorders, other mild factor Test for nonspecific inhibitors (rarely cause isolated deficiencies (if >25% of factor present), or a- increase in PT/INR) antiplasmin deficiency. Surreptitious use of Increased PT/INR and aPTT Test for inhibitors of X,V,prothrombin, fibrinogen medication might also be considered. Where Test for nonspecific inhibitors abnormal preoperative investigations are encountered, there is a rationale for further aPTT, activated partial thromboplastin time; INR, international nor- tests. A protocol is suggested in Table 5.4. malized ratio; PT, prothrombin time. 42

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In normal hemostasis, the blood vessel con- fibrinogen to generate fibrin monomers, which stricts in response to injury to reduce bleeding. then polymerize and link to one another to form Circulating platelets adhere to subendothelial a chemically stable clot. Thrombin also feeds collagen that is exposed by injury, promoted by back to activate cofactors VIII and V, thereby release of tissue factor (TF) from the damaged amplifying the coagulation mechanism. vessel wall. Platelets bind von Willebrand factor Together platelet aggregates and fibrin form the (vWF) at the glycoprotein Ib receptor, stabiliz- clot that achieves hemostasis. The coagulation ing adhesion. Fibrinogen binds to platelet gly- cascade is illustrated in Figure 5.1. Any disrup- coprotein IIb/IIIa receptors forming bridges tion of these pathways may lead to increased between adjacent platelets and causing aggre- bleeding. gation. Activated platelets also release potent Features in the history and physical examina- aggregating agents to recruit more platelets. tion that may help to differentiate among factor Coagulation is initiated through the extrinsic deficiencies, platelet disorders, and endothe- pathway. Exposed endothelium releases TF, lial (blood vessel) dysfunction are listed in which complexes with and activates factor VII. Table 5.5. Factor VIIa then activates both the common pathway and the intrinsic pathway. The intrin- sic pathway requires factor VIII and factor IX to Inherited Disorders proceed to the common pathway. Von Wille- of Coagulation brand factor also forms a noncovalent bond with factor VIII and is essential for its survival Factor Deficiencies in the circulation. Von Willebrand factor also potentiates factor VIII activity in clot formation Hemophilia A and B represent 80% of inherited and protects it from proteolysis. In the final step bleeding diatheses. These are both sex-linked of the coagulation pathway, thrombin cleaves recessive deficiencies affecting mostly males.

Figure 5.1. The coagulation cascade. Under physiological conditions, tissue factor is not exposed to blood. However, after injury, tissue factor is exposed to blood and activates the extrinsic pathway by acting in concert with activated VII and phospholipids to convert factor IX to IXa and factor X to Xa.The “intrinsic pathway” includes activation of factor XII to XIIa, which activates factor XI to XIa, IX to IXa, and X to Xa. Factor Xa is the active cat- alytic ingredient of the prothrombinase complex, which includes factor Va and phospholipase and converts prothrombin to thrombin. Thrombin is a protease that cleaves fibrinogen to fibrin. The result- ing fibrin monomers polymerize, forming a clot. 43

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Table 5.5. The relationship of factor disorders, platelet and blood vessel (endothelial) dysfunction to aspects of clinical presentation Clinical picture Factor disorder Platelet dysfunction Endothelial dysfunction Onset of bleeding Delayed Immediate Immediate Duration of bleeding Prolonged Short Variable Precipitant of bleeding Often spontaneous Trauma Variable Site Joints, muscle, viscera Skin, mucous membranes, GI tract Skin, GI tract Family history Usually present (unless factor Absent Usually absent inhibitor) Drug-related Rarely Often Sometimes Sex predominance Usually male Often female Usually female Response to focal pressure No response Sometimes responds Responds Platelet count Normal Normal, low, or high Normal Prothrombin time Abnormal in cases of factor II, Normal Normal VII, IX, and X deficiency (and inhibitors) Partial Thromboplastin Abnormal with factor VIII Normal Normal time or IX deficiency (and inhibitors)

GI, gastrointestinal.

