Prothrombin (Factor II) Deficiency

Disease Overview

Quick first described prothrombin (factor II, FII) deficiency, a very rare coagulation disorder, in 19471 and further described the condition in 19552 and 1962.3 In 1969 Shapiro reported the first prothrombin abnormality, prothrombin Cardeza, in which the activity was moderately decreased but the antigen level was normal.4,5

Thrombin, which is derived from the Greek word thrombos, meaning “to clot”, is a serine protease. It is synthesized in the liver as the inactive zymogen prothrombin. Prothrombin is a 72 KD, vitamin K dependent glycoprotein with a plasma concentration of 100 ug/ml and a half-life of approximately 3 days.6,7

Both the tissue factor and the contact factor pathways produce factor Xa (FXa), which is part of the prothrombinase complex with factor Va (FVa) and phospholipid. In the presence of calcium, FXa sequentially cleaves two peptide bonds in prothrombin to form thrombin.8 Thrombin in turn proteolytically cleaves fibrinogen to fibrin and is critical in the formation of a stable fibrin clot.

Thrombin has various functions in the hemostatic pathway. It promotes platelet activation, activates factor XIII (FXIII) to crosslink the fibrin clot, enhances clot stability by activating thrombin-activatable fibrinolysis inhibitor (TAFI), and upregulates its own production through feedback mechanisms. These mechanisms further enhance activation of factor IX (FIX), factor VIII (FVIII), and FV.9-12

The procoagulant activity of thrombin’s is carefully regulated to generate sufficient fibrin to stop bleeding but at the same time prevent excessive clot formation. When bound to thrombomodulin, thrombin downregulates the coagulation cascade by activating protein C, which in turn inactivates FVIIIa ( and FVa). In addition, members of the serine protease inhibitor (serpin) superfamily, which includes antithrombin, heparin cofactor II, and protease nexin I, inhibit the catalytic activity of thrombin, thus limiting clot formation. The presence of glycosaminoglycans such as heparin increases the activity of these serpins.11

Thrombin interacts via proteinase-activated receptors (PARs) on endothelial cells. This interaction leads to the release of tissue plasminogen activator (tPA) and up-regulation of cell surface molecules, which increase the rate of tPA conversion of plasminogen to plasmin, enhancing thrombolysis.13 Thrombin also plays a role in cytokine production as well as vessel wall biology. This includes regulation of vessel tone, smooth muscle cell proliferation, angiogenesis, atherogenesis, and vascular development.14-16

There are two types of inherited prothrombin deficiency. Type I or hypoprothrombinemia involves a decreased level of normally functioning protein. This condition is associated with a proportional decrease in protein antigen and activity. Type II or dysprothrombinemia is characterized by a normal antigen level with a decreased level of activity.

The hemostatic level of prothrombin is believed to range between 20% and 40%. The half-life is approximately 3 days.6,7 There are no reports in the literature of aprothrombinemia and complete deficiency is thought to be incompatible with life. In a murine FII knock-out model, complete prothrombin deficiency resulted in either embryonic or neonatal death.17

Acquired prothrombin deficiency can occur in persons with vitamin K deficiency or liver disease. The acquired deficiency may also occur in people receiving warfarin therapy and in the presence of inhibitors similar to those seen with a lupus anticoagulant.

The prothrombin gene comprises 20.3 kilobases and is located on chromosome 11p11.2. Isolated prothrombin deficiency is due to defects in the prothrombin gene and follows an autosomal recessive inheritance pattern. In addition combined deficiencies of the vitamin K dependent proteins, FII, FVII, FIX, and FX can result from an abnormality in the gamma-glutamyl carboxylase gene or the vitamin K epoxide reductase complex.18

Two groups of mutations associated with dysprothrombinemia have been described: those that produce defects in prothrombin activation and those associated with formation of a defective thrombin molecule. In the first group, the activation of prothrombin by FXa in the prothrombinase complex is reduced, but the thrombin that is generated is fully functional. In the second group, the thrombin that is produced is functionally abnormal either because of altered interactions with fibrinogen or abnormalities in the catalytic region of thrombin itself.5,10,19 All dysprothrombinemia mutations described to date are missense mutations located throughout the serine protease domain with many around the catalytic triad. In contrast the hypoprothrombinemia mutations described are also primarily missense mutations but also contain nonsense mutations and deletions. Missense mutations leading to hypoproteinemia lead to structural changes that affect secretion from cell or lead to rapid degradation (see references 24 and 25 for details).

Additionally, the prothrombin 20210 guanine to adenine mutation, first described in 1996, is associated with an increased risk of thrombosis. The G20210A gene variation located in the 3’ untranslated region results in higher baseline levels of prothrombin.20 Heterozygotes with this mutation have a 3-5 fold increased risk of venous thromboembolism; homozygote individuals have an even higher risk.20,21 This mutation is found in 2% to 3% of Caucasians and in 4% to 8% of subjects presenting with a first venous thromboembolus.9,20 The prevalence of the prothrombin 20210 mutation was also significantly higher in a group of pregnant women with venous thromboembolism than in those without.22,23

Occurring in approximately 1 in 1 to 2 million people, prothrombin deficiency is a very rare autosomal recessive coagulation disorder, with higher rates of the deficiency being reported in regions and ethnic groups with increased rates of consanguinity.6 Many of the patients who have been genotyped are homozygous for the same mutation rather than being compound heterozygotes.