Journal of Vascular Surgery
Volume 31, Issue 2 , Pages 396-405, February 2000

The caput medusae of hypercoagulability☆☆☆★

Department of Surgery, University of Missouri–Columbia. Columbia, Mo

Received 23 April 1999; accepted 19 July 1999.

Article Outline

Abstract 

Thrombosis may be the most common cause of death in the United States. Virchow postulated, approximately 150 years ago, that intravascular thrombosis 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 participates 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 the numerous poisonous snakes that sprang from the blood of Medusa (the mortal daughter of the sea god Phorcus) after her head was cut off by the sword of Perseus. Although the hypercoagulable syndromes are not snakes, they are numerous and potentially dangerous, and new disorders spring forth at frequent intervals.

Most investigators would agree that thrombosis is the cause of, or is related to the cause of, most deaths. Bick and Kaplan1 have estimated that almost two million individuals die in the United States each year from “an arterial or venous thrombosis or the consequences thereof” and that more than “…50% of all patients harbor a congenital or acquired blood coagulation protein or platelet defect that caused the thrombotic event.” Stassen and Nystrom2 suggested in 1997 that the “…annual hospitalizations due to all thrombotic disease exceeded 5,100,000 in the United States…” and that the annual costs for these disorders were “…about $13 billion.”

Physicians frequently encounter patients who have venous thromboses without obvious risk factors, who have recurrent venous thromboses develop in spite of the usual methods for preventing the recurrence, or who have venous thromboses develop in unusual locations. The vascular surgeon also occasionally encounters patients with unexplained arterial thromboses or with unexplained arterial reconstructive failures. Many of these patients will have congenital or acquired hypercoagulable disorders that sensitize them to prothrombotic conditions that are tolerated by most individuals.

We review the pathophysiology and management of the hypercoagulable disorders that are most likely to be of concern to vascular surgeons. If a disorder can be recognized, then the appropriate management may control the thrombotic tendency and prevent future thromboses.

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Acquired hypercoagulable disorders (Table I) 

Technical failures (badly diseased vessels, inadequate inflow or outflow, kinked or twisted grafts, etc) remain the most common cause of the early arterial reconstructive failures encountered by vascular surgeons and can be reduced with the appropriate preoperative planning and careful attention to operative detail. Most of the operative procedures that are performed by vascular surgeons predispose the patient, at least at the site of the operative procedure, to thrombosis. If there is inadequate anticoagulation therapy during the time the blood flow is diverted from the operative area, thromboses will form proximal and distal to the clamps and subsequently in the operative area. Procedures, such as endarterectomy, angioplasty, and thrombectomy catheter placement, remove or damage the intima and expose deep layers of the arterial wall, which activate platelets and the coagulation mechanism. Synthetic grafts are not protected by endothelial cells and are at risk for thrombosis. If adequate blood flow is restored to an operative site and if the blood was hypocoagulable during the time of cessation of flow, then the vascular surgical procedure is almost always successful. Small diameter prosthetic grafts or vascular reconstructions associated with low flow conditions are prone to thrombosis. This section will review some of the disorders that may adversely affect arterial vascular reconstructions or induce venous or arterial thromboses (Table I).

Table I. Causes of acquired hypercoagulability
Causes
Smoking*
Heparin-induced thrombocytopenia*
Warfarin*
Antiphospholipid syndrome*
Pregnancy*
Oral contraceptives*
Diabetes mellitus
Hyperlipidemia
Polycythemia vera
Hyperfibrinogenemia
Nephrotic syndrome
Vasculitis
Malignant disease
Surgery
Thrombocythemia
Homocystinemia
*Disorders that may adversely affect arterial vascular reconstructions or induce venous or arterial thromboses.

