Hypoprothrombinemia 

Prothrombin (factor II of the coagulation cascade) is a critical protein in hemostasis. Decreased levels of prothrombin can lead to a bleeding diathesis. The most common manifestations of hypoprothrombinemia are associated with mucocutaneous bleeding. However, hemorrhage involving deep structures can be observed with severe prothrombin deficiency.

Hypoprothrombinemia may be acquired or inherited. Acquired forms may be secondary to decreased production or increased consumption. Acquired isolated hypoprothrombinemia is usually autoimmune and associated with the lupus anticoagulant. A relatively common form of acquired hypoprothrombinemia is vitamin K deficiency. Levels of other vitamin K–dependent procoagulant factors (factors VII, IX, and X) and anticoagulant factors (protein C and protein S) are also decreased in vitamin K deficiency.

Inherited prothrombin deficiency is rare.^[1] Two phenotypes are described: hypoprothrombinemia (type I deficiency) and dysprothrombinemia (type II deficiency). In type I deficiency, prothrombin levels and prothrombin activity are reduced. In type II deficiency, prothrombin activity is reduced, but prothrombin levels are borderline or in the reference range. Both disorders are autosomal recessive. The prothrombin gene is found on chromosome 11. Heterozygotes for prothrombin deficiency have factor II levels of 30-60% of the reference range. Heterozygotes are usually asymptomatic. Compound heterozygotes who have type I and type II mutations are occasionally reported.

The treatment of hypoprothrombinemia depends on the underlying etiology. Plasma-derived products that contain factor II are available. Vitamin K-1 (phytonadione) is used to treat vitamin K deficiency as well as warfarin overdose. In autoimmune disease, treatment is not entirely straightforward, and immunosuppressive therapy is used in severe cases.

Thrombin is paramount to proper hemostasis. This powerful protease is at the core of the coagulation cascade. It not only plays a critical role in clot formation but also activates the protein C anticoagulant system by binding to thrombomodulin on the endothelial surface, indirectly controlling its own production.

Activated factor Xa converts prothrombin to thrombin on phospholipid surfaces in a calcium-dependent proteolytic reaction, which results in the cleavage of prothrombin at 2 sites. Activated factor Va is an enzymatic cofactor that increases the prothrombinase activity of factor Xa by more than 10,000-fold. Thrombin is a potent protease. Its most important function is the cleavage of fibrinogen to create insoluble fibrin. Cross-linking fibrin monomers stabilize the fibrin clot. Factor XIIIa, activated by thrombin, carries out this function.

Thrombin also stimulates platelet activation and converts factors V and VIII into activated cofactors for factors Xa and IXa respectively. In addition to its procoagulant properties, thrombin assists in controlling its own production by activating protein C when it is bound to thrombomodulin. Activated protein C inactivates factors Va and VIIIa by means of proteolytic cleavage. Protein S is a cofactor for activated protein C. Antithrombin can inactivate thrombin; heparin facilitates this process.

Prothrombin is a vitamin K–dependent protein. It contains 10 gamma-carboxylated glutamic acid residues. These residues are important for the calcium-dependent interactions with phospholipid surfaces. Vitamin K is necessary for the posttranslational gamma-carboxylation of glutamic acid residues in the amino terminus of vitamin K–dependent coagulation factors. Therefore, in the absence of vitamin K or in the presence of vitamin K antagonists (eg, warfarin), dysfunctional vitamin K–dependent clotting factors are produced and a bleeding diathesis ensues.

Lupus anticoagulants are a heterogeneous group of antibodies directed against phospholipids and phospholipid-binding proteins. Lupus anticoagulants prolong the clotting time in phospholipid-dependent tests. Lupus anticoagulants are associated with thrombotic symptoms in most patients; however, when prothrombin is their antigenic target, the patient can develop severe hypoprothrombinemia and hemorrhagic symptoms. This condition is known as lupus anticoagulant-hypoprothrombinemia syndrome.

Type I prothrombin deficiency (hypoprothrombinemia) is the result of decreased prothrombin production. Factor levels of 4-10% have been reported. Levels of factor II activity are also low. Type II prothrombin deficiency (dysprothrombinemia) is due to poor function of the prothrombin protein. Prothrombin antigen levels may be normal or low-normal, but activity is depressed.

Frequency

United States

Both acquired and inherited hypoprothrombinemia are exceedingly rare in the United States. Hypoprothrombinemia due to vitamin K deficiency is rarely seen because vitamin K injections are routinely given in the neonatal period.

International

The estimated prevalence of inherited prothrombin deficiency worldwide is 1 per 2,000,000 population. The prevalence is higher where consanguinity is common. In parts of the world where vitamin K is not routinely administered in the neonatal period, hypoprothrombinemia secondary to vitamin K deficiency is relatively common. The incidence of hemorrhagic disease of the newborn in the absence of active prophylaxis is about 1 in 500 newborns.

Mortality/Morbidity

In both acquired and inherited hypoprothrombinemia, the morbidity and mortality risks are related to the circulating level of factor II. The risks are less than 2% with severe deficiency, 2-10% with moderate deficiency, and 10-40% for mild deficiency.

In a prothrombin knockout-mouse model, complete prothrombin deficiency led to a 50% mortality rate on embryonic day 10.5.^[2] Some embryos survive to birth but die from hemorrhaging on the first day. In humans, severe life-threatening hemorrhage, including intracranial hemorrhage, is described in neonates with severe prothrombin deficiency. Severe prothrombin deficiency is likely to lead to spontaneous abortion and fetal demise in some cases. Complete prothrombin deficiency in humans has not been reported; this omission suggests that this condition is incompatible with life.

Race

No race predilection for hypoprothrombinemia is apparent. However, in 2003, the North American Registry for Rare Bleeding Disorders reported that 62% of patients with prothrombin deficiency in the United States and Canada were Hispanic.^[3]

Sex

Acquired hypoprothrombinemia associated with the lupus anticoagulant is slightly more common in women than in men. Severe inherited prothrombin deficiency typically has an autosomal recessive inheritance pattern. Therefore, unlike classic hemophilia, severe inherited prothrombin deficiency occurs with equal frequency in male and female individuals.

Age

Patients with inherited severe hypoprothrombinemia present early in life, whereas patients with mild forms present at various ages. Vitamin K deficiency is most common in young infants. Patients with autoimmune hypoprothrombinemia can present at any age.