Clotting factor II, or prothrombin, is a vitamin K–dependent proenzyme that functions in the blood coagulation cascade. Factor II deficiency is a rare, inherited or acquired bleeding disorder disorder with an estimated incidence of one case per 2 million population. 
Inherited factor II deficiency is an autosomal recessive disorder that can manifest as hypoprothrombinemia, a decrease in the overall synthesis of prothrombin; or as dysprothrombinemia, the synthesis of dysfunctional prothrombin. [2, 3, 4] Homozygous individuals are generally asymptomatic and have functional prothrombin levels of 2-25%. However, symptomatic individuals may experience one or more of the following  :
Excessive postoperative bleeding
In true hypoprothrombinemia, immunologic assays correlate well with functional assays in that both reveal low prothrombin values. Heterozygous patients are generally asymptomatic and have prothrombin levels of 50% or greater on both immunologic and functional assays.
In dysprothrombinemia, only the functional assay for prothrombin returns significantly reduced values, whereas the immunologic assay reveals normal values. Acquired factor II deficiency can be caused by severe liver disease, vitamin K deficiency, anticoagulant drugs (eg, warfarin), or the presence of an antibody directed against the protein. 
Aside from the prothrombin deficiencies, another disorder of prothrombin is the prothrombin 20210a mutation. First reported in 1996 as a familial cause of venous thromboembolism, the prothrombin 20210a mutation results in increased levels of plasma prothrombin and a concurrent increased risk for the development of thrombosis. 
Prothrombin 20210a has an estimated prevalence of 2% in whites. [7, 8] The mutation is more prevalent in those of southern European descent than in those of northern European descent, and it is rarely seen in Asians or Africans.  A study of patients in Turkey revealed the presence of the prothrombin 20210a mutation in 0.7% of subjects. 
Individuals carrying the prothrombin 20210a mutation have a 2- to 3-fold increased risk for developing thrombosis. [6, 10] One case-control study found evidence of an increased risk of developing an ischemic cerebrovascular event in men aged younger than 60 years with the prothrombin 20210a mutation.  A study of cancer patients in the Netherlands found that the presence of the prothrombin 20210a mutation in these patients may increase the risk of venous thrombosis to a level greater than that attributable to the malignancy alone. 
The prothrombin 20210a mutation can be identified without DNA analysis and should be considered in any patient experiencing a thrombotic event without other risk factors. Treatment with oral anticoagulants is useful in preventing recurrence in patients with the mutation who have already experienced a thrombotic event. Additionally, women who are known to carry the mutation may want to avoid oral contraceptives because of the additional risk of thrombosis.
Laboratory studies for factor II deficiency include coagulation studies and clotting factor assays (see Workup). Coagulation study results are as follows:
Prothrombin time (PT) is prolonged
Activated partial thromboplastin time (aPTT) is prolonged
Bleeding time is within reference range
Treatment of factor II deficiency is aimed at restoring circulating factor II to levels sufficient for hemostasis. Levels greater than 30% of normal are usually adequate. Treatment measures include fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), and vitamin K. Additionally, in patients with acquired factor II deficiency, the underlying cause should be found and treated. (See Treatment and Medication.)
The gene encoding prothrombin is primarily expressed in the liver  and is located on chromosome 11 in the region of the centromere.  It is composed of 14 exons and contains 24 kilobases of DNA.  The gene encodes a signal region, a propeptide region, a glutamic acid domain, two kringle regions, and a catalytic domain.  The enzyme gamma-glutamyl carboxylase, in the presence of vitamin K, converts the N- terminal glutamic acid residues to gamma-carboxyglutamic acid residues. These gamma-carboxyglutamic acid residues are necessary for the binding of prothrombin to phospholipids on platelet membranes.
The prothrombin 20210a mutation involves the substitution of an adenine for a guanine at position 20210 within the 3' untranslated region of the prothrombin gene.  This mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis, with a subsequent increase in protein expression. 
Because measurable prothrombin is present in all individuals with hypoprothrombinemia or dysprothrombinemia, authorities believe that the complete absence of prothrombin is incompatible with postnatal life. Studies of transgenic mice with a complete deficiency of prothrombin reveal embryonic lethality and neonatal death. [19, 20]
In the blood coagulation cascade, prothrombin is cleaved by factor Xa to form thrombin, an active serine protease.  This proteolytic reaction occurs on the phospholipid surfaces of platelets and requires calcium. Thrombin is responsible for inducing platelet aggregation and activating several other mediators in the coagulation cascade. It converts fibrinogen to fibrin, which then polymerizes to form a clot around platelet aggregates. Thrombin also converts factor XIII to factor XIIIa, an enzyme that cross-links and stabilizes fibrin polymers.
