What is the pathophysiology of hypoprothrombinemia?

Updated: Jun 16, 2021
  • Author: J Nathan Hagstrom, MD; Chief Editor: Cameron K Tebbi, MD  more...
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Answer

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 (LAHS).

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.


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