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The caput medusae of hypercoagulability

Donald Silver, MD, and Angela Vouyouka, MD, Columbia, Mo

Thrombosis may be the most common cause of death in the United States. Virchow pos- tulated, approximately 150 years ago, that intravascular was caused by changes of the vessel wall, by reduction in blood flow, and by alteration of the chemical composition of the blood. The hypercoagulability component of the Virchow triad has, until recently, been poorly defined. During the past 40 years, a number of acquired and congenital hypercoagulable disorders have been described so that currently the cause for thrombotic events can be determined in many patients. The hypercoagulable-related thromboses are usually venous but may, less often, be arterial, and the thromboses often are the cause of significant morbidity and mortality. The vascular surgeon often partic- ipates in the management of hypercoagulable disorders. This review of hypercoagulable disorders is presented with the hope that the early recognition of these disorders will lead to the appropriate diagnosis and proper management of hypercoagulable-related thromboses. (J Vasc Surg 2000;31:396-405.)

The hypercoagulable syndromes remind one of in unusual locations. The vascular surgeon also occa- the numerous poisonous snakes that sprang from the sionally encounters patients with unexplained arteri- blood of Medusa (the mortal daughter of the sea al thromboses or with unexplained arterial recon- god Phorcus) after her head was cut off by the sword structive failures. Many of these patients will have of Perseus. Although the hypercoagulable syn- congenital or acquired hypercoagulable disorders dromes are not snakes, they are numerous and that sensitize them to prothrombotic conditions that potentially dangerous, and new disorders spring are tolerated by most individuals. forth at frequent intervals. We review the pathophysiology and management Most investigators would agree that thrombosis of the hypercoagulable disorders that are most likely is the cause of, or is related to the cause of, most to be of concern to vascular surgeons. If a disorder deaths. Bick and Kaplan1 have estimated that almost can be recognized, then the appropriate manage- two million individuals die in the United States each ment may control the thrombotic tendency and pre- year from “an arterial or or the vent future thromboses. consequences thereof” and that more than “…50% of all patients harbor a congenital or acquired blood ACQUIRED HYPERCOAGULABLE DISOR- coagulation protein or platelet defect that caused the DERS (TABLE I) thrombotic event.” Stassen and Nystrom2 suggested Technical failures (badly diseased vessels, inade- in 1997 that the “…annual hospitalizations due to quate inflow or outflow, kinked or twisted grafts, all thrombotic disease exceeded 5,100,000 in the etc) remain the most common cause of the early United States…” and that the annual costs for these arterial reconstructive failures encountered by vascu- disorders were “…about $13 billion.” lar surgeons and can be reduced with the appropri- Physicians frequently encounter patients who ate preoperative planning and careful attention to have venous thromboses without obvious risk fac- operative detail. Most of the operative procedures tors, who have recurrent venous thromboses devel- that are performed by vascular surgeons predispose op in spite of the usual methods for preventing the the patient, at least at the site of the operative pro- recurrence, or who have venous thromboses develop cedure, to thrombosis. If there is inadequate antico- agulation therapy during the time the blood flow is From the Department of Surgery, University of Missouri–Columbia. diverted from the operative area, thromboses will Competition of interest: nil. form proximal and distal to the clamps and subse- Reprint requests: Dr Donald Silver, University of Missouri- quently in the operative area. Procedures, such as Columbia, Department of Surgery, One Hospital Dr, Columbia, endarterectomy, angioplasty, and thrombectomy MO 65212. catheter placement, remove or damage the intima Copyright © 2000 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American and expose deep layers of the arterial wall, which Chapter. activate platelets and the coagulation mechanism. 0741-5214/2000/$12.00 + 0 24/9/102322 Synthetic grafts are not protected by endothelial

