Inherited Thrombotic Disorders
Inherited thrombotic disorders are associated with genetic mutations that result in deficiencies of one or more of the naturally occurring inhibitors such as AT, heparin cofactor II, protein C, and protein S. Increased procoagulant factor such as in prothrombin G20210A mutation is associated with thrombosis. Other causes for inherited thrombotic disorders are AT, proteins C and S deficiencies, factor V Leiden, or an inherited form of hyperhomocysteinemia caused by an enzyme deficiency (see Table 19.2).
Protein C is a vitamin K-dependent protein made in the liver. Protein C circulates in the form of zymogen. Protein C should be activated to a serine protease (activated protein C) in order to exert its inhibitory effects against the clotting factors. Protein C is activated by the action of thrombin-thrombomodulin complex and protein S as a cofactor1,2,4 (Fig. 19.3).
AT deficiency was first discovered in 1965.1 This disorder is inherited as an autosomal dominant disorder. It has been reported that 1 in 600 people have AT deficiency.1 There are two types of AT deficiencies: type I and type II. Type I is a quantitative disorder in which there is a reduction in the concentration of AT. Type II is a qualitative disorder in which the concentration of AT is normal but the molecule is functionally abnormal. Deficiency of AT is associated with recurrent venous thrombosis, which may include almost every vein site.1 The thrombotic event may be primary (in the absence of triggering factors) or may be followed by another risk factor such as pregnancy, surgery, or any other acquired factors. Acquired AT deficiency may be associated with DIC, liver disease, nephrotic syndrome, oral contraceptives, and pregnancy.1
Heparin cofactor II was first discovered in 1974.3 Heparin cofactor II is inherited as an autosomal dominant trait. It is a heparin-dependent factor whose inhibitory effect is primarily against thrombin. Many studies have shown the heparin cofactor deficiency alone is not associated with thrombosis.1
Protein C deficiency is inherited as an autosomal dominant trait. Similar to AT deficiency, there are two types of protein C deficiencies: type I (quantitative defi ciency) and type II (qualitative deficiency). Type I deficiency is the most common form and is associated with both reduction of immunologic and functional activity of protein C to 50% of normal. Type II is characterized by a normal amount of an abnormal protein.4 More than 160 different protein C mutations has been reported between the two types.1,4 Most of the mutations are missense or nonsense mutations. The most common complications associated with protein C deficiency are venous thromboembolism in heterozygous adults. Other reported complications are arterial thrombosis, neonatal purpura fulminans in homozygous newborns, and warfarin-induced skin necrosis.1
Many studies show that most patients with protein C deficiency alone are asymptomatic.1 This finding indicates that thrombotic episodes may be provoked by some additional inherited or acquired risk factors in these patients. Acquired protein C deficiency may be associated with vitamin K deficiency, liver disease, malnutrition, DIC, and warfarin therapy.1
Protein S deficiency was discovered in 1984.1 It is inherited in an autosomal dominant fashion. Protein S circulates in plasma in two forms: free (40%) and bound to C4b-binding protein (60%). The cofactor activity of protein S is carried primarily by free protein S. As with AT and protein C, protein S deficiency is divided into two types. Type I is a quantitative disorder in which total protein S (free and bound), free protein S, and protein S activity levels are reduced to about 50% of normal.1 Type II protein S is a qualitative disorder deficiency and is divided into type IIa and type IIb. In type IIa protein S deficiency, free protein S is reduced while total protein S is normal. In type IIb, both free and total protein S levels are normal .1 Type IIb protein S deficiency has been reported in patients with factor V Leiden. Similar to protein C deficiency, many patients with thrombosis have additional inherited or acquired risk factors.1 Most patients with protein S deficiency may experience venous thrombosis. However, arterial thrombosis has been reported in 25% of patients with protein S deficiency. 1 Acquired protein S deficiency may be associated with vitamin K deficiency, liver disease, and DIC.
Activated Protein C Resistance (Factor V Leiden)
APCR is an autosomal dominant disorder discovered in 1993.1,4 APCR was found in 20% to 60% of patients with recurrent thrombosis with no previously recognized inherited thrombotic disorder. The majority of cases (92%) are inherited and caused by mutation of factor V Arg506Gln, referred to as factor V Leiden.1 Factor V Leiden is the most common inherited cause for thrombosis in the white population of northern and western Europe. In the United States, factor V Leiden is seen in 6% of whites.1 The homozygous form of factor V Leiden has a 80-fold increased risk of thrombosis, while heterozygous carriers have a 2- to 10-fold increase in thrombosis.1 Recall that factors V and VIII are inactivated by the protein C-protein S complex. Mutated factor V, factor V Leiden, is not inactivated and leads to excessive clot formation. The thrombotic risks are further increased if other inherited or acquired risk factors coexist. The thrombotic complications associated with factor V Leiden are venous thromboembolism (VTE). Another reported complication is recurrent miscarriage. Factor V Leiden has also been reported as a risk factor for myocardial infarction. Smoking increases the risk of thrombosis to 30-fold in individuals who have factor V Leiden.1 Other causes of activated protein C (8%) are related to pregnancy, oral contraceptives, cancer, and other acquired disorders (Fig. 19.4).
APCR may be evaluated by coagulation assays, which include a two-part aPTT test. The principle of the test is the inhibition of factor Va by APC, which will cause prolongation of aPTT. Therefore, the aPTT is performed on patient plasma with and without APC. The results are expressed in a ratio.1
Patient aPTT + APC
Patient aPTT - APC
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