Chapter 88: Hereditary Thrombophilia

• Risk factors for thromboembolism may be genetic and acquired (Table 88–1).

• Hereditary thrombophilia is a genetically determined increased risk of thrombosis.

• Up to 50% of patients presenting with a first deep venous thrombosis will have an abnormal laboratory test suggesting a thrombophilic defect, and patients with recurrent thromboses or with a strong family history are even more likely to have laboratory evidence of a thrombophilic state (Table 88–2).

• Up to 16% of patients with thrombophilia have inherited more than one abnormality.

• These inherited defects also interact frequently with acquired risk factors, such as inactivity, trauma, malignancy, or oral contraceptive use, to lead to clinical thrombosis.

Etiology and Pathogenesis

• Activated protein C (APC) resistance is an abnormally reduced anticoagulant response of a patient’s plasma that, in more than 90% of cases, is caused by a genetic abnormality of factor V (substitution of glutamine for arginine at position 506), which significantly retards inactivation of factor Va by APC. The abnormal factor V is generally referred to as “factor V Leiden.”

Clinical Features

• The factor V Leiden mutation occurs in 3% to 12% of Caucasians but is rare in other ethnic groups.

• Deep and superficial venous thromboses are the most common manifestations of factor V Leiden, which has been reported to account for 20% to 25% of first thromboembolic events.

• Heterozygosity for factor V Leiden increases the relative risk of developing venous thrombosis four to eight times. However, the vast majority of heterozygous carriers of this mutation will not develop thrombosis during their life. In contrast, it is estimated that one-half of homozygous carriers will have a clinically significant thrombotic episode during their lives.

• The evidence regarding the role of factor V Leiden in recurrent thrombosis is conflicting.

• Factor V Leiden induces a relatively mild hypercoagulable state, but the risks of thrombosis are greatly increased by combination with other inherited disorders, such as antithrombin deficiency, or with acquired risk factors, such as immobility or use of oral contraceptives. Use of contraceptives quadruples the risk of thrombosis in women with factor V Leiden.

• A significantly increased risk of arterial thrombosis has been reported in patients with factor V Leiden and other vascular risk factors, such as smoking.

Laboratory Features

• Patients with APC resistance can be identified by special coagulation assays.

• DNA-based assays provide confirmation for positive coagulation tests and distinguish homozygotes and heterozygotes.

Etiology and Pathogenesis

• Substitution of guanylic acid (G) for adenylic acid (A) at nucleotide 20210 in the 3′-untranslated end of the prothrombin gene leads to an elevated plasma prothrombin level and predisposes to thrombosis.

Clinical Features

• This mutation is found primarily in Caucasians.

• The mutation is associated with venous thrombosis in all age groups, sometimes in unusual sites. Arterial thromboses also occur.

• The mutation increases the odds ratio for thrombosis by 2- to 5.5-fold.

• The risk of thrombosis in patients with the G20210A polymorphism is further increased by another inherited thrombophilic state or by other risk factors such as oral contraceptive use or smoking.

Laboratory Features

• Diagnosis depends on DNA analysis to identify the mutation in the prothrombin gene.

Etiology and Pathogenesis

• Hyperhomocysteinemia is a plasma homocysteine level above the normal range.

• Severe hyperhomocysteinemia, or homocystinuria, is a rare autosomal recessive disorder with neurologic abnormalities, premature cardiovascular disease, stroke, and thromboses.

• Mild to moderate hyperhomocysteinemia is an independent risk factor for arteriosclerosis and arterial thrombosis and for venous thrombosis.

• Homocysteine appears to exert prothrombotic effects by interfering with endothelial cell function.

• Hyperhomocysteinemia may be the result of (1) mutations of enzymes involved in metabolism of sulfur-containing amino acids; or (2) nutritional deficiency of vitamin B₆, vitamin B₁₂, or folic acid; or (3) a combination of these causes.

Clinical Features

• Hyperhomocysteinemia is commonly associated with both venous and arterial thromboses.

• Hyperhomocysteinemia increases the odds ratio for venous thrombosis to 2.5 to 3.0.

