Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein S defects

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Prothrombin G20210A mutation and thrombosis

The prothrombin G20210A mutation was first described by Poort et al in 1996 [1]. In this initial study, 28 subjects from families with a documented history of venous thrombosis were assessed. Specifically, the 3′ untranslated region of the prothrombin gene was assessed by polymerase chain reaction by direct sequencing. It was found that 18% of this patient population had a prothrombin gene G20210A mutation in the 3′ untranslated region. A healthy control group also was studied, and the mutation

Antithrombin defects

Antithrombins (ATs) were first described in 1939 by Brinkhous et al [8]. The first large survey of ATs was reported by Seegers et al in 1952 [9]. Egeberg, in 1965, first noted the association between AT deficiency and thromboembolic complications in a Norwegian family [10]. Antithrombin is an alpha-2-globulin composed of 432 amino acids with a molecular weight of approximately 58,000 daltons [11], [12]. It is synthesized in liver and endothelial cells [13], [14]. Its specific characteristics

Hereditary defects of antithrombin

“Hereditary thrombophilia” initially was the term used to describe congenital AT deficiency; however, this term now is used generically for all the hypercoagulable or prethrombotic disorders caused by a hereditary defect. Hereditary thrombophilia also includes congenital heparin cofactor II, protein C, protein S, activated protein C resistance (factor V Leiden and other factor V mutations), plasminogen, and other similar defects. Hereditary deficiency of AT usually is inherited as an

Heparin cofactor II defects

Heparin cofactor II (HC-II) was first discovered by Briginshaw and Shanberge [92] when they noticed that besides the rapid inhibition of thrombin by heparin, which could be reversed by addition of polybrene or protamine, there was a slow, time-dependent inhibition representing an irreversible decrease in thrombin; this second inhibitory effect was called heparin cofactor A. Briginshaw and Shanberge also noted that unlike the activity of AT, their heparin cofactor A had no inhibitory effect on

Hereditary deficiency of heparin cofactor II

Many assays are available for assessing HC-II activity, and concomitant with assay availability have been the finding of congenitally deficient patients and the definition of acquired HC-II deficiency [95]. Shortly after the availability of specific assays, the first case of hereditary HC-II was reported by Tran et al in 1985 [96]; the patient was a 42-year-old woman with left middle cerebral artery thrombosis and an HC-II level that was 50% of normal. Two of four additional family members had

Acquired heparin cofactor II deficiency

Because HC-II is a normal physiologic inhibitor of thrombin, it is expected that with significant activation of the procoagulant system and subsequent thrombin generation, HC-II would be consumed, much like AT. Heparin cofactor II is decreased markedly in disseminated intravascular coagulation. Heparin cofactor II activity has been studied in patients with nephrotic syndrome and found to remain normal, unlike AT activity, which commonly is decreased [94], [95], [104]. Heparin cofactor II is

Summary

These defects are not as common as factor V Leiden, but they are more common than many other hereditary procoagulant defects. The incidence of the prothrombin gene (G20210A) mutation is not yet known with certainty, but it may approach or even exceed that of factor V Leiden. These defects also seem less common than hereditary sticky platelet syndrome; however, they are all common enough that they always should be considered in any individual with unexplained thrombosis and should be part of the

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