They are caused by factor VIII (classic hemo- concentrates are not available, cryoprecipitate philia) and factor IX (Christmas disease) or fresh frozen plasma (FFP) may be used. deficiencies, respectively. Hemophilia A is four The treatment for hemophilia B is similar, to six times more common than hemophilia using specific factor IX concentrates or factor IX B. Together they have a prevalence of about complex transfusion. The factor IX complex 20/100,000 in the United States and 9/100,000 to contains one unit of factor IX per milligram of 15/100,000 in Great Britain. protein with varying amounts of other vitamin The risk for bleeding depends on the degree K–dependent proteins. The concentrates are of factor deficiency. At levels less than 1% to preferred treatment. Again, loading dose and 2% of normal (severe disease), spontaneous maintenance doses are administered according bleeding is likely to occur and the aPTT is pro- to the given situation. longed. Patients may present with spontane- Another factor deficiency (vWF), which can ous soft tissue or intramuscular hemorrhage, present like hemophilia, occurs in von Wille- hemarthroses, hematuria, and spontaneous brand disease (vWD). Overall, this is the most retroperitoneal bleeding. Patients with mild common bleeding disorder with an incidence of (>5%) and moderate (1% to 5%) disease usually up to 1% in some populations. There are three have bleeding only with injury or surgery. subtypes of VWD, the most severe and uncom- Patients may have increased bleeding with levels mon being type 3. In this form, vWF in plasma above 25%, but these deficiencies are hard to and platelets is markedly reduced or absent, detect as the aPTT will be normal. thereby reducing factor VIII activity to 1% to Treatment for hemophilia A involves infusion 10% of normal. Patients can present with spon- of recombinant factor VIII concentrates of taneous or severe bleeding. Inheritance is auto- which several are commercially available, the somal recessive. Type 1 is the most common amount depending on the deficiency present. type, representing around 70% of cases. vWF is This includes a loading dose and then a main- reduced to the range of 20% to 50% with a con- tenance dose for the appropriate period comitant reduction of factor VIII activity. The depending on the location of the bleed if spon- structure of vWF is generally normal in this taneous or perioperative. For milder hemophilia type, and inheritance is autosomal dominant. or cases of mild hemorrhage, or if factor VIII Patients usually present with mild to moderate 44

VASCULAR SURGERY bleeding diatheses, and the levels of vWF do not ents with abnormal bruising, soft tissue hemor- necessarily correlate with clinical symptoms. rhage, and epistaxis. Bleeding from the umbili- This may be because some patients with type 1 cal stump at the time of birth is common. VWD have reduced levels of both plasma and Women commonly have abnormally heavy platelet vWF, whereas some just have reduced menstrual bleeding and postpartum bleeding. plasma levels. Most cases present in adulthood. Fresh frozen Type 2 VWD is divided into further subtypes plasma is the mainstay of treatment. 2A, 2B, 2M, and 2N based on the site of the Factor VII deficiency is inherited as an auto- genetic mutation. Type 2A is the most common somal-recessive disorder and affects males and and accounts for around 10% of all vWF females equally with an incidence of about 1 in deficiency cases. Inheritance is autosomal dom- 500,000. Clinical manifestations can be similar inant. The largest multimers of vWF are absent, to those of hemophilia with severe deficiencies and this leads to a lack of platelet binding.Activ- (<1% level) as the factor Va/tissue factor com- ity of factor VIII, however, can be near normal plex is the key initiator of coagulation in vivo. in this subgroup. Clinical presentations in this However, about half of patients are asymp- group are therefore variable. In type 2B, patients tomatic, and levels of factor V do not correlate lack multimers in the plasma but have near- well with clinical manifestations. Interestingly, normal levels in platelets. However, these diminished or defective function of tissue patients are usually thrombocytopenic, which factor has not been documented as a cause of can be made worse with exercise, stress, preg- decreased factor VII activity. The most common nancy, or advanced age. Levels of factor VIII are presentations include easy bruising, soft tissue low to normal. Presentation is again variable hemorrhage, and menorrhagia in women. and inheritance is autosomal dominant. Type Patients with levels less than 1% of normal may 2M is very rare and has abnormal multimers as present like hemophiliacs with pathology its cause of abnormal coagulation. This has not including intracranial bleeds and hemarthroses. been well defined in terms of inheritance. Type Current treatment in the United States is with 2N is inherited as an autosomal-recessive con- FFP, although factor VII concentrates and dition and sometimes mimics mild hemophilia. recombinant factor VII are available in Europe. These patients have normal vWF multimers and Factor X deficiency is transmitted as an auto- normal vWF activity but reduced factor VIII somal-recessive trait and has an estimated inci- activity due to poor binding between vWF and dence of 1 in 500,000. Usually those with greater factor VIII. This variant should be considered than 15% of normal levels do not have severe in the differential diagnosis of factor VIII bleeding, although bleeding with major surgery deficiency, especially if the patient is female or trauma may occur. However, with more and other aspects of the pedigree support severe deficiencies, severe bleeding episodes autosomal-recessive inheritance rather than similar to those seen in hemophilia may occur, sex-linked. Von Willebrand disease may be including hemarthroses, retroperitoneal treated with desmopressin acetate [deamino- , hematuria, pseudotumors, and 8-D-arginine vasopressin (DDAVP)], which menorrhagia. Another cause of factor X probably increases vWF, tissue plasminogen deficiency is amyloidosis. In this situation, activator (tPA), and factor VIII secretion from transfusion of factor X is not helpful because of stored sources. Some of the subtypes may also its absorption by the extracellular amyloid. require factor replacement. More recent treat- Improvement does not occur unless the amyloi- ments include recombinant factor VIII/vWF dosis resolves, although splenectomy may help concentrates, which reduce risks of transmis- by debulking splenic amyloid. Treatment for sion of infection. standard factor X deficiency is with FFP or pro- Other factor deficiencies are quite rare. Factor thrombin complex concentrates. Pure factor X V deficiency is inherited as an autosomal- concentrates are not available for commercial recessive trait. It has a wide range of clinical use yet. Concentrations of 10% to 15% give manifestations but seems to have less bleed- adequate hemostasis. Overtransfusion can lead ing associated with it than hemophilia A. Severe to thromboembolic events and disseminated factor V deficiency (levels <1% of normal) pres- intravascular coagulation (DIC). 45

