You are in: eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders Factor IIArticle Last Updated: Feb 15, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Christopher J Steen, MD, Staff Physician, Department of Dermatology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School Christopher J Steen is a member of the following medical societies: Alpha Omega Alpha and Sigma Xi Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Pere Gascon, MD, PhD, Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain Editors: Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Ronald A Sacher, MB, BCh, MD, FRCPC, Director of the Hoxworth Blood Center, Professor, Departments of Internal Medicine and Pathology, University of Cincinnati Medical Center; Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine; Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University Author and Editor Disclosure Synonyms and related keywords: acquired factor II deficiency, inherited factor II deficiency, deficiency of factor II, prothrombin deficiency, FII, F II, prothrombin, vitamin K–dependent proenzyme, vitamin K deficiency, prothrombin abnormality, clotting, coagulation, blood coagulation cascade, hypoprothrombinemia, dysprothrombinemia, prothrombin complex concentrates, prothrombin 20210a, thrombophilia INTRODUCTIONSection 2 of 10
  BackgroundClotting 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. In 1947, Quick and colleagues were the first to describe a deficiency of factor II; in 1969, Shapiro and colleagues were the first to report a structural prothrombin abnormality. Inherited factor II deficiency is an autosomal recessive disorder that can manifest as hypoprothrombinemia; a decrease in the overall synthesis of prothrombin; or dysprothrombinemia, the synthesis of dysfunctional prothrombin (Baudo, 1972; Girolami, 1998). Homozygous individuals are generally asymptomatic and have functional prothrombin levels of 2-25%. However, symptomatic individuals may experience easy bruising, epistaxis, soft tissue hemorrhage, excessive postoperative bleeding, and/or menorrhagia. 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 assay. In dysprothrombinemia, only the functional assay for prothrombin returns significantly reduced values, while 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 (Bajaj, 1985). The gene encoding prothrombin is primarily expressed in the liver (Royle, 1987) and is located on chromosome 11 in the region of the centromere (Degen, 1992). It is composed of 14 exons and contains 24 kilobases of DNA (Degen, 1992). The gene encodes a signal region, a propeptide region, a glutamic acid domain, 2 kringle regions, and a catalytic domain (Degen, 1992). 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. Since measurable prothrombin is present in all individuals with hypoprothrombinemia or dysprothrombinemia, authorities believe that 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 (Sun, 1998; Sun, 2002). 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 (Poort, 1996). While the exact mechanism of this disorder has not been elucidated, 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 (Pollak, 2002). This mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis with a subsequent increase in protein expression (Ceelie, 2004). Prothrombin 20210a has an estimated prevalence of 2% in whites (Rosendaal, 1998; Atasay, 2003). The mutation is more prevalent in those of southern European descent than in those of northern European descent and is rarely seen in Asians or Africans (Rosendaal, 1998). A recent study of patients in Turkey revealed the presence of the prothrombin 20210a mutation in 0.7% of subjects (Irdem, 2005). Individuals carrying the mutation have a 2- to 3-fold increased risk for developing thrombosis (Poort, 1996; Margaglione, 1998). 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 (Lalouschek, 2005). 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 (Blom, 2005). The mutation can be identified with DNA analysisand 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. PathophysiologyIn the blood coagulation cascade, prothrombin is cleaved by factor Xa to form thrombin, an active serine protease (Narayanan, 1999). 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 (Zhou, 1998). Decreased levels or a dysfunctional structure of factor II can lead to absent or defective clot formation and dysfunctional platelet aggregation. Several specific missense mutations of the prothrombin gene have been documented (Akhavan, 2000; Sun, 1999; Wang, 2004; Jayandharan, 2005). These single amino acid substitutions can cause hypoprothrombinemia and/or dysprothrombinemia. A family in San Antonio, Tex, was found to have normal antigenic levels of prothrombin but half the normal levels of prothrombin activity (Sun, 1999). A single guanine-to-adenine mutation was found, which resulted in the substitution of His for Arg at residue 320. The arginine 320–to–isoleucine 321 bond is 1 of 2 sites in prothrombin cleaved by factor Xa to form thrombin. Substitution of histidine for arginine at this site resulted in the blockage of factor Xa cleavage, forming a dysfunctional molecule and resulting in dysprothrombinemia. Two members of a family from Venezuela were found to have undetectable antigen levels and prothrombin activity levels at 4% of normal (Sun, 2001). 