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Smoking 

Smoking contributes to arterial thrombosis and atherogenesis through a variety of mechanisms. Nicotine and carbon monoxide appear to be the most harmful constituents. The incidence rates of critical limb ischemia (16% vs 0%) and myocardial infarction (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 being patent in nonsmokers than in smokers at the end of 2 years.4 The patients who continue to smoke after vascular reconstruction have a high risk of recurring ischemia and subsequent loss of limb or organ.5

Nicotine results in endothelial damage and desquamation, which leads to platelet deposition, the release of platelet-derived growth factor, and platelet-mediated intimal and medial hyperplasia. Carbon monoxide increases the permeability of the endothelium, which results in an increased deposition of lipids (nicotine increases the levels of circulating free fatty acids) in the media, leading to the production of atheromas. Smoking reduces the synthesis of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. Smoking has adverse effects on blood viscosity (increased), coagulation (increased), and platelet activation (increased).6, 7 All patients, especially those with arterial occlusive disease, should be encouraged to refrain from, or discontinue, smoking.

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Heparin-induced thrombocytopenia 

Heparin-induced thrombocytopenia occurs in 2% to 3% of the patients who undergo heparin therapy. Of the patients who underwent vascular reconstruction, 21% had heparin-associated antiplatelet antibodies develop, and 18.2% of these patients had heparin-induced thromboses develop.8

When patients who have heparin-associated antiplatelet antibodies undergo heparin therapy, their activated platelets induce platelet aggregation and thrombosis and rarely hemorrhage. The antibodies also activate endothelial cells that contribute to the production of thromboses. The development of the antibodies is independent of patient age or sex, the route of the administration of heparin, or the amount of heparin received. All forms of heparin, including low–molecular weight heparin, can result in the production of these antibodies. The antibodies usually occur in patients between the 5th to the 8th day during the first exposure to heparin and may recur during the first day of a patient's reexposure to heparin. The clinical manifestations include: a falling platelet count; an increasing resistance to anticoagulation therapy with heparin; or new thrombotic, rarely hemorrhagic, events. The paradox is that heparin anticoagulation therapy places these patients at risk for a heparin-induced thrombosis.

When the vascular surgeon completes a technically successful procedure, with normal postoperative angiographic or ultrasound scan study results, only to have a thrombosis occur in the operating room or in the recovery room, he should suspect heparin-induced thrombocytopenia with thrombosis. When this occurs, one must inhibit platelet function, usually with aspirin or dextran, and discontinue the use of all forms of heparin. The patient's plasma should be tested for the presence of the heparin-associated antiplatelet antibodies. If the antibodies are present, the patient should be warned not to accept any form of heparin therapy in the future without testing for the specific type of heparin to which that patient is to be exposed. The heparin-associated antiplatelet antibodies, like drug-induced antibodies, remit in a few weeks to months. However, we have found that the heparin-associated antiplatelet antibodies can persist as long as 13 years.

The heparin-induced thrombocytopenia syndrome is one of the more common and potentially devastating hypercoagulable disorders encountered in patients who undergo vascular surgery. The management of heparin-induced thrombocytopenia syndrome includes the avoidance of all forms of heparin to which the patient is sensitized. We routinely test the patient's antibodies against beef heparin, pork heparin, enoxaparin, and fragmin. The rare patient may react with all four heparins, but most patients do not. If a heparin to which a patient does not cross react is found, we offer a brief exposure to that type of heparin, with retesting in a few days to determine whether the patient has now developed antibodies to the “new” type of heparin. We have found positive reactions with enoxaparin in 34% and a positive reaction with fragmin in 25.5% of our patients with heparin-induced thrombocytopenia.9, 10 For the rare patient who is unable to undergo any form of heparin anticoagulation therapy, the recent Food and Drug Administration–approved thrombin inhibitor lepirudin (Refludan, Hoechst Marion Roussel, Kansas City, Mo) is a satisfactory anticoagulant.

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Warfarin-induced thrombosis 

The most serious nonhemorrhagic complication of oral anticoagulation therapy is warfarin-induced skin necrosis, which is manifested by thrombosis and hemorrhage of venules and capillaries within the subcutaneous fat and the overlying skin. The skin necrosis occurs most typically in the subcutaneous fat of the breasts, thighs, buttocks, and legs. Warfarin inhibits the action of vitamin K in the liver, which leads to reductions of functional factors II, VII, IX, and X and proteins C and S. Protein C and factor VII have short half lives of approximately 6 hours and are quickly reduced early during warfarin therapy. The other vitamin K–dependent factors have significantly longer half lives, and therapeutic anticoagulation treatment with warfarin requires 3 to 4 days. However, the induced deficiency of protein C (an anticoagulant that inactivates activated factors Va and VIIIa) induces a hypercoagulable state during the first 2 to 3 days of warfarin therapy. It is recommended that the patients with risk factors for intravascular thrombosis, especially those patients with protein C and S deficiencies, or the patients who have had previous episodes of warfarin-induced skin necrosis should be protected with heparin for the first 2 to 4 days of anticoagulation therapy with warfarin. The low–molecular weight heparins allow one to “protect” the patients much more easily than has been possible in the past.