BLEEDING AND CLOTTING DISORDERS

Factor XI deficiency occurs mostly in control may be helpful with menorrhagia, and Ashkenazi Jews with a gene frequency in this DDAVP may be useful for prophylaxis prior to population of 4.3%. Bleeding usually occurs procedures. with levels £20% of normal and usually only Deficiencies of platelet collagen receptors after major trauma or surgery. Rarely, there is also exist but do not cause significant bleeding, spontaneous bleeding as seen with hemophilia, although they may prolong bleeding time. although soft tissue hemorrhage, epistaxis, and Disorders of platelet aggregation include a bleeding after dental extraction and with major deficiency of IIb/IIIa, known as Glanzmann’s surgical procedures may occur. Menorrhagia thrombasthenia, characterized by a prolonged may occur in females. Bleeding risk is signifi- bleeding time and abnormal clot retraction. It is cantly increased in patients taking aspirin. inherited as an autosomal-recessive trait in Treatment when necessary is with FFP and with clusters of disease. It presents with mucocuta- cryoprecipitate-poor plasma. Factor XI concen- neous bleeding in the neonatal period or in trates are available. infancy and occasionally as bleeding following circumcision. Epistaxis and are the Fibrinogen Abnormalities most common presentation. Severe bleeding with menses may be encountered. If it is unrec- The dysfibrinogenemia are mostly inheritable ognized, significant bleeding with surgery or abnormalities of fibrinogen structure and func- trauma will occur if the patient is not transfused tion. Clinically, many patients are asymptomatic with normal platelets. Platelet counts and but some present with either bleeding or a smears are normal, but bleeding times are very thromboembolic event or both. There are mul- prolonged. Platelet aggregation is absent in tiple different abnormalities too diverse to dis- normal testing except with epinephrine, where cuss in detail in this chapter because they have it is weak. Platelet secretion is normal with variable inheritance, affect different portions of strong agonists like thrombin but is absent with the molecule, and have different manifestations. weak stimulators like epinephrine and adeno- Suffice it to say they should be considered in sine diphosphate (ADP). Clot retraction is patients with a history of bleeding and abnor- either absent or reduced. Treatment is under- mal coagulation testing. Inheritable afibrino- taken with platelet transfusion if bleeding is genemias and hypofibrinogenemias also exist. present. Leukocyte-depleted platelets may Patients present with bleeding episodes in the reduce risks with future transfusions.Hormonal afibrinogenemias and with hypofibrinogene- therapy is useful with menorrhagia. Regular mias with levels above 50mg/dL. Afibrinogene- dental care is important to reduce the risk of mias are inherited as an autosomal-recessive gingival bleeding but Amicar (e-aminocaproic trait but hypofibrinogenemias are less pre- acid) may be valuable in helping to control dictable. Bleeding complications when they bleeding after dental extractions. occur can be severe, with a high incidence of Disorders of platelet secretion are related to bleeding in the neonatal period. This may result deficiencies in one or more of the four types in death in about one third of patients with of platelet granules or to abnormalities in the severe hypo- and afibrinogenemias. secretory mechanism. Platelets have four types of granules: Platelet Disorders 1. Dense or d granules containing ADP, Bernard-Soulier syndrome (glycoprotein Ib-IX adenosine triphosphate (ATP), calcium, deficiency) is a disorder of platelet adhesion and serotonin, and pyrophosphates is a relatively rare cause of bleeding. It is char- 2. a-granules containing a variety of pro- acterized by a prolonged bleeding time, large teins, some of which are obtained from platelets, and thrombocytopenia due to an the plasma and others synthesized by inability to adhere to vWF in the subendothelial ; these include fibrinogen, matrix. It presents in infancy or childhood with vWF, albumin, factor V, immunoglobulin epistaxis, ecchymosis, and bleeding gums. Treat- G (IgG), fibronectin, and proteinase ment is with platelet transfusion. Hormonal inhibitors from the plasma and platelet 46