396 JOURNAL OF VASCULAR SURGERY Volume 31, Number 2 Silver and Vouyouka 397 cells and are at risk for thrombosis. If adequate Table I. Causes of acquired hypercoagulability blood flow is restored to an operative site and if the Causes blood was hypocoagulable during the time of cessa- tion of flow, then the vascular surgical procedure is Smoking* almost always successful. Small diameter prosthetic Heparin-induced thrombocytopenia* Warfarin* grafts or vascular reconstructions associated with low Antiphospholipid syndrome* flow conditions are prone to thrombosis. This sec- Pregnancy* tion will review some of the disorders that may Oral contraceptives* Diabetes mellitus adversely affect arterial vascular reconstructions or Hyperlipidemia induce venous or arterial thromboses (Table I). Polycythemia vera Hyperfibrinogenemia SMOKING Smoking contributes to arterial thrombosis and Malignant disease atherogenesis through a variety of mechanisms. Surgery Thrombocythemia Nicotine and carbon monoxide appear to be the most Homocystinemia harmful constituents. The incidence rates of critical limb ischemia (16% vs 0%) and myocardial infarction *Disorders that may adversely affect arterial vascular reconstruc- tions or induce venous or arterial thromboses. (53% vs 11%) are much greater in smokers than in nonsmokers, when followed for as long as 10 years.3 Furthermore, cigarette smoking has an adverse effect on arterial bypass grafts, with twice as many grafts bodies also activate endothelial cells that contribute being patent in nonsmokers than in smokers at the to the production of thromboses. The development end of 2 years.4 The patients who continue to smoke of the antibodies is independent of patient age or after vascular reconstruction have a high risk of recur- sex, the route of the administration of heparin, or ring ischemia and subsequent loss of limb or organ.5 the amount of heparin received. All forms of Nicotine results in endothelial damage and heparin, including low–molecular weight heparin, desquamation, which leads to platelet deposition, the can result in the production of these antibodies. The release of platelet-derived growth factor, and platelet- antibodies usually occur in patients between the 5th mediated intimal and medial hyperplasia. Carbon to the 8th day during the first exposure to heparin monoxide increases the permeability of the endothe- and may recur during the first day of a patient’s reex- lium, which results in an increased deposition of lipids posure to heparin. The clinical manifestations (nicotine increases the levels of circulating free fatty include: a falling platelet count; an increasing resis- acids) in the media, leading to the production of tance to anticoagulation therapy with heparin; or . Smoking reduces the synthesis of prosta- new thrombotic, rarely hemorrhagic, events. The cyclin, a potent vasodilator and inhibitor of platelet paradox is that heparin anticoagulation therapy aggregation. Smoking has adverse effects on blood places these patients at risk for a heparin-induced viscosity (increased), coagulation (increased), and thrombosis. platelet activation (increased).6,7 All patients, especial- When the vascular surgeon completes a technical- ly those with arterial occlusive disease, should be ly successful procedure, with normal postoperative encouraged to refrain from, or discontinue, smoking. angiographic or ultrasound scan study results, only to have a thrombosis occur in the operating room or in HEPARIN-INDUCED the recovery room, he should suspect heparin- THROMBOCYTOPENIA induced thrombocytopenia with thrombosis. When Heparin-induced thrombocytopenia occurs in this occurs, one must inhibit platelet function, usual- 2% to 3% of the patients who undergo heparin ther- ly with aspirin or dextran, and discontinue the use of apy. Of the patients who underwent vascular recon- all forms of heparin. The patient’s plasma should be struction, 21% had heparin-associated antiplatelet tested for the presence of the heparin-associated antibodies develop, and 18.2% of these patients had antiplatelet antibodies. If the antibodies are present, heparin-induced thromboses develop.8 the patient should be warned not to accept any form When patients who have heparin-associated of heparin therapy in the future without testing for antiplatelet antibodies undergo heparin therapy, the specific type of heparin to which that patient is to their activated platelets induce platelet aggregation be exposed. The heparin-associated antiplatelet anti- and thrombosis and rarely hemorrhage. The anti- bodies, like drug-induced antibodies, remit in a few JOURNAL OF VASCULAR SURGERY 398 Silver and Vouyouka February 2000 weeks to months. However, we have found that the therapy with warfarin. The low–molecular weight heparin-associated antiplatelet antibodies can persist heparins allow one to “protect” the patients much as long as 13 years. more easily than has been possible in the past. The heparin-induced thrombocytopenia syn- drome is one of the more common and potentially ANTIPHOSPHOLIPID SYNDROME devastating hypercoagulable disorders encountered The antiphospholipid syndrome is another of the in patients who undergo vascular surgery. The man- commonly acquired causes of hypercoagulability. It agement of heparin-induced thrombocytopenia syn- occurs in 1% to 5% of the population and increases drome includes the avoidance of all forms of heparin with age (50% of patients older than 80 years have to which the patient is sensitized. We routinely test antiphospholipid antibodies.)11 The antiphospho- the patient’s antibodies against beef heparin, pork lipid syndrome occurs in patients with lupus antico- heparin, enoxaparin, and fragmin. The rare patient agulants or anticardiolipin antibodies. The patients may react with all four heparins, but most patients with these disorders develop antibodies