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Antiphospholipid syndrome 

The antiphospholipid syndrome is another of the commonly acquired causes of hypercoagulability. It occurs in 1% to 5% of the population and increases with age (50% of patients older than 80 years have antiphospholipid antibodies.)11 The antiphospholipid syndrome occurs in patients with lupus anticoagulants or anticardiolipin antibodies. The patients with these disorders develop antibodies to protein-phospholipid complexes. The antibodies are directed against neoepitopes of the plasma proteins, especially those of β 2 glycoprotein I and prothrombin, which are formed when the substances bind to anti-anionic-phospholipids. Antibodies have also been identified that react to other phospholipid complexes with protein C or protein S, factors XI and XII, and high–molecular weight kininogen. The antibodies also react with phospholipids on platelets and endothelial cells. The endothelial reactions block the antithrombin inactivation of thrombin and the thrombomodulin activation of protein C.

Recurrent venous thrombosis is a manifestation of the antiphospholipid syndrome.12 The incidence rate of thrombotic complications after vascular surgical procedures in patients with lupus anticoagulants has been reported to be as high as 50%.13 The patients with systemic lupus erythematosus, malignant disease, and peripheral vascular occlusive disease, who have circulating lupus anticoagulants or anticardiolipin antibodies, have a high incidence of pulmonary embolism, vena cava thrombosis, myocardial infarction, acute arterial occlusion, and abortion.14 Arterial thromboses are known to occur in the brain, eye, and heart, and in the periphery. Another clinical manifestation of the antiphospholipid syndrome is that of recurrent, usually mid-pregnancy, abortion. Thrombocytopenia is a common occurrence.

The diagnosis of the antiphospholipid syndrome includes testing for the lupus anticoagulant, which is manifested with prolongation of clotting assays (activated partial thromboplastin time, prothrombin time, Russel's viper venom time). These tests do not correct with a 1:1 mixture of healthy plasma with the patient's plasma. The anticardiolipin antibodies are detected with enzyme-linked immunosorbent assay. Patients should undergo both tests.

The management of the antiphospholipid syndrome includes the elimination of risk factors in those patients with known antibodies (eg, warn against pregnancies, avoid oral contraceptives, avoid major trauma). Those patients with recurrent venous thromboses should be treated immediately with heparin or urokinase and then later with the life-long administration of warfarin. An international normalized ratio (INR) of 2.0 to 3.0 usually provides adequate protection. However, a few patients require an INR of 3.0 to 4.0. Patients with anticardiolipin antibodies and previous deep venous thrombosis or abortion who become pregnant undergo treatment during the pregnancy with heparin and after the pregnancy with warfarin. Warfarin therapy should be continued as long as the antibodies or anticoagulant persist.

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Pregnancy 

Women who are pregnant (particularly during the puerperium) and women who use exogenous estrogens have increased risks for thromboembolism. The hypercoagulable state of pregnancy has been described as a state of disseminated intervascular coagulation.15 During pregnancy, there is an increase in coagulation factors I, VII, VIII, IX, X, XI, and XII, an increase in platelet count, a decrease in protein S, and a decrease of antithrombin. In addition, the fibrinolytic system may be inhibited by increased levels of plasminogen-activated inhibitor-1 and inhibitor-2, which are produced by the placenta. These events contribute to an increased (five-fold) risk of venous thrombosis during pregnancy, which is compounded by the venous stasis produced by the pregnant uterus compressing the veins draining the lower extremities. The risk of thrombosis is higher in the antepartum period (by 20 fold) than in the anti-partum period.16 The coagulation and fibrinolytic systems return to normal approximately 2 months after delivery.

