Parahemophilia: New Insights into Factor V Deficiency

Abstract

Blood coagulation factor V (FV) plays a pivotal role in blood coagulation. It is found in both plasma and in platelets and has a profound impact on thrombin generation. Deficiency of this clotting factor due to inherited or acquired conditions results in a broad spectrum of bleeding symptoms. Surprisingly however, some patients with undetectable levels of FV experience relatively mild bleeding. The aim of this review is to highlight this rare coagulation factor disorder and touch upon its clinical manifestations, diagnosis, and treatment. Furthermore, recent advances that shed new light on the importance of platelet FV and other modifiers which influence bleeding tendencies in severe FV deficiency will be discussed.

Keywords

factor V - factor V deficiency - hemostasis - bleeding phenotype

• References

• 1 Owren PA. Parahaemophila: haemorrhagic diathesis due to absence of a previously unknown clotting factor. Lancet 1947; 249: 446-448
• 2 Stormorken H. The discovery of factor V: a tricky clotting factor. J Thromb Haemost 2003; 1 (2) 206-213
• 3 Mann KG, Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde. Blood 2003; 101 (1) 20-30
• 4 Camire RM, Bos MHA. The molecular basis of factor V and VIII procofactor activation. J Thromb Haemost 2009; 7 (12) 1951-1961
• 5 Cripe LD, Moore KD, Kane WH. Structure of the gene for human coagulation factor V. Biochemistry 1992; 31 (15) 3777-3785
• 6 Kane WH, Davie EW. Cloning of a cDNA coding for human factor V, a blood coagulation factor homologous to factor VIII and ceruloplasmin. Proc Natl Acad Sci U S A 1986; 83 (18) 6800-6804
• 7 Jenny RJ, Pittman DD, Toole JJ , et al. Complete cDNA and derived amino acid sequence of human factor V. Proc Natl Acad Sci U S A 1987; 84 (14) 4846-4850
• 8 Kane WH, Ichinose A, Hagen FS, Davie EW. Cloning of cDNAs coding for the heavy chain region and connecting region of human factor V, a blood coagulation factor with four types of internal repeats. Biochemistry 1987; 26 (20) 6508-6514
• 9 Wilson DB, Salem HH, Mruk JS, Maruyama I, Majerus PW. Biosynthesis of coagulation Factor V by a human hepatocellular carcinoma cell line. J Clin Invest 1984; 73 (3) 654-658
• 10 Mazzorana M, Baffet G, Kneip B, Launois B, Guguen-Guillouzo C. Expression of coagulation factor V gene by normal adult human hepatocytes in primary culture. Br J Haematol 1991; 78 (2) 229-235
• 11 Tracy PB, Eide LL, Bowie EJW, Mann KG. Radioimmunoassay of factor V in human plasma and platelets. Blood 1982; 60 (1) 59-63
• 12 Mann KG, Nesheim ME, Church WR, Haley PE, Krishnaswamy S. Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood 1990; 76 (1) 1-16
• 13 Asselta R, Peyvandi F. Factor V deficiency. Semin Thromb Hemost 2009; 35 (4) 382-389
• 14 Duckers C, Simioni P, Rosing J, Castoldi E. Advances in understanding the bleeding diathesis in factor V deficiency. Br J Haematol 2009; 146 (1) 17-26
• 15 Cui J, O'Shea KS, Purkayastha A, Saunders TL, Ginsburg D. Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V. Nature 1996; 384 (6604) 66-68
• 16 Mannucci PM, Peyvandi F, Franchini M, Rare inherited coagulation disorders other than hemophilia. In: Marder VJ, Aird WC, Bennett JS, Schulman S, White GC. , eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013: 684-692
• 17 Acharya SS, Coughlin A, Dimichele DM. North American Rare Bleeding Disorder Study Group. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost 2004; 2 (2) 248-256
• 18 Zhang B. Recent developments in the understanding of the combined deficiency of FV and FVIII. Br J Haematol 2009; 145 (1) 15-23
• 19 Zhang B, Cunningham MA, Nichols WC , et al. Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Nat Genet 2003; 34 (2) 220-225
• 20 Nichols WC, Seligsohn U, Zivelin A , et al. Linkage of combined factors V and VIII deficiency to chromosome 18q by homozygosity mapping. J Clin Invest 1997; 99 (4) 596-601
• 21 Neerman-Arbez M, Antonarakis SE, Blouin JL , et al. The locus for combined factor V-factor VIII deficiency (F5F8D) maps to 18q21, between D18S849 and D18S1103. Am J Hum Genet 1997; 61 (1) 143-150