to protein- do not. If a heparin to which a patient does not cross phospholipid complexes. The antibodies are direct- react is found, we offer a brief exposure to that type ed against neoepitopes of the plasma proteins, espe- of heparin, with retesting in a few days to determine cially those of β 2 glycoprotein I and prothrombin, whether the patient has now developed antibodies to which are formed when the substances bind to anti- the “new” type of heparin. We have found positive anionic-phospholipids. Antibodies have also been reactions with enoxaparin in 34% and a positive reac- identified that react to other phospholipid complex- tion with fragmin in 25.5% of our patients with es with protein C or protein S, factors XI and XII, heparin-induced thrombocytopenia.9,10 For the rare and high–molecular weight kininogen. The antibod- patient who is unable to undergo any form of ies also react with phospholipids on platelets and heparin anticoagulation therapy, the recent Food and endothelial cells. The endothelial reactions block the Drug Administration–approved thrombin inhibitor antithrombin inactivation of thrombin and the lepirudin (Refludan, Hoechst Marion Roussel, thrombomodulin activation of protein C. Kansas City, Mo) is a satisfactory anticoagulant. Recurrent venous thrombosis is a manifestation of the antiphospholipid syndrome.12 The incidence rate WARFARIN-INDUCED THROMBOSIS of thrombotic complications after vascular surgical The most serious nonhemorrhagic complication procedures in patients with lupus anticoagulants has of oral anticoagulation therapy is warfarin-induced been reported to be as high as 50%.13 The patients skin necrosis, which is manifested by thrombosis and with systemic lupus erythematosus, malignant disease, hemorrhage of venules and within the and peripheral vascular occlusive disease, who have cir- subcutaneous and the overlying skin. The skin culating lupus anticoagulants or anticardiolipin anti- necrosis occurs most typically in the subcutaneous bodies, have a high incidence of pulmonary , fat of the breasts, thighs, buttocks, and legs. vena cava thrombosis, myocardial infarction, acute Warfarin inhibits the action of vitamin K in the liver, arterial occlusion, and abortion.14 Arterial thromboses which leads to reductions of functional factors II, are known to occur in the brain, eye, and heart, and in VII, IX, and X and proteins C and S. Protein C and the periphery. Another clinical manifestation of the factor VII have short half lives of approximately 6 antiphospholipid syndrome is that of recurrent, usual- hours and are quickly reduced early during warfarin ly mid-pregnancy, abortion. Thrombocytopenia is a therapy. The other vitamin K–dependent factors common occurrence. have significantly longer half lives, and therapeutic The diagnosis of the antiphospholipid syndrome anticoagulation treatment with warfarin requires 3 includes testing for the lupus anticoagulant, which is to 4 days. However, the induced deficiency of pro- manifested with prolongation of clotting assays tein C (an anticoagulant that inactivates activated (activated partial thromboplastin time, prothrombin factors Va and VIIIa) induces a hypercoagulable time, Russel’s viper venom time). These tests do not state during the first 2 to 3 days of warfarin therapy. correct with a 1:1 mixture of healthy plasma with It is recommended that the patients with risk factors the patient’s plasma. The anticardiolipin antibodies for intravascular thrombosis, especially those are detected with enzyme-linked immunosorbent patients with protein C and S deficiencies, or the assay. Patients should undergo both tests. patients who have had previous episodes of warfarin- The management of the antiphospholipid syn- induced skin necrosis should be protected with drome includes the elimination of risk factors in those heparin for the first 2 to 4 days of anticoagulation patients with known antibodies (eg, warn against preg- JOURNAL OF VASCULAR SURGERY Volume 31, Number 2 Silver and Vouyouka 399 nancies, avoid oral contraceptives, avoid major trau- (22% for the patients with complications as com- ma). Those patients with recurrent venous thromboses pared with 8% of the control group). The authors should be treated immediately with heparin or uroki- recommended that “…women with severe compli- nase and then later with the life-long administration of cated pregnancies should be tested for markers of warfarin. An international normalized ratio (INR) of thrombophilia….” 