Recent studies have indicated that the hypercoagulable potential of the pregnant state is significantly amplified by inherited conditions of hypercoagulability (eg, antithrombin and protein C deficiencies and the presence of the Leiden mutation).17 Kupferminc et al18 have demonstrated that “Women with serious obstetrical complications have an increased incidence of mutations predisposing them to thrombosis and other inherited and acquired forms of thrombophilia.” They demonstrated that 52% of women with severe thrombotic obstetrical complications had congenital hypercoagulable syndromes including: factor V Leiden mutation; the prothrombin gene variant (20210A); protein C, protein S, antithrombin deficiencies; and the presence of anticardiolipin antibodies. The “complicated group” also had increased hyperhomocystinemia (22% for the patients with complications as compared with 8% of the control group). The authors recommended that “…women with severe complicated pregnancies should be tested for markers of thrombophilia….”

Heparin is the preferred anticoagulant therapy for pregnant women because it does not cross the placenta. Warfarin crosses the placenta, is teratogenic, is associated with fetal hemorrhage, and should not be offered to the pregnant patient. In addition, the pregnant woman should be encouraged to avoid the position of stasis and to use elastic support for the lower extremities. It has been suggested that the patients with congenital thrombophilia undergo prophylactic heparin therapy (ie, subcutaneous standard heparin therapy or low–molecular weight heparin therapy) throughout their pregnancy.

Estrogens have been associated with a two-fold to 11-fold increase in the incidence of venous thrombosis in women.19, 20 There is also an increased risk for coronary and cerebral arterial thromboses in women who use oral contraceptives. The thrombosis rate increases as the estrogen dose increases. Estrogens are associated with falls in antithrombin and protein S activities and increases in the levels of activated factors VII and X.21, 22 Women who use the third generation “pills,” which contain newer progestin derivatives, have a higher risk for deep vein thrombosis (2.6-fold increase as compared with the first generation contraceptives, and a 9.1-fold increase as compared with nonusers).23 The estrogens have also been associated with decreased levels of thrombomodulin, which leads to a reduction in the activity of protein C.21 An acquired activated protein C resistance (APC-R), or the presence of factor V Leiden mutation, plus third generation contraceptive use places the patient at a markedly increased risk, as much as a 49.8-fold increase, for thrombosis as compared with control patients.24 The vascular surgeon must be aware that the patient who uses an estrogen contraceptive is at an increased risk for venous and arterial thromboembolism and should be especially wary of the patient who uses a third generation contraceptive.

A woman in whom a venous thrombosis develops while undergoing estrogen therapy should be treated like any patient with acute venous thrombosis and should be advised to use other forms of birth control. If there is family history of venous thrombosis, or if there is recurrent venous thrombosis, then a search should be made for congenital hypercoagulable disorder (ie, APC-R, the Leiden mutation, prothrombin variant, or reductions in protein C, protein S, or antithrombin.) If the patient has congenital hypercoagulability and recurrent thrombosis, she should undergo long-term warfarin anticoagulation therapy with the prothrombin at an INR of 2.0 to 3.0.

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Other acquired hypercoagulable disorders 

Many clinical disorders predispose patients to thrombosis by activating the coagulation system, inhibiting the fibrinolytic system, or initiating platelet activation. Soft tissue trauma, thermal injuries, and operative dissection predispose one to thrombosis through the activation of the extrinsic pathway of coagulation with the release of tissue factor. Sepsis predisposes a patient to thrombosis with the increased production and expression of tissue factor by endothelial cells, macrophages, and neutrophils; with the decrease of antithrombin, protein C, and protein S, and thrombomodulin activity (uninhibited thrombogenesis); and with the increase in production of plasminogen activator inhibitor-1 (suppressed fibrinolytic activity).25, 26, 27

Malignant diseases are associated with the increased incidence of venous thrombosis. Many malignant diseases cause the secretion of tissue thromboplastin, and others are known to cause the release of proteases capable of activating factor X. Some patients with malignant disease have increased concentrations of factors V, VIII, IX, and X.