The prothrombotic effects of thrombin are ultimately suppressed by the binding of thrombin to thrombomodulin on endothelial cell surfaces to form a complex that activates protein C. Protein C then degrades factors Va and VIIIa to inhibit the coagulation cascade.
Thrombin also has cytokine and growth-factor functions, inducing mitosis and chemotaxis in cell lines, including smooth muscle, fibroblasts, endothelial cells, and mononuclear phagocytes.  Decreased levels or a dysfunctional structure of factor II can lead to absent or defective clot formation and dysfunctional platelet aggregation. Thus, thrombin functions not only in the clotting cascade, but also as a cytokine and growth factor capable of inducing mitosis and chemotaxis in several different cell lines.
Several specific missense mutations of the prothrombin gene have been documented. [23, 24, 25, 26] These single amino acid substitutions can cause hypoprothrombinemia and/or dysprothrombinemia. In fact, most hypoprothrombinemia-associated mutations are missense ones. 
A family in San Antonio, Texas, was found to have normal antigenic levels of prothrombin but half the normal levels of prothrombin activity. 
Two members of a family from Venezuela were found to have undetectable antigen levels and prothrombin activity levels at 4% of normal.  A mutation was identified that had resulted in the substitution of cystine for tyrosine at residue 44. Substitution of a cystine at residue 44, located in the aromatic stack region of the protein, would result in an abnormal folding of the protein and could be the cause for the observed lack of secretion of prothrombin. 
Other mutations, affecting various regions of the prothrombin gene, have also been described. Prothrombin Puerto Rico I involves an arginine to glycine substitution at position 457. [28, 29] Prothrombin Saint-Denis involves an aspartic acid to glutamine substitution at position 552.  Two novel mutations in the prothrombin gene were delineated in association with compound heterozygous type 1/2 prothrombin deficiency. 
Acquired factor II deficiency has several possible etiologies. Because prothrombin is synthesized almost exclusively in the liver, severe liver disease can have a dramatic impact on prothrombin levels. Vitamin K deficiency can also result in decreased prothrombin levels. Vitamin K is produced in the gut by enteric flora, and levels can be affected by intestinal malabsorption, bile duct obstruction, or antibiotic administration. 
Vitamin K deficiency can be iatrogenically induced by the administration of propylthiouracil or vitamin K antagonists such as warfarin. Vitamin K deficiency can also be seen in neonates.
Finally, acquired factor II deficiency can sometimes be observed in patients with lupus anticoagulant. [33, 34] These patients can develop specific prothrombin autoantibodies that form a complex with prothrombin and cause excessive clearance of prothrombin from the body. [35, 36] This condition, sometimes referred to as "lupus anticoagulant hypoprothrombinemia syndrome," is most often seen with systemic lupus erythematosus (SLE).  It is a rare cause of intracranial bleeding  and may be associated with severe thrombocytopenia. 
The lupus anticoagulant hypoprothrombinemia syndrome may also occur in individuals without SLE. Bleeding attibuted to acquired hypoprothrombinemia caused by antiphospholipid antibodies may follow acute adenovirus gastroenteritis and mycoplasma pneumonia.  The lupus anticoagulant hypoprothrombinemia syndrome is associated with a high mortality. 
Both congenital and acquired factor II deficiencies are rare. The prevalence of congenital factor II deficiency is approximately 1 per 1 to 2 million population. 
Congenital factor II deficiency is a lifelong bleeding disorder. Death can result because of massive hemorrhage from relatively minor accidents or trauma. Hemorrhage can also occur as a result of surgery if precautions are not taken. Intracranial bleeding is another serious sequela of this disorder. Rarely, hemarthroses can occur. 
Myocardial infarction is a rare complication in young people, with coronary thrombosis due to hypercoagulable states being one cause. A heterozygote prothrombin gene mutation (G-20210-A) and protein S deficiency were described in a 19-year-old with a myocardial infarction with normal coronary arteries. 
Race- sex-, and age-related demographics
Factor II deficiency has no known racial or ethnic predilection. Males and females are affected equally. Patients with severe congenital factor II deficiency present early in life, whereas those with less severe forms can present at any age. Acquired forms can be observed in all age groups.