2.0 to 3.0 usually provides adequate protection. Heparin is the preferred anticoagulant therapy for However, a few patients require an INR of 3.0 to 4.0. pregnant women because it does not cross the pla- Patients with anticardiolipin antibodies and previous centa. Warfarin crosses the placenta, is teratogenic, is deep venous thrombosis or abortion who become associated with fetal hemorrhage, and should not be pregnant undergo treatment during the pregnancy offered to the pregnant patient. In addition, the preg- with heparin and after the pregnancy with warfarin. nant woman should be encouraged to avoid the posi- Warfarin therapy should be continued as long as the tion of stasis and to use elastic support for the lower antibodies or anticoagulant persist. extremities. It has been suggested that the patients with congenital thrombophilia undergo prophylactic PREGNANCY heparin therapy (ie, subcutaneous standard heparin Women who are pregnant (particularly during therapy or low–molecular weight heparin therapy) the puerperium) and women who use exogenous throughout their pregnancy. estrogens have increased risks for thromboem- Estrogens have been associated with a two-fold bolism. The hypercoagulable state of pregnancy has to 11-fold increase in the incidence of venous been described as a state of disseminated intervascu- thrombosis in women.19,20 There is also an lar coagulation.15 During pregnancy, there is an increased risk for coronary and cerebral arterial increase in coagulation factors I, VII, VIII, IX, X, thromboses in women who use oral contraceptives. XI, and XII, an increase in platelet count, a decrease The thrombosis rate increases as the estrogen dose in protein S, and a decrease of antithrombin. In increases. Estrogens are associated with falls in addition, the fibrinolytic system may be inhibited by antithrombin and protein S activities and increases in increased levels of plasminogen-activated inhibitor-1 the levels of activated factors VII and X.21,22 Women and inhibitor-2, which are produced by the placen- who use the third generation “pills,” which contain ta. These events contribute to an increased (five- newer progestin derivatives, have a higher risk for fold) risk of venous thrombosis during pregnancy, deep thrombosis (2.6-fold increase as compared which is compounded by the venous stasis produced with the first generation contraceptives, and a 9.1- by the pregnant compressing the drain- fold increase as compared with nonusers).23 The ing the lower extremities. The risk of thrombosis is estrogens have also been associated with decreased higher in the antepartum period (by 20 fold) than in levels of thrombomodulin, which leads to a reduc- the anti-partum period.16 The coagulation and fibri- tion in the activity of protein C.21 An acquired acti- nolytic systems return to normal approximately 2 vated protein C resistance (APC-R), or the presence months after delivery. of factor V Leiden mutation, plus third generation Recent studies have indicated that the hyperco- contraceptive use places the patient at a markedly agulable potential of the pregnant state is signifi- increased risk, as much as a 49.8-fold increase, for cantly amplified by inherited conditions of hyperco- thrombosis as compared with control patients.24 agulability (eg, antithrombin and protein C defi- The vascular surgeon must be aware that the patient ciencies and the presence of the Leiden mutation).17 who uses an estrogen contraceptive is at an increased Kupferminc et al18 have demonstrated that “Women risk for venous and arterial thromboembolism and with serious obstetrical complications have an should be especially wary of the patient who uses a increased incidence of mutations predisposing them third generation contraceptive. to thrombosis and other inherited and acquired A woman in whom a venous thrombosis devel- forms of thrombophilia.” They demonstrated that ops while undergoing estrogen therapy should be 52% of women with severe thrombotic obstetrical treated like any patient with acute venous thrombo- complications had congenital hypercoagulable syn- sis and should be advised to use other forms of birth dromes including: factor V Leiden mutation; the control. If there is family history of venous throm- prothrombin gene variant (20210A); protein C, bosis, or if there is recurrent venous thrombosis, protein S, antithrombin deficiencies; and the pres- then a search should be made for congenital hyper- ence of anticardiolipin antibodies. The “complicated coagulable disorder (ie, APC-R, the Leiden muta- group” also had increased hyperhomocystinemia tion, prothrombin variant, or reductions in protein JOURNAL OF VASCULAR SURGERY 400 Silver and Vouyouka February 2000

Table II. Congenital coagulation disorders CONGENTIAL HYPERCOAGULABLE SYN- DROMES (TABLE II) Disorders

Antithrombin deficiency* The congenital defects of coagulation/anticoagu- Protein C deficiency* lation proteins may result in an imbalance in hemo- Protein S deficiency* Activated protein C resistance* stasis, which leads to an increased thrombotic risk for Prothrombin 20210A* the patient. All of the congenital hypercoagulable Heparin cofactor II deficiency * disorders increase the risk for venous thrombosis, but Homocystinemia* Dysfibrinogenemia several also contribute to increased arterial throm- Increased factor VIII boses. Some patients who are thrombophilic have Abnormal plasminogen multiple genetic disorders (eg, the frequent associa- Decreased plasminogen activator Increased plasminogen activator inhibitor tion of factor V Leiden mutation with deficiencies of antithrombin and proteins C and S). Table II lists the *The more prevalent congential hypercoagulable disorders. congential hypercoagulable disorders: the more prevalent ones are subsequently discussed.