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 gene, have also been described. 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 (Bhat, 2003). 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 (Baudo, 1990). These patients can develop specific prothrombin autoantibodies that form a complex with prothrombin and cause excessive clearance of prothrombin from the body (Cote, 1997; Vivaldi, 1997). FrequencyUnited StatesBoth congenital and acquired factor II deficiencies are rare. InternationalOnly 30 cases of congenital factor II deficiency have been documented worldwide (Degen, 1995). Mortality/MorbidityCongenital 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 (Baudo, 1972). RaceThis disorder has no known racial or ethnic predilection. SexMales and females are affected equally. AgePatients 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. CLINICALSection 3 of 10
HistoryPatients with a factor II deficiency may report a family history of bleeding disorders. They may also report a history of the following symptoms:
Physical
Causes
DIFFERENTIALSSection 4 of 10
Cryoglobulinemia Cushing Syndrome Disseminated Intravascular Coagulation Dysfibrinogenemia Factor IX Factor V Factor VII Factor VIII Factor XI Deficiency Factor XI Deficiency Factor XIII Hemolytic-Uremic Syndrome Hemophilia, Overview Immune Thrombocytopenic Purpura Multiple Myeloma Myelodysplastic Syndrome Osler-Weber-Rendu Disease Scurvy Thrombotic Thrombocytopenic Purpura Vitamin K Deficiency Waldenstrom Hypergammaglobulinemia Wiskott-Aldrich Syndrome
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| Drug Name | Fresh frozen plasma |
|---|---|
| Description | Plasma is the fluid compartment of blood containing the soluble clotting factors. Indications for using FFP include bleeding in patients with congenital coagulation defects and multiple coagulation factor deficiencies (severe liver disease). |
| Adult Dose | Loading dose: 15-20 mL/kg IV Maintenance dose: 3-6 mL/kg IV q12-24h (half-life of factor II is ~3 d) |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | A - Safe in pregnancy |
| Precautions | Viral contamination and infection are possible but unlikely because of prescreening; may induce an anamnestic response |
| Drug Name | Prothrombin complex concentrates |
|---|---|
| Description | Product made from pooled human plasma. PCC contains factors II, VII, IX, X; protein C; and trace amounts of heparin to guard against thrombosis. Currently recommended for patients with coagulation factor inhibitors only. |
| Adult Dose | Dosages must be clinically determined and are case dependent; typical dosage is 50-125 U/kg; because of risk of thrombotic complications, no more than 3 standard doses should be administered in first 36-48 h |
| Pediatric Dose | Administer as in adults |
| Contraindications | Documented hypersensitivity |
| Interactions | When administered simultaneously with rFVIIa, may lead to thrombotic complications; should not be used in combination with antifibrinolytics as may increase risk of thrombosis |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Monitor for thrombotic complications and hypersensitivity reaction; clinical response, PT, and aPTT should be monitored closely throughout therapy; if no clinical response, another treatment modality should be considered |
Agents in this class may play essential role in the function of clotting factors.
| Drug Name | Phytonadione (AquaMEPHYTON) |
|---|---|
| Description | Fat-soluble vitamin K absorbed by the gut and stored in the liver. Necessary for the function of clotting factors in the coagulation cascade. Used to replace essential vitamins not obtained in sufficient quantities in the diet or to further supplement levels. |
| Adult Dose | 10 mg PO/IV/IM/SC to replete liver stores |
| Pediatric Dose | 1 mg IM as single dose |
| Contraindications | Documented hypersensitivity |
| Interactions | Antagonizes effects of warfarin, sodium, and dicumarol |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Ineffective in hereditary hypoprothrombinemia; rapid infusion may result in flushing and a feeling of constriction in chest; relatively nontoxic, even in massive doses |
Article Last Updated: Feb 15, 2006
