Factor II

Factor II

Author: Robert A Schwartz, MD, MPH; Chief Editor: Emmanuel C Besa, MD more...

Updated: Jul 12, 2012

Background

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. In 1947, Quick and colleagues were the first to

describe a deficiency of factor II[1]

; in 1969, Shapiro and colleagues were the first to report a structural prothrombin

abnormality.[2]

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.[3, 4] 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 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.[5]

The gene encoding prothrombin is primarily expressed in the liver[6] and is located on chromosome 11 in the region of

the centromere.[7] It is composed of 14 exons and contains 24 kilobases of DNA.[7] The gene encodes a signal

region, a propeptide region, a glutamic acid domain, 2 kringle regions, and a catalytic domain.[7]

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.

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.[8, 9]

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.[10]

Although 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.[11]

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This mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis, with a subsequent

increase in protein expression.[12]

Prothrombin 20210a has an estimated prevalence of 2% in whites.[13, 14] 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.[13]

A study of patients in Turkey revealed the presence of the prothrombin 20210a mutation in 0.7% of subjects.[15]

Individuals carrying the prothrombin 20210a mutation have a 2- to 3-fold increased risk for developing thrombosis.[10,

16] 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.[17] 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.[18]

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.

Prothrombin plays a role in a role in chronic urticaria and various vascular disorders.[19, 20] Livedo vasculopathy is

associated with immunoglobulin (Ig)M antiphosphatidylserine-prothrombin complex antibody.[21] The presence of

antiphosphatidylserine-prothrombin complex antibodies and histopathological necrotizing vasculitis in the upper-

to-middle dermis indicates cutaneous leukocytoclastic angiitis rather than cutaneous polyarteritis nodosa.[20]

Chronic urticaria is an autoimmune disease found in one half of cases with circulating histamine-releasing

autoantibodies, mainly directed against the high affinity IgE-receptor Fc ε RI on mast cells and basophils or against

IgE. Chronic urticaria may be associated with the activation of coagulation that is due to the involvement of eosinophils

and a tissue factor pathway, with generation of thrombin potentially contributing to an increased vascular permeability.

This may provide the rationale for clinical trials on the use of anticoagulant drugs as adjuvant treatment in patients with

chronic urticaria.

Pathophysiology

In the blood coagulation cascade, prothrombin is cleaved by factor Xa to form thrombin, an active serine protease.[22]

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.[23] 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.[24, 25, 26, 27] These single amino

acid substitutions can cause hypoprothrombinemia and/or dysprothrombinemia.

A family in San Antonio, Texas, was found to have normal antigenic levels of prothrombin but half the normal levels of

prothrombin activity.[25] A single guanine-to-adenine mutation was found, which resulted in the substitution of histidine

for arginine 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.[25]

Two members of a family from Venezuela were found to have undetectable antigen levels and prothrombin activity

levels at 4% of normal.[28] 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.[28]


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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.[29, 30]

Prothrombin Saint-Denis involves an aspartic

acid to glutamine substitution at position 552.[31]

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.[32]

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.[34]

Epidemiology

Frequency

United States

Both congenital and acquired factor II deficiencies are rare.

International

Only approximately 30 cases of congenital factor II deficiency have been documented worldwide.[37]

Mortality/Morbidity

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.[3]

Race

Factor II deficiency has no known racial or ethnic predilection.

Sex

Males and females are affected equally in cases of factor II deficiency.

Age

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.

Contributor Information and DisclosuresAuthor

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine,

and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey

Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American

Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Coauthor(s)


3 dari 7 3/16/2013 6:14 AM

Christopher J Steen, MD Dermatologist, Private Practice

Christopher J Steen, MD is a member of the following medical societies: Alpha Omega Alpha and Sigma Xi


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

Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of

Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi


Specialty Editor Board

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas

Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine;

Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart

Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New

York Academy of Sciences


Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College

of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood

Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for

the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological

Association, American Society for Clinical Pathology, American Society of Hematology, College of American

Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis,

and Royal College of Physicians and Surgeons of Canada

Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of

Nephrology, West Virginia University School of Medicine

Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of

Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology,

National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association

Disclosure: Renal Ventures Ownership interest Other

Chief Editor

Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and

Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson

University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer

Education, American College of Clinical Pharmacology, American Federation for Medical Research, American

Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences


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