C, protein S, or antithrombin.) If the patient has ANTITHROMBIN DEFICIENCY congenital hypercoagulability and recurrent throm- Antithrombin, the major plasma inhibitor of bosis, she should undergo long-term warfarin anti- thrombin, also inhibits factors IXa, Xa, XIa, and coagulation therapy with the prothrombin at an XIIa. The antithrombin deficiency, described in INR of 2.0 to 3.0. 1965 by Egeberg30 in a Norwegian family with repeated thrombotic episodes, has a prevalence of OTHER ACQUIRED HYPERCOAGULABLE 1:5000. Patients with low levels of antithrombin are DISORDERS at risk for venous thromboses, especially lower Many clinical disorders predispose patients to extremity and mesenteric, but are also at increased thrombosis by activating the coagulation system, risk for arterial thromboses. The risk of thrombosis inhibiting the fibrinolytic system, or initiating increases as the functional antithrombin activity platelet activation. Soft tissue trauma, thermal decreases to less than 80% of the normal level, with injuries, and operative predispose one to the highest risk occurring when antithrombin levels thrombosis through the activation of the extrinsic are less than 60%.31 The level of antithrombin in pathway of coagulation with the release of tissue fac- heterozygotes usually is 40% to 70% of the normal tor. Sepsis predisposes a patient to thrombosis with level. Antithrombin levels are decreased in several the increased production and expression of tissue disease states, including hepatic insufficiency, dis- factor by endothelial cells, macrophages, and neu- seminated intravascular coagulation, venous throm- trophils; with the decrease of antithrombin, protein bosis, and sepsis, and in women who use oral con- C, and protein S, and thrombomodulin activity traceptives. (uninhibited thrombogenesis); and with the increase Thromboembolism is rare before the second in production of plasminogen activator inhibitor-1 decade of life. Although thromboembolism may (suppressed fibrinolytic activity).25-27 occur spontaneously, it usually is associated with pre- Malignant diseases are associated with the cipitating events, such as surgery, trauma, or preg- increased incidence of venous thrombosis. Many nancy. Heparin therapy remains the mainstay of malignant diseases cause the secretion of tissue management for patients with antithrombin defi- thromboplastin, and others are known to cause the ciency and acute thrombosis. Although the optimal release of proteases capable of activating factor X. level of antithrombin for the treatment of thrombo- Some patients with malignant disease have increased sis is unknown, it is recommended that the concentrations of factors V, VIII, IX, and X. antithrombin concentration be adjusted to more Patients with hyperlipidemia, myeloproliferative than 80% of normal activity during the management diseases, diabetes mellitus, and thrombotic thrombo- of the thrombotic event with heparin and before cytopenia are all predisposed to thrombosis through surgery in a patient with an acquired or congenital the effects on platelets. Hyperlipidemia causes the acti- antithrombin deficiency. The management of vation of platelets, with the increase of thromboxane antithrombin deficiency includes infusions of fresh A2 and the decrease of platelet response to prostacy- frozen plasma or antithrombin concentrate. The clin.28,29 concentrates are preferred. Long-term warfarin ther- JOURNAL OF VASCULAR SURGERY Volume 31, Number 2 Silver and Vouyouka 401 apy is recommended for patients with antithrombin frozen plasma infusions can restore functional levels deficiencies who have had thrombotic events. The of protein C. Life-long anticoagulation therapy with patients with antithrombin deficiencies should warfarin is recommended for patients with protein C undergo heparin therapy during pregnancy. The deficiencies who have had idiopathic, recurrent, or patients from families with antithrombin deficiencies life-threatening thromboses. should be studied and, if they have antithrombin Cutaneous necrosis is more likely to occur when deficiencies, should be protected with heparin or warfarin anticoagulation therapy is offered to warfarin therapy during times of increased risk (ie, patients with protein C deficiencies. Consequently, surgery, trauma, pregnancy, sepsis). all patients, especially those with protein C deficien- cies, should undergo heparin therapy during the first PROTEIN C AND PROTEIN S 3 to 4 days of warfarin therapy, because protein C is DEFICIENCIES decreased more rapidly than are coagulation factors Protein C and protein S are vitamin K–depen- II, IX, and X. dent proteins that are synthesized in the liver. Their The histories of patients with