Patients with hyperlipidemia, myeloproliferative diseases, diabetes mellitus, and thrombotic thrombocytopenia are all predisposed to thrombosis through the effects on platelets. Hyperlipidemia causes the activation of platelets, with the increase of thromboxane A2 and the decrease of platelet response to prostacyclin.28, 29

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Congenital hypercoagulable syndromes (TABLE II) 

The congenital defects of coagulation/anticoagulation proteins may result in an imbalance in hemostasis, which leads to an increased thrombotic risk for the patient. All of the congenital hypercoagulable disorders increase the risk for venous thrombosis, but several also contribute to increased arterial thromboses. Some patients who are thrombophilic have multiple genetic disorders (eg, the frequent association of factor V Leiden mutation with deficiencies of antithrombin and proteins C and S). Table II lists the congential hypercoagulable disorders: the more prevalent ones are subsequently discussed.

Table II. Congenital coagulation disorders
Disorders
Antithrombin deficiency*
Protein C deficiency*
Protein S deficiency*
Activated protein C resistance*
Prothrombin 20210A*
Heparin cofactor II deficiency *
Homocystinemia*
Dysfibrinogenemia
Increased factor VIII
Abnormal plasminogen
Decreased plasminogen activator
Increased plasminogen activator inhibitor
*The more prevalent congential hypercoagulable disorders.

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Antithrombin deficiency 

Antithrombin, the major plasma inhibitor of thrombin, also inhibits factors IXa, Xa, XIa, and XIIa. The antithrombin deficiency, described in 1965 by Egeberg30 in a Norwegian family with repeated thrombotic episodes, has a prevalence of 1:5000. Patients with low levels of antithrombin are at risk for venous thromboses, especially lower extremity and mesenteric, but are also at increased risk for arterial thromboses. The risk of thrombosis increases as the functional antithrombin activity decreases to less than 80% of the normal level, with the highest risk occurring when antithrombin levels are less than 60%.31 The level of antithrombin in heterozygotes usually is 40% to 70% of the normal level. Antithrombin levels are decreased in several disease states, including hepatic insufficiency, disseminated intravascular coagulation, venous thrombosis, and sepsis, and in women who use oral contraceptives.

Thromboembolism is rare before the second decade of life. Although thromboembolism may occur spontaneously, it usually is associated with precipitating events, such as surgery, trauma, or pregnancy. Heparin therapy remains the mainstay of management for patients with antithrombin deficiency and acute thrombosis. Although the optimal level of antithrombin for the treatment of thrombosis is unknown, it is recommended that the antithrombin concentration be adjusted to more than 80% of normal activity during the management of the thrombotic event with heparin and before surgery in a patient with an acquired or congenital antithrombin deficiency. The management of antithrombin deficiency includes infusions of fresh frozen plasma or antithrombin concentrate. The concentrates are preferred. Long-term warfarin therapy is recommended for patients with antithrombin deficiencies who have had thrombotic events. The patients with antithrombin deficiencies should undergo heparin therapy during pregnancy. The patients from families with antithrombin deficiencies should be studied and, if they have antithrombin deficiencies, should be protected with heparin or warfarin therapy during times of increased risk (ie, surgery, trauma, pregnancy, sepsis).

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Protein C and protein S deficiencies 

Protein C and protein S are vitamin K–dependent proteins that are synthesized in the liver. Their plasma levels may be decreased in patients with hepatic insufficiency, chronic renal failure, vitamin K deficiency, and disseminated intravascular coagulation, in patients who undergo major operative procedures, and during times of active thrombosis.

Protein C, when activated by thrombin, becomes a major anticoagulant and significantly enhances fi-brinolytic activity. The activation of protein C is enhanced 20,000-fold when thrombin is bound to thrombomodulin on the endothelial cell surface. Activated protein C degrades activated forms of factor V (Va) and factor VIII (VIIIa). Protein C also decreases tissue plasminogen activator inhibitor activity, thus increasing fibrinolytic potential by reducing the inhibition of the conversion of plasminogen to plasmin. Protein S has no anticoagulant or fibrinolytic potential on its own but serves as a cofactor for protein C and enhances the expression of the anticoagulant effect of protein C.

