Factor V Deficiency

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Background

Factor V is an essential component in the blood coagulation cascade. Inherited or acquired deficiencies in factor V are rare causes of bleeding disorders.[1, 2]

Factor V deficiency is also known as Owren disease. Dr. Paul Owren identified this defect in Norway in 1943. Using relatively primitive technology, he was able to deduce the existence of a fifth component required for fibrin formation, which he named factor V, thus beginning the era of Roman numerology for coagulation factors.

Dr. Owren's work defined factor V as the activity in normal plasma that corrected the prothrombin time (PT) of the plasma in a patient with factor V deficiency. Factor V deficiency has also been called parahemophilia, since hemarthrosis can occur with severe deficiencies and with increased bleeding time.[3, 4]

Pathophysiology

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.



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Antithrombin sites of action.



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Cell surface-directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor (TF)–bearing cell. Following ....

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]  

Anothe 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]

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.[14, 15]

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.[16] 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.

Epidemiology

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.

Mortality/Morbidity

The severity of factor V deficiency varies from bruising to lethal hemorrhage.

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.

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

History

Clinical manifestations of factor V deficiency include the following:

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]

Physical

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.

Causes

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.

Laboratory Studies

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:

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. However, this test is not routinely ordered to diagnose factor V deficiency. A factor V inhibitor panel should also be ordered.

Imaging Studies

See the list below:

Medical Care

Although a plasma-derived factor V concentrate is undergoing preliminary testing,[21]  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.[22]

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

Female patients with factor V deficiency can be given oral contraceptives to decrease menometrorrhagia, thereby improving anemia and decreasing transfusion needs.[17]

The optimal treatment of patients with factor V inhibitors is uncertain. 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 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.[25] 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.[15] 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.[22]

Consultations

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

Medication Summary

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

Class Summary

Plasma is the fluid compartment of blood that contains the soluble clotting factors.

Fresh frozen plasma (FFP, Octaplas)

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

Further Outpatient Care

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

Deterrence/Prevention

See the list below:

Complications

Complications of factor V deficiency are directly related to the site of bleeding (eg, hemarthrosis, intracranial hemorrhage, uncontrolled postoperative bleeding).

Prognosis

The prognosis of factor V deficiency is good with diagnosis and proper treatment.

Patient Education

See the list below:

What is factor V deficiency?What is the pathophysiology of factor V deficiency?What is the prevalence of factor V deficiency?What is the mortality and morbidity associated with factor V deficiency?What are the racial predilections of factor V deficiency?Which age groups have the highest prevalence of factor V deficiency?Which clinical history findings are characteristic of factor V deficiency?Which physical findings are characteristic of factor V deficiency?What causes factor V deficiency?What are the differential diagnoses for Factor V Deficiency?What is the role of lab tests in the workup of factor V deficiency?What is the role of imaging studies in the workup of factor V deficiency?How is factor V deficiency treated?Which specialist consultations are beneficial to patients with factor V deficiency?What is the role of medications in the treatment of factor V deficiency?Which medications in the drug class Blood Products are used in the treatment of Factor V Deficiency?Which medications in the drug class Blood products are used in the treatment of Factor V Deficiency?Which specialist should provide long-term monitoring of patients with factor V deficiency?How is factor V deficiency prevented?What are the possible complications of factor V deficiency?What is the prognosis of factor V deficiency?What is included in patient education about factor V deficiency?

Author

Olga Kozyreva, MD, Attending Physician, Division of Hematology-Oncology, St Elizabeth's Medical Center; Assistant Professor, Tufts University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Karl J D'Silva, MD, Assistant Clinical Professor of Medicine, Department of Hematology/Oncology, Lahey Clinic, Sophia Gordon Cancer Center

Disclosure: Nothing to disclose.

Sarah K May, MD, Consulting Staff, Department of Hematology-Oncology, Caritas Carney Hospital, Commonwealth Hematology-Oncology PC

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MBBCh, FRCPC, DTM&H, Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Disclosure: Nothing to disclose.

Chief Editor

Perumal Thiagarajan, MD, Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Additional Contributors

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

Disclosure: Nothing to disclose.

