Factor V Deficiency

Factor V is an essential component in the blood coagulation cascade. Factor V is synthesized in the liver and possibly in megakaryocytes. Factor V circulates in an inactive form. During coagulation, factor V is converted to the active cofactor, factor Va, via limited proteolysis by the serine protease a-thrombin. Factor Va and activated factor Xa form the prothrombinase complex. The prothrombinase complex is responsible for the rapid conversion of the zymogen prothrombin to the active serine protease a-thrombin.[5, 6] Thrombin cleaves fibrinogen to form fibrin, leading to the ultimate step in coagulation, the formation of a fibrin clot.[7] See images below.

Antithrombin sites of action.

Cell surface-directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor (TF)–bearing cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation. Adapted from Hoffman and Monroe, Thromb Haemost 2001, 85(6): 958-65.

Inherited factor V deficiency is a rare autosomal recessive disorder that is associated with an abnormal factor V plasma level. Numerous mutations in the F5 gene have been identified in these patients.[5, 8, 9, 10, 11, 12]  

Another rare autosomal recessive disorder, combined factor V and factor VIII deficiency, results from  mutations in either LMAN1 (lectin mannose binding–1) or MCFD2  (multiple coagulation factor deficiency gene 2). Alterations in the proteins encoded by those two genes interfere with efficient secretion of factors V and FVIII.[13]  The LMAN1 mutation is more common in Middle Eastern populations and MCFD2 is more common among Indian and European populations.[14]

Acquired factor V deficiency is a rare clinical condition in which the development of antibodies to factor V (factor V inhibitors) leads to hemorrhagic complications of varying severity. The addition of normal plasma cannot correct the prolonged PT and activated partial thromboplastin time (aPTT). Factor V inhibitors can occur after surgery, childbirth, use of bovine thrombin or medications, and in patients with autoimmune diseases and certain neoplasms.[15, 16]   Acquired factor V deficiency is idiopathic in approximately 15% of cases.[17]

Factor V Leiden is a completely different inherited disorder that involves a single point mutation in the factor V gene. Factor V activity levels in patients with factor V Leiden are normal.[18] Proteolytic inactivation of factor Va and factor VIIIa by activated protein C (APC) normally limits clot formation; however, factor V Leiden resists inactivation by APC. Consequently, individuals who are homozygous for factor V Leiden have a high incidence of thrombosis. For more information, see Hereditary and Acquired Hypercoagulability.

Factor V deficiency is caused by a large number of genetic abnormalities. The deficiency is a rare bleeding disorder whose genetic bases have been characterized in only a limited number of cases.[9]  The inheritance of factor V deficiency is autosomal recessive, with varying expressivity in the heterozygote; however, other modes of inheritance have been described. Heterozygotes have lowered levels of factor V but probably never bleed abnormally.

Consanguinity has been observed in families with factor V deficiency, related to its autosomal recessive inheritance. Heterozygous deficiency states are generally unrecognized because of a lack of significant clotting time prolongation or bleeding risk.

Frequency

International

Fewer than 200 cases of congenital factor V deficiency have been reported worldwide since 1943. Homozygous factor V deficiency is rare, occurring in approximately 1 per million population.

Delev et al presented 39 German patients with factor V deficiency.[8] In 36 cases with an identifiable causative mutation, 20 patients were heterozygous for the mutation, whereas 9 were homozygous, 6 were compound heterozygous, and 1 proband was pseudohomozygous.[8] There were no mutations found in the remaining 3 patients.

The investigators identified 33 uniquely different mutations of a total 42 genetic mutations: 19 missense mutations, 8 nonsense mutations, 4 small deletions, and 2 splice site mutations.[8] Of the 33 unique mutations, 23 were novel sequence variations not previously reported, and all changes found in exon 13 led to null alleles as nonsense mutations or small deletions.

Race-, sex-, and age-related demographics

No apparent racial predilection for factor V deficiency exists. Factor V deficiency affects males and females with equal frequency.

Combined factor V and factor VIII deficiency is more prevalent in areas of the Middle East, Mediterranean, and South Asia where consanguineous marriage is more common.[14]  

Factor V deficiency affects persons of all ages. The age at presentation indirectly varies with the severity of disease.

The prognosis of patients with factor V deficiency is good with diagnosis and proper treatment. The severity of factor V deficiency varies from bruising to lethal hemorrhage. Complications of factor V deficiency are directly related to the site of bleeding (eg, hemarthrosis, intracranial hemorrhage, uncontrolled postoperative bleeding).

Recurrent miscarriage has been reported in women with factor V deficiency.[19]   

Give patients and families instruction and educational materials to enable them to understand factor V deficiency. For patient education information, see Hemophilia.

Clinical manifestations of factor V deficiency include the following:

• Bleeding into the skin
• Excessive bruising with minor injuries
• Nosebleeds
• Bleeding gums
• Excessive menstrual bleeding and prolonged or excessive loss of blood with surgery or trauma
• Bleeding in mucosal tracts (gastrointestinal, urinary)
• Hemarthrosis and flexion contracture
• Bleeding during delivery and postpartum ^[20]
• Intracerebral hemorrhages ^{[21, 22]}
• Pulmonary hemorrhage ^[23]

The severity of bleeding symptoms is only partly related to the degree of factor V deficiency in plasma. Some patients with undetectable plasma levels of factor V experience only relatively mild bleeding.[1]

The most common physical findings of factor V deficiency are ecchymoses, bleeding from mucosal surfaces, and pallor secondary to blood loss. Petechiae are uncommon because platelet numbers and function are not affected.