Congenital protein C deficiency is transmitted as an autosomal dominant trait, with a prevalence from 1 in 200 to 1 in 300. The incidence rates of thrombotic events in patients who are heterozygous range from 0% to 50%.32, 33 Patients who are homozygous often die in early life from thrombotic complications. Congenital protein C deficiencies are responsible for 2% to 5% of venous thromboses. Protein C is often 30% to 70% of the normal level in patients who are heterozygous and 5%, or less, in patients who are homozygous. The patients with protein C deficiencies have venous thromboses at an early age, especially in the lower extremity, cerebral, mesenteric, and renal veins. Arterial thrombosis is rare. Protein C and protein S deficiencies have been found in 15% to 20% of the patients with peripheral vascular disease who are younger than 50 years of age.34

The management of protein C deficiency includes prophylaxis with heparin or warfarin therapy during times of risk (ie, surgery, trauma, pregnancy). Fresh frozen plasma infusions can restore functional levels of protein C. Life-long anticoagulation therapy with warfarin is recommended for patients with protein C deficiencies who have had idiopathic, recurrent, or life-threatening thromboses.

Cutaneous necrosis is more likely to occur when warfarin anticoagulation therapy is offered to patients with protein C deficiencies. Consequently, all patients, especially those with protein C deficiencies, should undergo heparin therapy during the first 3 to 4 days of warfarin therapy, because protein C is decreased more rapidly than are coagulation factors II, IX, and X.

The histories of patients with congenital protein S deficiencies are similar to those histories of patients with deficiencies of protein C. Protein S has been identified as responsible for venous thromboses and, rarely, arterial thrombosis. However, recent data suggest that many of the patients with protein S deficiency also have APC-R, which may have been the major factor that led to the thromboses.

Protein S circulates either as a free protein (30% to 40%) or bound to the complement pathway protein, C4b-binding protein. C4b is an acute phase reactant and is increased during times of acute inflamation, which leads to a decrease in free protein S and thus contributes to the increased tendency toward thrombosis during inflammatory conditions.35 The management of protein S deficiency is similar to that of protein C deficiency.

Patients who are homozygous for protein C and S may have extensive cutaneous necrosis develop as newborns (purpura fulminans).

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Activated protein C resistance 

APC-R, the most common risk factor for venous thrombosis, was initially described by Dahlbäck et al36 in 1993 and accounts for 52% to 64% of the inherited causes of thromboses.37 The prevalence of APC-R in the general population of white origin ranges from 3% to 15%.38, 39, 40 However, it is relatively uncommon in populations of other origins. Many patients previously diagnosed with functional antithrombin and protein C and S deficiencies have been found to have APC-R.

APC-R is characterized by a poor anticoagulant response to activated protein C. When protein C is activated, it degrades the activated clotting factors V and VIII. A molecular defect in factor V occurs when arginine 506 is replaced with glutamine, rendering Va resistant to degradation by activated protein C. The altered factor V (factor V Leiden) retains its procoagulant activity, thus favoring thrombosis.

Patients with the heterozygous form of APC-R have as much as a seven-fold increased risk of venous thrombosis. Those who are homozygous have an increased risk of approximately 80 fold, and most will have at least one episode of thrombosis during their lifetime.38, 41 There is increasing evidence that APC-R is associated with arterial thrombosis, especially myocardial infarction. The risk for thrombosis is increased during pregnancy, surgery, and trauma, with the use of oral contraceptives, and in other situations that increase the risk for thrombosis. Patients with APC-R in high thrombotic risk situations should undergo thrombosis prophylaxis therapy, and those patients with recurrent or life-threatening thrombotic events should undergo life-long anticoagulation therapy with warfarin.

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Homocystinemia 

Homocysteine, a sulphur-containing amino acid formed during the metabolism of methionine, is metabolized with remethylation to methionine or with transsulfuration to cysteine. Elevated homocysteine levels may result from inherited disorders that alter enzyme activity in the transsulfuration and methylation pathways. In addition, acquired hyperhomocystinemia may occur in patients with deficiencies of vitamins B12 or B6 or folate. It was first suggested in 1969 that hyperhomocystinemia was associated with arterial thrombosis and atherosclerosis.42 It is now well established that hyperhomocystinemia is a definite risk factor for atherosclerosis, atherothrombosis, and recurrent venous thrombosis.