• 22 Franchini M, Lippi G. Acquired factor V inhibitors: a systematic review. J Thromb Thrombolysis 2011; 31 (4) 449-457
• 23 Ortel TL. Clinical and laboratory manifestations of anti-factor V antibodies. J Lab Clin Med 1999; 133 (4) 326-334
• 24 Weiss HJ. Impaired platelet procoagulant mechanisms in patients with bleeding disorders. Semin Thromb Hemost 2009; 35 (2) 233-241
• 25 Blavignac J, Bunimov N, Rivard GE, Hayward CP. Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment. Semin Thromb Hemost 2011; 37 (6) 713-720
• 26 ThoMurray JM, Rand MD, Egan JO, Murphy S, Kim HC, Mann KG. Factor VNew Brunswick: Ala221-to-Val substitution results in reduced cofactor activity. Blood 1995; 86 (5) 1820-1827
• 27 Paraboschi EM, Kayiran SM, Özbek N , et al. Functional characterization of a novel missense mutation identified in a Turkish patient affected by severe coagulation factor V deficiency. Haemophilia 2012; 18 (2) 205-210
• 28 Lak M, Sharifian R, Peyvandi F, Mannucci PM. Symptoms of inherited factor V deficiency in 35 Iranian patients. Br J Haematol 1998; 103 (4) 1067-1069
• 29 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; 15 (5) 1143-1153
• 30 Dahlbäck B, Villoutreix BO. Molecular recognition in the protein C anticoagulant pathway. J Thromb Haemost 2003; 1 (7) 1525-1534
• 31 Simioni P, Scudeller A, Radossi P , et al. “Pseudo homozygous” activated protein C resistance due to double heterozygous factor V defects (factor V Leiden mutation and type I quantitative factor V defect) associated with thrombosis: report of two cases belonging to two unrelated kindreds. Thromb Haemost 1996; 75 (3) 422-426
• 32 Camire RM, Pollak ES, Kaushansky K, Tracy PB. Secretable human platelet-derived factor V originates from the plasma pool. Blood 1998; 92 (9) 3035-3041
• 33 Thomassen MC, Castoldi E, Tans G , et al. Endogenous factor V synthesis in megakaryocytes contributes negligibly to the platelet factor V pool. Haematologica 2003; 88 (10) 1150-1156
• 34 Gould WR, Simioni P, Silveira JR, Tormene D, Kalafatis M, Tracy PB. Megakaryocytes endocytose and subsequently modify human factor V in vivo to form the entire pool of a unique platelet-derived cofactor. J Thromb Haemost 2005; 3 (3) 450-456
• 35 Bouchard BA, Williams JL, Meisler NT, Long MW, Tracy PB. Endocytosis of plasma-derived factor V by megakaryocytes occurs via a clathrin-dependent, specific membrane binding event. J Thromb Haemost 2005; 3 (3) 541-551
• 36 Bouchard BA, Meisler NT, Nesheim ME, Liu CX, Strickland DK, Tracy PB. A unique function for LRP-1: a component of a two-receptor system mediating specific endocytosis of plasma-derived factor V by megakaryocytes. J Thromb Haemost 2008; 6 (4) 638-644
• 37 Gould WR, Silveira JR, Tracy PB. Unique in vivo modifications of coagulation factor V produce a physically and functionally distinct platelet-derived cofactor: characterization of purified platelet-derived factor V/Va. J Biol Chem 2004; 279 (4) 2383-2393
• 38 Duckers C, Simioni P, Spiezia L , et al. Residual platelet factor V ensures thrombin generation in patients with severe congenital factor V deficiency and mild bleeding symptoms. Blood 2010; 115 (4) 879-886
• 39 Castoldi E, Duckers C, Radu C , et al. Homozygous F5 deep-intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet-rich plasma. J Thromb Haemost 2011; 9 (5) 959-968
• 40 Yang TL, Cui J, Taylor JM, Yang A, Gruber SB, Ginsburg D. Rescue of fatal neonatal hemorrhage in factor V deficient mice by low level transgene expression. Thromb Haemost 2000; 83 (1) 70-77
• 41 Mann KG. How much factor V is enough?. Thromb Haemost 2000; 83 (1) 3-4
• 42 Duckers C, Simioni P, Spiezia L , et al. Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency. Blood 2008; 112 (9) 3615-3623
• 43 Talbot K, Song J, Hewitt J , et al. A novel compensating mechanism for homozygous coagulation factor V deficiency suggested by enhanced activated partial thromboplastin time after reconstitution with normal factor V. Br J Haematol 2010; 151 (2) 198-200