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factor-4, b-thromboglobulin, platelet- deficiency of a-granules. The content of lysoso- derived growth factor, and throm- mal hydrolase is normal, but thrombin-induced bospondin from megakaryocytes acid hydrolase secretion is impaired, which can 3. Lysosomes containing acid hydrolase only be corrected with ADP. Patients present 4. Microperoxisomes containing peroxidase with mild to moderate bleeding. Platelet counts activity are usually normal, but bleeding times are prolonged. The quantity of thromboxane B2, Secretory dysfunction usually results in mild a metabolite of thromboxane A1, is reduced. to moderate bleeding manifested by easy bruis- Secondary aggregation induced by ADP and ing, menorrhagia, and excessive postoperative epinephrine is reduced. Collagen-induced or peripartum bleeding. Testing reveals a pro- aggregation is abnormal at low concentrations longed bleeding time, a decreased second wave of collagen but is normal with high concentra- of aggregation with ADP and epinephrine tions. Therapy requires transfusions of normal stimulation, and decreased aggregation with platelets if there is massive bleeding. Otherwise, collagen. Secretory dysfunction should be dif- DDAVP is the initial treatment and cryoprecip- ferentiated from acquired disorders with acetyl- itate can also be used. In one study, pred- salicylic acid (ASA) use, uremia, and multiple nisolone seemed to reduce bleeding in patients myeloma, and from VWD. with inherited platelet disorders but not in Gray platelet syndrome is an a-granule patients with thrombasthenia or ASA use. deficiency. Platelets occur without these gran- Platelet function in patients with inherited ules but with vacuoles and small a-granule pre- disorders of platelet secretion resembles that of cursors containing material that stain positive patients receiving platelet function inhibitors for vWF and fibrinogen. Additionally, the vac- like ASA. These disorders are a heterogeneous uoles and these precursors contain P-selectin collection of abnormalities of secretion- and GIIb-IIIa. These factors indicate the pres- response adhesion. In families where these dis- ence of a-granules,but the normal proteins they orders have been noted, the pattern appears to contain cannot be packaged. Other granules be autosomal dominant. A prolonged bleeding are present in normal quantity. Patients have time and marked impairment of aggregation a history of mild to moderate mucocutaneous and secretion in response to ADP, epinephrine, bleeding. They have prolonged bleeding times and low concentrations of collagen occur. with moderate thrombocytopenia (60,000 to Stronger agonists like high levels of collagen, 100,000), reticular fibrosis of the bone marrow, however, may induce a near-normal or normal and large platelets that appear gray on Wright- response. Treatment is the same as that for stained blood smears–hence the name. Platelet patients with platelet storage disorders. aggregation studies are variable. Treatment requires transfusion of normal platelets and at Vascular Defects least one patient responded to DDAVP. The Quebec platelet disorder is extremely rare and Inheritable conditions that lead to defects in the again involves a-granules that appear grossly vascular bed include Marfan’s syndrome and normal but are deficient in many of the proteins Osler-Weber-Rendu disease. These may increase normally seen including factor V, fibrinogen, bleeding through mechanisms that are not vWF, and fibronectin. Patients present similarly entirely clear. to the gray platelet syndrome and are treated the same way. Dense granule deficiency or d-storage pool Acquired Disorders disease is a heterogeneous group of disorders, which can be divided into deficiency states asso- of Coagulation ciated with albinism and those in otherwise normal patients. With albinism, the disease is This group of disorders includes factor related to a qualitative deficiency in these gran- inhibitors as well as acquired diseases that affect ules. In nonalbinos, the number of granules platelet and endothelial function. Factor is near normal. In some of these nonalbino inhibitory proteins can be classified as neutral- patients it is associated with a variable izing, nonneutralizing, or altering. They are 47