Although severe hyperhomocystinemia is rare, mild homocystinemia occurs in approximately 5% to 7% of the population.43 Homocystinemia may be detected with the measurement of fasting plasma homocysteine or after a standardized methionine-loading test (100 mg/kg). Hyperhomocystinemia is present if the homocysteine concentration after methionine loading is increased to more than two standard deviations above the mean. In addition to the patient with vitamin deficiencies, hyperhomocystin-emia has been found in patients with histories of renal failure, hypothyroidism, pernicious anemia, breast and pancreas carcinoma, and cigarette smoking.

Hyperhomocystinemia has been shown to cause endothelial disruption and dysfunction, platelet activation, and thrombus formation. When homocysteine is oxidized, potent oxygen radicals (especially hydrogen peroxide, hydroxyl radical, and superoxide radical) are formed. These superoxide radicals induce endothelial damage, smooth muscle proliferation, and activation of platelets and leukocytes. Hyperhomocystinemia alters the normal anti-thrombotic activity of the endothelium by enhancing the activity of factors VII and V and decreasing the activation of protein C by altering the expression of thrombomodulin. Hyperhomocystinemia-damaged endothelium has reduced nitric oxide production. Homocysteine inhibits the antithrombin binding activity of the endothelial heparan sulfate and indirectly stimulates platelet aggregation. Homocysteine interferes with the binding of tissue plasminogen activator. These toxic effects of hyperhomocystinemia contribute to the development of atherosclerotic plaques, arterial atherothrombosis (especially cerebral, coronary, and peripheral) events, and idiopathic venous thromboses.44, 45

It is clear that elevated plasma homocysteine concentration is a risk factor for atherosclerosis and arterial and venous thrombosis. Patients with premature atherosclerosis, or unexplained atherothrombosis, or venous thrombosis should undergo testing for hyperhomocystinemia. Patients with high homocysteine levels should undergo treatment with folate (1 to 5 mg/day, as much as 15 mg/day in patients with renal failure) or B12 or B6. The normalization of the homocysteine level usually occurs within 4 to 6 weeks.44 The normalization has returned platelet and endothelial cell function toward a normal level. Studies of clinical outcomes after normalization of homocysteine are in progress.

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Prothrombin gene variant (20210a) 

In 1996, Poort et al46 examined the prothrombin gene in patients with documented family histories of venous thrombophilia. A nucleotide change (a G to A transition) was detected at position 20210 in 18% of the patients.46 In “…a population based control study, the 20201A allele was identified as a common allele…” in 1.2% who had a three-fold increased risk of venous thrombosis.46 Although the patients with the 20201A allele are at risk for venous thrombosis, the mechanism for the increased risk is unclear, except that the patients have elevated levels of prothrombin (an identified risk factor for thrombosis). There are few reports of the homologous 20210AA genotype. The expected prevalence rate is 0.014%.46

Initial reports suggested that the prothrombin 20210G/A genotype was not related to arterial thrombotic disorders.47 Subsequent reports have indicated that the allele has a high prevalence rate (5.7%) in selected patients with arterial thromboses.48, 49 Patients with the 20210 allele have had increased frequency of cerebral and coronary thromboses. It has been suggested that the prothrombin 20210A allele and the factor V Leiden mutation will be found in 63% of families with thrombophilia.50

The management of the prothrombin gene variation has not been clearly defined, but is likely to require long-term anticoagulation therapy with warfarin for those patients with early or recurrent thromboses.

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Heparin cofactor II deficiency 

Heparin cofactor II is produced by the liver and is a specific inhibitor of thrombin. Heparin cofactor II deficiency is a rare condition that is transmitted as an autosomal dominant. It inactivates thrombin by binding to it in a 1:1 relationship. Heparin enhances the rate of thrombin inactivation by heparin cofactor II. Patients with heparin cofactor II deficiencies are at risk for thrombosis when the cofactor level becomes 50% or less than normal.51 Heparin cofactor II deficiencies have been reported, in a few patients, as a risk factor for venous, and fewer arte-rial, thromboses.

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Deficient plasminogen and plasminogen activator activity 

Increased thrombotic tendencies have been reported in patients with structural defects in plasminogen or defects in the plasminogen activator system. Twelve variant forms of the plasminogen molecule have been described.52 These variants have functional abnormalities, including altered active sites and the inability to form activator complexes. A few patients with recurrent thromboembolism have been identified as having decreased production of endothelial-derived plasminogen activator. Patients with these deficiencies of fibrinolysis may have arterial and venous thromboses and undergo treatment with long-term warfarin therapy.