• The combination of hyperhomocysteinemia with another prothrombotic disorder, such as factor V Leiden, substantially increases the risk of thromboembolism.

• Hyperhomocysteinemia is a strong predictor of recurrent thrombosis.

Laboratory Features

• Homocysteine levels can be measured on properly collected plasma.

• Mutations in the genes for enzymes concerned with homocysteine metabolism (eg, the MTHFR gene) can be determined using molecular biology techniques.

Etiology and Pathogenesis

• APC functions as an anticoagulant by inactivating activated factor V and activated factor VIII. Deficiency of protein C reduces this anticoagulant effect and leads to hypercoagulability.

• Protein C deficiency is inherited as an autosomal dominant trait.

• Affected heterozygotes have protein C levels of approximately 50%.

• Type I deficiency is caused by decreased synthesis of a normal protein.

• Type II deficiency is caused by production of an abnormally functioning protein.

Clinical Features

• Clinical expression of protein C deficiency is variable, perhaps because of coinheritance of other thrombophilic conditions.

• Most deficient patients are identified by screening apparently normal individuals who have no personal or family history of thrombosis.

• Deep and superficial venous thrombosis is the most common presentation. Venous thrombosis may occur in unusual sites. Arterial thrombosis is uncommon.

• By age 45 years, up to one-half of heterozygous persons from clinically affected families will have had venous thromboembolism.

• Homozygous patients with protein C levels less than 1% may develop severe thrombotic syndromes, such as neonatal purpura fulminans.

• Protein C deficiency may also be responsible for warfarin skin necrosis (see Chap. 90).

Laboratory Features

• Protein C deficiency may be detected by properly performed protein C assays.

• Immunoassays can distinguish type I deficiencies (decreased antigen, decreased activity) from type II (normal antigen, decreased activity).

• The large numbers of mutations thus far identified make DNA analysis impractical.

• In patients who have been treated with warfarin, it is necessary to wait at least 2 weeks after stopping warfarin therapy before measuring protein C levels.

Etiology and Pathogenesis

• Protein S functions as an anticoagulant by enhancing the activity of APC and also may directly inhibit factors Va, VIIIa, and Xa.

• Plasma protein S circulates both unbound (free) and bound to C4b-binding protein. Only the free form is active.

• Protein S deficiency is inherited as an autosomal dominant trait.

• Protein S deficiency may be due to reduced synthesis of active protein (type I), normal synthesis of a defective protein (type II), or low levels of free protein S (the active form) combined with normal levels of bound protein S (type III).

Clinical Features

• The clinical features of inherited protein S deficiency are similar to those of protein C deficiency.

• Reduced levels of protein S occur in a number of clinical conditions, including oral contraceptive use, pregnancy, oral anticoagulant therapy, disseminated intravascular coagulation, liver disease, nephrotic syndrome, and inflammatory diseases.

Laboratory Features

• For screening purposes, estimation of free protein S antigen or APC-cofactor anticoagulant activity is better than determining total protein S antigen.

• Assessment of total and free protein S and of protein S activity permits classification into types I, II, and III.

• The high frequency of acquired protein S deficiency makes it difficult to identify hereditary defects.

• DNA techniques may be useful within a family with a previously established mutation, but the large number of mutations otherwise limit their value.

Etiology and Pathogenesis

• Antithrombin is a protease inhibitor that forms irreversible, inactive complexes with thrombin and factors IXa, Xa, and XIa in reactions that are accelerated by heparin or heparan sulfate on endothelial surfaces.

• Antithrombin deficiency is inherited as an autosomal dominant trait.

• Type I deficiency is a result of reduced synthesis of the antithrombin protein.

• Type II deficiency is a result of production of an antithrombin protein with abnormal function.

Clinical Features

• Venous thrombosis of the lower extremities is the most common presentation. Venous thrombosis may also occur in unusual sites. Arterial thrombosis occurs infrequently.

• Antithrombin deficiency is found in about 1% of individuals younger than 70 years of age with a first documented venous thrombosis.

• The odds ratio for thrombosis in patients with antithrombin deficiency is 10 to 20.

• The occurrence of thrombosis peaks in the second decade of life.