BLEEDING AND CLOTTING DISORDERS usually autoantibodies. The most common Hypercoagulable States factor inhibitor is factor VIII, often referred to as acquired hemophilia, but inhibitors have Like bleeding disorders, these states can be been found to thrombin and prothrombin, categorized as inherited or acquired (Table 5.6). fibrinogen, thrombin and prothrombin, fibrino- Hyperhomocystinemia, however, can be either gen, vWF, and factors V, VII, IX, X, and XI as inherited or acquired. Indications for throm- well (Fig. 5.1). These are seen in response bophilia screening have already been outlined to inflammatory diseases such as rheumatoid and the components of such a screen are arthritis and other autoimmune diseases like referred to in Table 5.3. For most of the hyper- systemic lupus erythematosus (SLE) and coagulable states, treatment involves the use of Sjögren’s syndrome and even inflammatory LMWH or unfractionated heparin with conver- bowel syndrome. They also appear during preg- sion to oral warfarin. Often, if the patient has nancy and the puerperium, as well as with already had a thrombotic episode, anticoagula- various tumors. They may be associated with a tion is undertaken for life. variety of medications including aminoglyco- sides, penicillins, valorous acid, etc. They are also seen with cirrhosis and major surgery. Interestingly, factors V and X and thrombin Table 5.6. Differential diagnosis for hypercoagulable states inhibitors have been seen following the use of topical thrombin and fibrin glue, usually after Inherited (primary) multiple exposures. Not only can this lead to Protein C and S deficiencies Antithrombin III deficiency perioperative bleeding, but also inhibitors of Factor V Leiden mutation leading to activated factor X can interfere with monitoring of low- protein C resistance molecular-weight heparin (LMWH) anticoagu- Prothrombin 20210A gene mutation lation with the antifactor Xa assay. Heparin cofactor II deficiency and other heparin Factor inhibitors may lead to increased bleed- binding proteins ing and, rarely, spontaneous bleeding. Most Cystathionine synthase deficiency conditions are initially detected as a prolonga- (hyperhomocystinemia) tion of one or more of the coagulation screen- Dysfibrinogenemia ing tests—PT/INR/aPTT—or thrombin time. Dys- and hypoplasminogenemia To differentiate between the different types of Acquired (secondary) inhibitors, a clotting study should be done on a Cancer 1:1 mixture of the patient’s plasma with normal Pregnancy plasma. A lack of correction of clotting time Oral contraceptives and other hormone replacement indicates a neutralizing antibody. Vigilance in therapy (HRT) testing is essential because at body temperature Myeloproliferative disorders Hyperlipidemia some studies initially correct and then return to Diabetes mellitus a prolonged state after an hour. This is particu- Vasculitis larly true of factor V and VIII inhibitors. Antiphospholipid syndrome (lupus anticoagulant, If the mixing study corrects, this suggests the anticardiolipin antibodies) presence of a nonneutralizing antibody that Postoperative states/trauma may facilitate clearance of the clotting factor Immobilization from circulation. The antibody should be Nephrotic syndrome isolated to differentiate its presence from a Congestive heart failure deficiency of the factor. Increased levels of factor VII and fibrinogen Treatment of bleeding includes infusion of Obesity Heparin thrombocytopenia factors to levels that overwhelm the antibodies Anticancer drugs (bleomycin, vinca alkaloids, and return the coagulation profile to normal. mitomycin, etc.) Long-term treatment includes immunosup- Paroxysmal nocturnal hemoglobinuria pression with steroids or other agents and Age plasmapheresis with immunoabsorption with Undetermined Ig-Therasorb. The latter can be used in con- Elevated factor XI levels and VIII levels junction with transfusion. 48