The presence of a mild prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT) may be the first indication of factor V deficiency. Coagulation study results are as follows:

• Bleeding time can be prolonged in severe cases
• aPTT - Prolonged
• PT - Prolonged
• Thrombin time - Normal
• Stypven time (Russell viper venom time [RVVT]) - Prolonged
• Mixing study - Correction of PT or partial thromboplastin time (PTT) with the mixing of equal amounts of normal and patient plasma

Use specific factor V activity and antigen assays for confirmation. The factor V antigen assay quantifies factor V levels but does not test for functional factor V. Some patients have factor V deficiency caused by dysfunctional factor V while the level of factor V protein, estimated by factor V antigen levels, is normal.[24] However, this test is not routinely ordered to diagnose factor V deficiency. A factor V inhibitor panel should also be ordered.

Early and aggressive imaging studies are indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated, and may include the following:

• Head computed tomography (CT) scan (noncontrast) - To assess spontaneous or traumatic hemorrhage
• Body CT scan - Perform as indicated by clinical suspicion and anatomical location, to assess spontaneous or traumatic hemorrhage. May be performed with or without intravenous contrast, oral contrast, or both.
• Head and spinal column MRI - To further assess spontaneous or traumatic hemorrhage
• Radiograph for joint assessment - This is of limited value in an acute setting of hemarthrosis. Chronic degenerative joint disease is often present.
• Special studies - Perform angiography and nucleotide bleeding scan as clinically indicated.

Although a plasma-derived factor V concentrate is undergoing preliminary testing,[25]  no concentrates of factor V are commercially available. Instead, fresh plasma or fresh frozen plasma (FFP, Octaplas) infusions are used to correct the deficiency temporarily and should be given daily during a bleeding episode. The loading dose of FFP is 15-20 mL/kg and then 3-6 mL/kg daily. Subsequent dosages depend on monitoring the factor V level by obtaining peak and trough factor V level assays. The half-life ranges from 24-36 hours, with the aim being a factor V level of 25%. Fluid overload and viral transmission may be a complication of plasma therapy.

Alternatively, platelet transfusions are emerging as an alternative to FFP. Factor V stored within platelet alpha granules has greater procoagulant potential and is released locally at sites of vascular injury.[26]

Preoperative and postoperative care when patients with factor V deficiency require surgery include the following:

• In pregnant women, considerable bleeding can occur at the time of delivery; however, the administration of FFP can properly control bleeding, with excellent fetal outcome.

• The safe level of factor V for adequate surgical hemostasis is 25% of the activity of factor V in normal control plasma.[27]

• Postoperatively, FFP should be administered for 3-10 days, with careful observation of wound bleeding.

• Tooth extraction in a patient with factor V hereditary deficiency is safely performed with both supplementation of FFP and application of local hemostasis.[28]

Female patients with factor V deficiency can be given oral contraceptives to decrease menometrorrhagia, thereby improving anemia and decreasing transfusion needs.[20] Patients who may require plasma-derived coagulation factor concentrates should receive hepatitis B vaccine.

The optimal treatment of patients with factor V inhibitors is uncertain. Plasma exchange combined with immunosuppression has proved effective.[29] Fu et al were successful in using a combination of factor replacement, chemotherapy, and plasmapheresis in a patient with spontaneous, life-threatening intracranial bleeding caused by a factor V inhibitor. The patient's condition deteriorated after initial treatment with FFP and platelet transfusions. He was subsequently treated with a combination of plasma exchange and chemotherapy, and he completely recovered.[30] The experience of Fu et al shows that combinations of therapies may be needed in patients with serious hemorrhage caused by acquired factor V deficiency.

Corticosteroids have been used successfully in acquired factor V deficiency. A case report by Wang et al describes successful elimination of a low-level factor V inhibitor and control of bleeding with corticosteroid therapy, in a patient with reduced factor V activity and a factor V inhibitor level of 1.9 BU, probably secondary to a urinary tract infection.[16] Gavva et al report two cases successfully treated with corticosteroids, one likely secondary to antibiotics and the other, to either hepatitis C virus or antibiotic exposure.[26] Wu et al report successful treatment with immunosuppressive therapy including steroids and cyclophosphamide in a patient with acquired factor V deficiency and life-threatening pelvic hemorrhage.[31]

Gene therapy is a promising future approach to treatment of factor V deficiency. Nakamura et al report successful correction of F5 mutation in induced pluripotent stem cells from a factor V–deficient patient through the use of a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9).[32]

Consultations may include hematologists, blood bank specialists, pathologists, and others as indicated based on hemorrhagic complications.

Ideally, a hematologist who has experience in the diagnosis and management of inherited bleeding disorders should monitor individuals with severe factor V deficiency.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Fresh frozen plasma (FFP, Octaplas)

For use in patients with blood coagulation deficiencies. Octaplas is a solvent detergent treated, pooled FFP.