• Coinheritance of another gene for thrombophilia or coexistence of prothrombotic environmental factors substantially increases the risk of thrombosis.

• Antithrombin deficiency with values less than 5% is extremely rare and causes severe arterial and venous thromboses.

• Resistance to heparin therapy occurs frequently in patients not deficient in antithrombin, and is not a useful indicator of the deficiency.

Laboratory Features

• Antithrombin deficiency can be detected using appropriate functional assays. Immunologic assays are needed to distinguish between type I and type II defects.

• Antithrombin activity levels usually range from 40% to 60% in deficient patients.

• Antithrombin activity may be reduced to similar levels by mild liver disease, thrombosis, or heparin therapy, and it may be necessary to repeat the assays and to perform family studies to establish the diagnosis.

• Factor VIII levels above 150% of normal have been defined as an independent risk factor for thrombosis.

• Preliminary data suggest that elevation of levels of factors V, IX, X, and XI above 150% similarly predispose to thrombosis.

• The mechanism of elevation of coagulation factor levels is unknown. Pathogenesis of the thrombi may be increased thrombin generation.

• The clinical features of patients with elevated factor VIII levels are those of patients with other forms of thrombophilia.

• Levels of factor VIII antigen are increased corresponding to factor VIII procoagulation activity.

• Dysfibrinogenemia is a qualitative defect in the molecule that can be asymptomatic (50%), or lead to either bleeding (30%) or thrombosis (20%). See Chapter 80.

• Dysfibrinogenemia is found in approximately 0.8% of patients presenting with thromboembolism.

• Patients with thrombotic dysfibrinogenemia usually present with venous thrombosis in the third to fourth decade of life.

• These patients have an increased rate of spontaneous abortion and stillbirth and may have postpartum hemorrhage.

• Prolongation of a dilute thrombin time or a reptilase time, and a disparity between levels of immunoreactive and clottable fibrinogen are common in dysfibrinogenemia.

• Hereditary defects of the fibrinolytic system or of thrombomodulin are potential causes of thrombophilia but are not yet clearly established.

• There is increasing consensus that routine testing for thrombophilia in patients with venous thromboembolism in routine practice is not useful because of a complete lack of clinical consequences and the associated costs.

• Nevertheless, when the choice for testing is made, comprehensive analysis of patients with venous thromboembolism should include the assays for the common and rare causes of thrombophilia as listed in Table 88–1.

• Thrombophilic factors can be evaluated in patients receiving oral anticoagulants, except for protein C resistance, and protein C and protein S levels. Proteins C and S can be assayed in blood from patients who have received heparin therapy instead of oral anticoagulants for approximately 2 weeks before performing the tests. Factor V Leiden genotype can be performed instead of testing for APC resistance.

• Women with prior thromboembolism or with a strong family history of thromboembolism may be evaluated for thrombophilia before oral contraceptives are administered.

• Children with venous or arterial thrombosis are likely to have thrombophilia.

• Diagnostic studies for thrombophilia should be considered for women with recurrent midtrimester fetal loss or other adverse pregnancy outcomes.

• Patients with thrombophilia who develop thrombosis or pulmonary embolism should be treated according to standard protocols for treatment of venous thromboembolism—that is, they should initially receive standard treatment with heparin followed by vitamin K antagonists to maintain the INR between 2 and 3. There is no need for prolonged treatment after a first episode of venous thromboembolism.

• After a recurrent thromboembolic event in a patient with thrombophilia, prolonged anticoagulant treatment is advised, sometimes for indefinite duration.

• If oral anticoagulant therapy is not continued, antithrombotic prophylaxis with low-molecular-weight heparin can be initiated with high-risk events such as surgery, trauma, an intercurrent infection, or immobility.

• B vitamins and folic acid are known to reduce plasma homocysteine levels, but their preventive value is not established. In clinical practice, however, this treatment is often prescribed.

• Low-molecular-weight heparin therapy should be considered for pregnant women who have had previous thromboembolism. The optimal dose of heparin in this situation is subject of ongoing clinical trials.

• Venous thromboembolism that occurs during pregnancy requires heparin throughout the pregnancy and anticoagulant therapy for 4 to 6 weeks postpartum (see Chap. 87).