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Inherited Protein C and S deficiencies have relatively the same incidence. They both result from Inherited hypercoagulable states account for 5% numerous different mutations. A heterozygote to 15% of patients with venous thromboem- pattern is much more frequent as homozygotes bolism (VTE). The most common appear to be present soon after birth with the factor V Leiden mutation followed by the or massive venous thrombosis. Protein C has mutation of the pro- type I and type II deficiencies. Type I deficien- thrombin gene among the white population, but cies are those mutations causing a decrease in these are rare in Asians and Africans. Table 5.7 levels and in activity; most of these are missense shows the overall incidence of the various inher- mutations. Type II deficiencies are those in ited hypercoagulable states. These are estimates which levels are normal but activity is affected; from several studies and vary with ethnic back- most of these are point mutations. Patients with ground and location. protein C deficiency tend to present with VTE Factor V Leiden, also known as activated pro- and fetal loss and rarely with arterial thrombo- tein C resistance (APCR), results from a point sis. Protein S deficiency is harder to define. mutation in the factor V gene, leading to a loss Many studies have shown the coexistence of of protein C cleavage sites (Ouriel et al., 1996). protein S deficiency with APCR in as high as The consequence of this is impaired activation 40% of the patient population studied. This of protein C. The most common presentations makes it hard to determine which is more are VTE and fetal loss. It usually does not result important. However, there are more numerous in arterial thrombosis unless other risk factors reports of arterial thrombosis with protein S are also present, for example smoking. deficiency, including stokes, compared to Homozygotes have an 80-fold increased risk of protein C deficiency. Many conditions may DVT, and heterozygotes have much less. Many result in lowered levels of these proteins, partic- patients with factor V Leiden remain asympto- ularly protein S (for instance in liver disease, matic, and about 60% of those who present with nephrotic syndrome, pregnancy, sepsis, etc.) thrombosis have another risk factor such as use and some medications like HRT may have the of oral contraceptives (OCs) or hormone same effect. Therefore, measurement of levels of replacement therapy (HRT). The overall risk of protein S may need to be repeated to ensure VTE is 3% to 7%. accuracy as well as to allow checking for specific The prothrombin 20210A gene mutation genetic defects. Overall, as many as 50% of appears in 2.3% of healthy control patients. The heterozygotes for protein C and S deficiencies incidence is twice as high in southern Euro- develop VTE up to the age of 50 years. peans compared to northern Europeans and is Antithrombin III (AT III) deficiency occurs as rare in Asians and Africans. The mutation an autosomal-dominant disorder and in 1/5000 increases prothrombin levels and activity. The healthy blood donors. It may also have type I relative risk of clotting is two to three times that and type II deficiencies. The type I deficiencies of normal individuals. are caused by both gene segment mutations as well as point mutations, whereas the type II deficiencies are caused mostly by point muta- tions. Most patients are heterozygotes, Table 5.7. Incidence of inherited disorders as homozygous deficiency is probably incom- Disorder Incidence patible with life unless it is a type II deficiency Factor V Leiden (activated protein 25% of the heparin-binding site. All types are at C resistance) increased risk of VTE, with as many as 80% of 14% heterozygotes by age 50 having an episode of Protein C deficiency 10% VTE. Like protein C and S, AT III deficiency can Protein S deficiency 10% be acquired in association with the medical con- Prothrombin G20210A 5–10% ditions described above. Increased homocysteine 5–10% Hyperhomocystinemia and homocystinuria Dysfibrinogenemia 1.5% have both been described as associated with Antithrombin III <1% (1/250–500) Dys- or hypoplasminogenemia 1–3% VTE and arterial thrombotic events (Nehler et al., 1997). Homocysteine is an intermediate of 49