congenital protein plasma levels may be decreased in patients with S deficiencies are similar to those histories of patients hepatic insufficiency, chronic renal failure, vitamin K with deficiencies of protein C. Protein S has been deficiency, and disseminated intravascular coagula- identified as responsible for venous thromboses and, tion, in patients who undergo major operative pro- rarely, arterial thrombosis. However, recent data cedures, and during times of active thrombosis. suggest that many of the patients with protein S Protein C, when activated by thrombin, becomes deficiency also have APC-R, which may have been a major anticoagulant and significantly enhances fi- the major factor that led to the thromboses. brinolytic activity. The activation of protein C is Protein S circulates either as a free protein (30% enhanced 20,000-fold when thrombin is bound to to 40%) or bound to the complement pathway pro- thrombomodulin on the endothelial cell surface. tein, C4b-binding protein. C4b is an acute phase Activated protein C degrades activated forms of fac- reactant and is increased during times of acute infla- tor V (Va) and factor VIII (VIIIa). Protein C also mation, which leads to a decrease in free protein S decreases tissue plasminogen activator inhibitor and thus contributes to the increased tendency activity, thus increasing fibrinolytic potential by toward thrombosis during inflammatory condi- reducing the inhibition of the conversion of plas- tions.35 The management of protein S deficiency is minogen to plasmin. Protein S has no anticoagulant similar to that of protein C deficiency. or fibrinolytic potential on its own but serves as a Patients who are homozygous for protein C and cofactor for protein C and enhances the expression S may have extensive cutaneous necrosis develop as of the anticoagulant effect of protein C. newborns (purpura fulminans). Congenital protein C deficiency is transmitted as an autosomal dominant trait, with a prevalence from ACTIVATED PROTEIN C RESISTANCE 1 in 200 to 1 in 300. The incidence rates of throm- APC-R, the most common risk factor for venous botic events in patients who are heterozygous range thrombosis, was initially described by Dahlbäck et from 0% to 50%.32,33 Patients who are homozygous al36 in 1993 and accounts for 52% to 64% of the often die in early life from thrombotic complications. inherited causes of thromboses.37 The prevalence of Congenital protein C deficiencies are responsible for APC-R in the general population of white origin 2% to 5% of venous thromboses. Protein C is often ranges from 3% to 15%.38-40 However, it is relative- 30% to 70% of the normal level in patients who are ly uncommon in populations of other origins. Many heterozygous and 5%, or less, in patients who are patients previously diagnosed with functional homozygous. The patients with protein C deficien- antithrombin and protein C and S deficiencies have cies have venous thromboses at an early age, espe- been found to have APC-R. cially in the lower extremity, cerebral, mesenteric, APC-R is characterized by a poor anticoagulant and renal veins. Arterial thrombosis is rare. Protein C response to activated protein C. When protein C is and protein S deficiencies have been found in 15% to activated, it degrades the activated clotting factors V 20% of the patients with peripheral and VIII. A molecular defect in factor V occurs who are younger than 50 years of age.34 when arginine 506 is replaced with glutamine, ren- The management of protein C deficiency includes dering Va resistant to degradation by activated pro- prophylaxis with heparin or warfarin therapy during tein C. The altered factor V (factor V Leiden) retains times of risk (ie, surgery, trauma, pregnancy). Fresh its procoagulant activity, thus favoring thrombosis. JOURNAL OF VASCULAR SURGERY 402 Silver and Vouyouka February 2000

Patients with the heterozygous form of APC-R cytes. Hyperhomocystinemia alters the normal anti- have as much as a seven-fold increased risk of venous thrombotic activity of the endothelium by enhancing thrombosis. Those who are homozygous have an the activity of factors VII and V and decreasing the increased risk of approximately 80 fold, and most activation of protein C by altering the expression of will have at least one episode of thrombosis during thrombomodulin. Hyperhomocystinemia-damaged their lifetime.38,41 There is increasing evidence that endothelium has reduced nitric oxide production. APC-R is associated with arterial thrombosis, espe- Homocysteine inhibits the antithrombin binding cially myocardial infarction. The risk for thrombosis activity of the endothelial heparan sulfate and indi- is increased during pregnancy, surgery, and