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Clinical implications 

Most of the disorders of hypercoagulability contribute to venous thromboembolism. Of the patients with heterozygous protein factor deficiency, 60% to 80% will have venous thromboembolism develop by the ages of 40 to 45 years and 50% will have recurrent thromboembolism.53 All patients with juvenile, idiopathic, or idiopathic recurrent venous thrombosis and a family history of venous thrombosis should undergo testing for hypercoagulability. Venous thromboses in unusual sites (eg, mesenteric, portal, hepatic, cerebral, retinal, and so forth) are often associated with hypercoagulable disorders.54, 55

A hypercoagulable disorder should also be suspected in patients with juvenile, idiopathic, recurrent, or multi-level arterial thromboses (eg, 15% to 70% of young patients with arterial occlusive disease may have a hypercoagulable syndrome).56, 57 Arterial reconstructions have increased rates of failure in patients with hypercoagulable syndrome, with a six-fold increase in the need for a second procedure within 1 year after primary reconstruction in patients who are hypercoagulable.56, 58 The antiphospholipid syndrome has been detected in 36% of patients with failed vascular procedures.12, 57, 59 Twenty-one percent of patients with vascular surgical reconstructions had heparin-associated antiplatelet antibodies develop and had a 2.6-fold increase in graft failures.8 Patients with infrainguinal grafts and APC-R had patency rates of 48% and 33% at 1 and 3 years, and the “routine” vascular patients had 88% and 71% patency rates, respectively.60, 61 Patients with hypercoagulability and infrainguinal vascular reconstruction have an alarming frequency (20% to 27%) of acute thrombosis within the first 30 days of reconstruction when compared with healthy individuals (1.6% to 2%).34, 60 These adverse thrombotic events are reduced in patients who undergo treatment with heparin, provided that their hypercoagulable syndrome is not caused by heparin. Long-term warfarin and aspirin therapy substantially reduce the overall failure rates.34, 57, 58, 61

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When to test 

The patient with a suspected hypercoagulable disorder can undergo testing during the episode of thrombosis for heparin-associated antiplatelet antibodies, anticardiolipin antibodies, homocysteine, the Leiden mutation, and the prothrombin variant. The other factors may be consumed during the clotting process or reduced by the administration of warfarin, liver failure, or sepsis. The authors treat suspected hypercoagulable disorders with warfarin therapy for 6 months or more, until the patient have not had a thrombosis for 2 or more months. The warfarin therapy is then discontinued, and the patient undergoes treatment with heparin (usually low–molecular weight heparin) for 2 weeks. When the heparin therapy is discontinued, and 2 to 3 days later, blood is obtained for hypercoagulable studies. Heparin therapy is immediately restarted and warfarin therapy is begun while the physicians await the results of the studies.

If a patient is found to have one of the hypercoagulable conditions, the family of the patients should also undergo testing. In our experience, heparin-associated antiplatelet antibodies, the lupus anticoagulant, and homocystinemia are the more common causes of reconstructive arterial failures.

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Summary 

The recognition of acquired or congenital hypercoagulable disorders has major implications for the patient and the family. Congenital and acquired hypercoagulable defects are associated with increased risk of arterial and venous thrombosis and arterial reconstructive failures.

Greek mythology notes that Athena saved the blood from Medusa's body and gave it to Aesculapius. The blood from the left side of her body was a fatal poison, and the blood from the right side of her body had the power to revive the dead. It is hoped that a better understanding of the hypercoagulable disorders, although it would not cause patients to arise from their deathbeds, will reduce the morbidity and mortality.

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☆ Competition of interest: nil.

☆☆ Reprint requests: Dr Donald Silver, University of Missouri-Columbia, Department of Surgery, One Hospital Dr, Columbia, MO 65212.

★ 0741-5214/2000/$12.00 + 0  24/9/102322

PII: S0741-5214(00)90170-8

doi:10.1016/S0741-5214(00)90170-8

Journal of Vascular Surgery
Volume 31, Issue 2 , Pages 396-405, February 2000

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