BLEEDING AND CLOTTING DISORDERS methionine metabolism. Elevated levels arise be difficult to monitor with a baseline elevated from both genetic defects affecting the transsul- aPTT. Acquired dysfibrinogenemia is seen with furation or remethylation pathways as well as liver disease, multiple myeloma, Waldenström’s with folate, B6 and B12 deficiency, renal failure, macroglobulinemia, and autoimmune diseases; hypothyroidism, increased age, and smoking. the end result of all of these conditions is altered Homozygotes for cystathionine b-synthase polymerization or delayed fibrinopeptide deficiency and methylene-tetrahydrofolate re- release. ductase may have severe vascular disease and Dys- or hypoplasminogenemias occur even appear even in childhood. As many as 60% have more rarely. These are usually autosomal dom- thromboembolic events before age 40 and 50% inant. Patients usually present in their late teens, by age 29. Heterozygotes have a high incidence most commonly with VTE. Routine tests are of premature arterial occlusive disease, which normal. There are also rare congenital deficien- may represent as much as 1/70 of the normal cies of tPA and congenital increases of plas- population. However, the most common cause is minogen activator inhibitor (PAI). These dietary folate and B6 and B12 deficiencies, which disorders are more commonly acquired with account for around two thirds of the cases diabetes, inflammatory bowel disease, and coro- of hyperhomocystinemia. Measuring fasting nary atherosclerosis. homocysteine plasma levels establishes the Factor XII is involved with plasmin genera- diagnosis. The mechanism of thrombosis is tion. There is an autosomal-dominant genetic thought to involve several mechanisms includ- deficiency, which is quite rare but results in both ing induction of endothelial cell tissue factor VTE and arterial thrombosis. About 8% of activity, inhibition of thrombomodulin, deficient patients have thrombotic episodes. An decreased AT III activity, decreased protein C elevated PTT is present, but it corrects with the activation, increased factor V activity, and addition of normal plasma. Treatment is with increased affinity of lipoprotein (a) and fibrin. LMWH and then warfarin. Standard unfrac- Dietary supplements with B6,B12, and folate help tionated heparin again is difficult to monitor lower the homocysteine levels, but unfortu- with baseline elevated PTT. nately this may not reduce the risk of thrombo- Heparin factor II and other heparin-binding sis and therefore anticoagulation may also be molecules are found to have deficiencies; how- indicated. ever, the association with thrombotic events is The dysfibrinogenemias can cause thrombo- weak. The same is true for thrombomodulin sis as well as bleeding in around 20% of patients. defects. The conversion of fibrinogen to fibrin consists The sticky platelet syndrome is a rare of three main steps: release of fibrinopeptides A autosomal-dominant disorder that results in and B from the alpha and beta chains to form platelets that aggregate more readily with epi- fibrin monomers, followed by polymerization of nephrine or ADP.Venous and arterial thrombo- these monomers to a visible fibrin gel, which is sis occur, and retinal vascular thrombosis then stabilized by activated factor XIII. Fibrin appears to be associated with this entity. Treat- may then be broken down via fibrinolysis path- ment is initially with low-dose aspirin. If aggre- ways. Inherited dysfibrinogenemias result from gation does not normalize, then this dose can be mutations that alter one or more of these steps. increased to 325mg daily. Clopidogrel (Plavix) They are usually autosomal dominant. One may provides an alternative potential therapy. be suspicious if there is a prolongation of the Another platelet defect is the Wein-Penzing PT and PTT. Thrombosis can occur secondary deficit. This is a deficiency of the lipoxygenase to either an abnormal fibrinogen with reduced metabolic pathway resulting in an increase in binding to thrombin and increased thrombin the cyclooxygenase pathway and therefore ele- levels, or decreased fibrinolysis. It is relatively vated thromboxane levels. Platelets are thus in a rare for this to be the sole cause of VTE (around state of increased activation. 0.8% of VTE) and is frequently associated with Other abnormalities that may be genetically precipitating risk factors such as HRT, pro- based include elevated factor XI and factor XIII longed bed rest, etc. Treatment remains anti- levels. Both these groups seem to have increased coagulation, but it is preferable initially to use risk of VTE, and the level of increased risk LMWH, as unfractionated heparin activity can appears to be proportional to the increase in the 50