References

  1. Thalji N, Camire RM. Parahemophilia: new insights into factor v deficiency. Semin Thromb Hemost. 2013 Sep. 39(6):607-12. [View Abstract]
  2. Quek JKS, Wong WH, Tan CW, Tha MH, Nagarajan C, Lee LH, et al. Acquired factor V deficiency in a patient with myeloma and amyloidosis. Thromb Res. 2018 Apr. 164:1-3. [View Abstract]
  3. Owren P. Parahaemophilia: haemorrhagic diathesis due to absence of a previously unknown clotting factor. Lancet. 1947. Vol I:446-8.
  4. Duckers C, Simioni P, Rosing J, Castoldi E. Advances in understanding the bleeding diathesis in factor V deficiency. Br J Haematol. 2009 Jun. 146(1):17-26. [View Abstract]
  5. Asselta R, Peyvandi F. Factor V deficiency. Semin Thromb Hemost. 2009 Jun. 35(4):382-9. [View Abstract]
  6. Cramer TJ, Gale AJ. The anticoagulant function of coagulation factor V. Thromb Haemost. 2011 Nov 24. 107(1):[View Abstract]
  7. Ni Ainle F, Preston RJ, Jenkins PV, et al. Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation. Blood. 2009 Aug 20. 114(8):1658-65. [View Abstract]
  8. Delev D, Pavlova A, Heinz S, Seifried E, Oldenburg J. Factor 5 mutation profile in German patients with homozygous and heterozygous factor V deficiency. Haemophilia. 2009 Sep. 15(5):1143-53. [View Abstract]
  9. Liu HC, Shen MC, Eng HL, Wang CH, Lin TM. Asp68His mutation in the A1 domain of human factor V causes impaired secretion and ineffective translocation. Haemophilia. 2014 Jul. 20(4):e318-26. [View Abstract]
  10. Mitterstieler G, Muller W, Geir W. Congenital factor V deficiency. A family study. Scand J Haematol. 1978 Jul. 21(1):9-13. [View Abstract]
  11. Zehnder JL, Hiraki DD, Jones CD, Gross N, Grumet FC. Familial coagulation factor V deficiency caused by a novel 4 base pair insertion in the factor V gene: factor V Stanford. Thromb Haemost. 1999 Sep. 82(3):1097-9. [View Abstract]
  12. Liu S, Luo S, Yang L, Jin Y, Xie H, Xie Y, et al. A novel homozygous mutation (Gly1715Ser) causing hereditary factor V deficiency in a Chinese patient. Blood Coagul Fibrinolysis. 2019 Nov 26. [View Abstract]
  13. Zheng C, Zhang B. Combined deficiency of coagulation factors V and VIII: an update. Semin Thromb Hemost. 2013 Sep. 39 (6):613-20. [View Abstract]
  14. Van den Berg SA, Verwer PE, Idema RN, Van Guldener C. Transient cefuroxime/metronidazole treatment induced factor V antibodies. BMJ Case Rep. 2014 Aug 19. 2014:[View Abstract]
  15. Wang X, Qin X, Yu Y, Wang R, Liu X, Ji M, et al. Acquired factor V deficiency in a patient with a urinary tract infection presenting with haematuria followed by multiple haemorrhages with an extremely low level of factor V inhibitor: a case report and review of the literature. Blood Coagul Fibrinolysis. 2017 Jun. 28 (4):334-341. [View Abstract]
  16. Hamedani AG, Cole JW, Cheng Y, Sparks MJ, O'Connell JR, Stine OC, et al. Factor V Leiden and Ischemic Stroke Risk: The Genetics of Early Onset Stroke (GEOS) Study. J Stroke Cerebrovasc Dis. 2011 Nov 17. [View Abstract]
  17. Girolami A, Scandellari R, Lombardi AM, Girolami B, Bortoletto E, Zanon E. Pregnancy and oral contraceptives in factor V deficiency: a study of 22 patients (five homozygotes and 17 heterozygotes) and review of the literature. Haemophilia. 2005 Jan. 11(1):26-30. [View Abstract]
  18. Totan M, Albayrak D. Intracranial haemorrhage due to factor V deficiency. Acta Paediatr. 1999 Mar. 88(3):342-3. [View Abstract]
  19. Sacco S, Dragani A, Davi G, Carolei A. Four recurrent intracerebral haemorrhages. Cerebrovasc Dis. 2003. 16(4):435-6. [View Abstract]
  20. Satoh H, Yamashita YT, Ohtsuka M, Sekizawa K, Hasegawa Y. Pulmonary hemorrhage in factor V deficiency. Can Respir J. 1999 Jul-Aug. 6(4):320. [View Abstract]
  21. Bulato C, Novembrino C, Anzoletti MB, Spiezia L, Gavasso S, Berbenni C, et al. "In vitro" correction of the severe factor V deficiency-related coagulopathy by a novel plasma-derived factor V concentrate. Haemophilia. 2018 Jul. 24 (4):648-656. [View Abstract]
  22. Gavva C, Yates SG, Rambally S, Sarode R. Transfusion management of factor V deficiency: three case reports and review of the literature. Transfusion. 2016 Jul. 56 (7):1745-9. [View Abstract]
  23. Bello A, Salazar E, Heyne K, Varon J. Aortic Valve Replacement in Severe Factor V Deficiency and Inhibitor: Diagnostic and Management Challenges. Cureus. 2019 Oct 15. 11 (10):e5918. [View Abstract]
  24. Passarelli PC, De Angelis P, Pasquantonio G, Manicone PF, Verdugo F, D'Addona A. Management of Single Uncomplicated Dental Extractions and Postoperative Bleeding Evaluation in Patients With Factor V Deficiency: A Local Antihemorrhagic Approach. J Oral Maxillofac Surg. 2018 Jun 21. 3(3):196-8. [View Abstract]
  25. Fu YX, Kaufman R, Rudolph AE, Collum SE, Blinder MA. Multimodality therapy of an acquired factor V inhibitor. Am J Hematol. 1996 Apr. 51(4):315-8. [View Abstract]

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.

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.