trauma, rectly stimulates platelet aggregation. Homocysteine with the use of oral contraceptives, and in other sit- interferes with the binding of tissue plasminogen uations that increase the risk for thrombosis. activator. These toxic effects of hyperhomocystine- Patients with APC-R in high thrombotic risk situa- mia contribute to the development of atherosclerot- tions should undergo thrombosis prophylaxis thera- ic plaques, arterial atherothrombosis (especially cere- py, and those patients with recurrent or life-threat- bral, coronary, and peripheral) events, and idiopathic ening thrombotic events should undergo life-long venous thromboses.44,45 anticoagulation therapy with warfarin. It is clear that elevated plasma homocysteine con- centration is a risk factor for and arte- HOMOCYSTINEMIA rial and venous thrombosis. Patients with premature Homocysteine, a sulphur-containing amino acid atherosclerosis, or unexplained atherothrombosis, or formed during the metabolism of methionine, is venous thrombosis should undergo testing for hyper- metabolized with remethylation to methionine or homocystinemia. Patients with high homocysteine with transsulfuration to cysteine. Elevated homocys- levels should undergo treatment with folate (1 to 5 teine levels may result from inherited disorders that mg/day, as much as 15 mg/day in patients with renal alter enzyme activity in the transsulfuration and failure) or B12 or B6. The normalization of the homo- methylation pathways. In addition, acquired hyper- cysteine level usually occurs within 4 to 6 weeks.44 homocystinemia may occur in patients with deficien- The normalization has returned platelet and endothe- cies of vitamins B12 or B6 or folate. It was first sug- lial cell function toward a normal level. Studies of clin- gested in 1969 that hyperhomocystinemia was asso- ical outcomes after normalization of homocysteine are ciated with arterial thrombosis and atherosclerosis.42 in progress. It is now well established that hyperhomocystinemia is a definite risk factor for atherosclerosis, PROTHROMBIN GENE VARIANT (20210A) atherothrombosis, and recurrent venous thrombosis. In 1996, Poort et al46 examined the prothrom- Although severe hyperhomocystinemia is rare, bin gene in patients with documented family histo- mild homocystinemia occurs in approximately 5% to ries of venous thrombophilia. A nucleotide change 7% of the population.43 Homocystinemia may be (a G to A transition) was detected at position 20210 detected with the measurement of fasting plasma in 18% of the patients.46 In “…a population based homocysteine or after a standardized methionine- control study, the 20201A allele was identified as a loading test (100 mg/kg). Hyperhomocystinemia is common allele…” in 1.2% who had a three-fold present if the homocysteine concentration after increased risk of venous thrombosis.46 Although the methionine loading is increased to more than two patients with the 20201A allele are at risk for venous standard deviations above the mean. In addition to the thrombosis, the mechanism for the increased risk is patient with vitamin deficiencies, hyperhomocystin- unclear, except that the patients have elevated levels emia has been found in patients with histories of renal of prothrombin (an identified risk factor for throm- failure, hypothyroidism, pernicious anemia, breast and bosis). There are few reports of the homologous pancreas carcinoma, and cigarette smoking. 20210AA genotype. The expected prevalence rate is Hyperhomocystinemia has been shown to cause 0.014%.46 endothelial disruption and dysfunction, platelet Initial reports suggested that the prothrombin activation, and thrombus formation. When homo- 20210G/A genotype was not related to arterial cysteine is oxidized, potent oxygen radicals (espe- thrombotic disorders.47 Subsequent reports have cially hydrogen peroxide, hydroxyl radical, and indicated that the allele has a high prevalence rate superoxide radical) are formed. These superoxide (5.7%) in selected patients with arterial throm- radicals induce endothelial damage, smooth muscle boses.48,49 Patients with the 20210 allele have had proliferation, and activation of platelets and leuko- increased frequency of cerebral and coronary throm- JOURNAL OF VASCULAR SURGERY Volume 31, Number 2 Silver and Vouyouka 403 boses. It has been suggested that the prothrombin rent, or multi-level arterial thromboses (eg, 15% to 20210A allele and the factor V Leiden mutation will 70% of young patients with arterial occlusive disease be found in 63% of families with thrombophilia.50 may have a hypercoagulable syndrome).56,57 Arterial The management of the prothrombin gene varia- reconstructions have increased rates of failure