VASCULAR SURGERY levels of these factors. Hormone replacement and may have hemolytic anemia (14–23%) and therapy and pregnancy are also implicated in livedo reticularis (11–22%). Renal involvement raised levels of these factors. Patients on HRT or may occur, and when it does it usually results in OC and with elevated factor VIII levels have a hypertension. 10-fold increased risk of VTE compared to those Catastrophic APA syndrome is acute, and without these risk factors. multiple simultaneous vascular thrombotic events can occur throughout the body. Small Acquired vessels of multiple organs are often affected.The syndrome may result in death. In 78% of these The most common cause in this group of con- patients the kidneys are involved, followed by ditions is the antiphospholipid antibody (APA) the lungs in 66%, the central nervous system in syndrome (Fligelstone et al., 1995). These anti- 56%, the heart in 50%, and the skin in 50%. Dis- bodies bind to plasma proteins that have a high seminated intravascular coagulation is a com- affinity for phospholipid surfaces. The most ponent of this event in 25% of patients. The common of these proteins are the lupus antico- mortality rate is 50%, usually due to multisys- agulant (LA), anticardiolipin (ACL) antibodies, tem organ failure. The optimal treatment is and anti–b2-glycoprotein-1 antibodies (B2G). not well defined but includes, in various com- These are usually acquired. Lupus anticoagulant binations of anticoagulation, steroids and either can be suspected if there is an elevated PTT,and plasmapheresis or intravenous immune globu- ACL and B2G are detected only by immunoas- lin. The condition can be precipitated by says. These conditions can be primary, that is, surgery, infection, withdrawal of anticoagula- not associated with other autoimmune condi- tion therapy, and drugs, including oral tions. They can present with VTE or arterial contraceptives. thrombosis as well as fetal demise. Antiphos- Heparin-induced thrombocytopenia (HIT) pholipid antibodies may be associated with also warrants some discussion. The entity was infections, cancer, and even certain drugs and first described by Towne in 1979 as the white hemodialysis, but these are usually IgM as clot syndrome and occurs in 1% to 30% of opposed to IgG antibodies and are present in patients on heparin. Heparin-induced thrombo- low levels. They do not seem to be associated cytopenia is diagnosed by one or more HIT- with thrombotic events. associated clinical events, such as thrombosis of The overall incidence is 1% to 5% of the a graft, and the presence of heparin antibodies. normal population. The incidence increases Various tests (Table 5.8) are now available to with age and coexisting chronic disease. The help in making the diagnosis (Warkentin and incidence in patients with SLE is 12% to 30% for Greinacher, 2004). The problem is that the onset ACL and 15% to 34% for LA. The risk of throm- of HIT is often delayed or seen after multiple bosis in patients found to have these autoanti- exposures to heparin, where the first few expo- bodies is unclear but seems to be increased in sures resulted in minimal or no decrease in those with a history of previous thrombosis, platelets. Additionally, the delayed onset may with LA and with increased IgG ACL—each of be seen only after the offending heparin has which increases the risk of thrombosis fivefold. been removed. The initial exposure can be The persistent presence of APA also increases as inconsequential as heparin lock flushes to the risk of thrombosis. These patients have a maintain the patency of intravenous lines or high proportion of pregnancy losses as well as standard subcutaneous heparin prophylaxis. an increased incidence of premature births. Treatment includes stopping the heparin. These patients are best treated with ASA plus Coumadin alone is not a good treatment due to heparin to achieve live births. the hypercoagulable period before anticoagula- Interestingly, not all arterial episodes of tion is achieved, leading to potential skin necro- ischemia or infarction are due to primary sis. Additional therapy is switching to hirudin thrombosis. Up to 63% of patients with APA (Refludan), argatroban (Novastartan), or dana- syndrome have coexisting valve abnormalities parnol (Orgaran). Additionally, some of the on echocardiography and 4% have vegetations GIIb-IIIa inhibitors have been successfully of the mitral or aortic valve. These patients may employed in this situation. Newer agents are also be thrombocytopenic (as many as 40–50%) under investigation including a recently Food 51

BLEEDING AND CLOTTING DISORDERS

Table 5.8. Testing for heparin-induced thrombocytopenia Sensitivity Specificity Positive Negative (%) (%) predictive value predictive value (%) (%) PF4 + heparin coated plate: anti IgG, IgA, 97 86 93 91 and IgM Serotonin release 88 100 100 81 Platelet aggregation 91 77 89 81

Ig, immunoglobulin; PF4, platelet factor 4. and Drug Administration (FDA)-approved oral appropriate anticoagulation with the exception anti–factor Xa agent. of catastrophic amyotrophic lateral sclerosis Most malignancies can be associated with a (ALS). The cumulative risks of different inher- higher incidence of thromboembolic events, in ited and acquired thrombophilic factors have particular, adenocarcinoma and myeloprolifer- appreciable significance. Individual personal- ative disorders. ized risk profiles for thrombotic events may have a role to play for patients in the future. An awareness of the broad extent of these condi- tions helps vascular surgeons provide optimal Conclusion management for their patients. Bleeding and clotting disorders are encountered sufficiently frequently in vascular surgical prac- References tice to encourage an awareness of the range of disorders and of the different available thera- Donaldson MC, Weinberg DS, Belkin M, Whittemore AD, peutic modalities. A high index of suspicion, a Mannick JA. (1990) J Vasc Surg 11:825–31. comprehensive medical history, and judicious Fligelstone LJ, Cachia PG, Ralis H, et al. (1995) Eur J Vasc employment of investigations help guide the Endovasc Surg 9:277–83. experienced clinician to a correct diagnosis.The Nehler MR, Taylor LM Jr, Porter JM. (1997) Cardiovasc Surg 5:559–67. bleeding disorders are varied, and each requires Ouriel K, Green RM, DeWeese JA, Cimino C. (1996) J Vasc specific management. The majority of throm- Surg 23:46–51, discussion 51–2. bophilic tendencies may simply be treated with Warkentin TE, Greinacher A. (2004) Chest 126:311S–337S.