in tion has not been clearly defined, but is likely to require patients with hypercoagulable syndrome, with a six- long-term anticoagulation therapy with warfarin for fold increase in the need for a second procedure those patients with early or recurrent thromboses. within 1 year after primary reconstruction in patients who are hypercoagulable.56,58 The antiphospholipid HEPARIN COFACTOR II DEFICIENCY syndrome has been detected in 36% of patients with Heparin cofactor II is produced by the liver and failed vascular procedures.12,57,59 Twenty-one per- is a specific inhibitor of thrombin. Heparin cofactor cent of patients with vascular surgical reconstruc- II deficiency is a rare condition that is transmitted as tions had heparin-associated antiplatelet antibodies an autosomal dominant. It inactivates thrombin by develop and had a 2.6-fold increase in graft failures.8 binding to it in a 1:1 relationship. Heparin enhances Patients with infrainguinal grafts and APC-R had the rate of thrombin inactivation by heparin cofactor patency rates of 48% and 33% at 1 and 3 years, and II. Patients with heparin cofactor II deficiencies are the “routine” vascular patients had 88% and 71% at risk for thrombosis when the cofactor level patency rates, respectively.60,61 Patients with hyper- becomes 50% or less than normal.51 Heparin cofac- coagulability and infrainguinal vascular reconstruc- tor II deficiencies have been reported, in a few tion have an alarming frequency (20% to 27%) of patients, as a risk factor for venous, and fewer arte- acute thrombosis within the first 30 days of recon- rial, thromboses. struction when compared with healthy individuals (1.6% to 2%).34,60 These adverse thrombotic events DEFICIENT PLASMINOGEN AND PLAS- are reduced in patients who undergo treatment with MINOGEN ACTIVATOR ACTIVITY heparin, provided that their hypercoagulable syn- Increased thrombotic tendencies have been drome is not caused by heparin. Long-term warfarin reported in patients with structural defects in plas- and aspirin therapy substantially reduce the overall minogen or defects in the plasminogen activator sys- failure rates.34,57,58,61 tem. Twelve variant forms of the plasminogen mol- ecule have been described.52 These variants have WHEN TO TEST functional abnormalities, including altered active The patient with a suspected hypercoagulable dis- sites and the inability to form activator complexes. A order can undergo testing during the episode of few patients with recurrent thromboembolism have thrombosis for heparin-associated antiplatelet antibod- been identified as having decreased production of ies, anticardiolipin antibodies, homocysteine, the endothelial-derived plasminogen activator. Patients Leiden mutation, and the prothrombin variant. The with these deficiencies of fibrinolysis may have arte- other factors may be consumed during the clotting rial and venous thromboses and undergo treatment process or reduced by the administration of warfarin, with long-term warfarin therapy. , or sepsis. The authors treat suspected hypercoagulable disorders with warfarin therapy for 6 CLINICAL IMPLICATIONS months or more, until the patient have not had a Most of the disorders of hypercoagulability con- thrombosis for 2 or more months. The warfarin ther- tribute to venous thromboembolism. Of the patients apy is then discontinued, and the patient undergoes with heterozygous protein factor deficiency, 60% to treatment with heparin (usually low–molecular weight 80% will have venous thromboembolism develop by heparin) for 2 weeks. When the heparin therapy is dis- the ages of 40 to 45 years and 50% will have recur- continued, and 2 to 3 days later, blood is obtained for rent thromboembolism.53 All patients with juvenile, hypercoagulable studies. Heparin therapy is immedi- idiopathic, or idiopathic recurrent venous thrombo- ately restarted and warfarin therapy is begun while the sis and a family history of venous thrombosis should physicians await the results of the studies. undergo testing for hypercoagulability. Venous If a patient is found to have one of the hyperco- thromboses in unusual sites (eg, mesenteric, portal, agulable conditions, the family of the patients hepatic, cerebral, retinal, and so forth) are often should also undergo testing. In our experience, associated with hypercoagulable disorders.54,55 heparin-associated antiplatelet antibodies, the lupus A hypercoagulable disorder should also be sus- anticoagulant, and homocystinemia are the more pected in patients with juvenile, idiopathic, recur- common causes of reconstructive arterial failures. JOURNAL OF VASCULAR SURGERY 404 Silver and Vouyouka February 2000

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