160 Review
Inherited and acquired factor V deficiency
Giuseppe Lippia, Emmanuel J. Favalorob, Martina Montagnanac,
Franco Manzatod, Gian C. Guidic and Massimo Franchinie
The clotting factor V, also known as proaccelerin or labile
factor, is synthesized by the liver and possibly by the
megakaryocytes. Factor V exerts a pivotal role in
hemostasis, as it participates in both procoagulant and
anticoagulant pathways, being an essential cofactor of the
prothrombinase complex in the former case and
participating in the inactivation of factor VIII (FVIII) in the
latter. Isolated factor V deficiency due to mutations in the F5
gene is a rare inherited coagulopathy typically associated
with a broad spectrum of bleeding symptoms, ranging from
easy bruising, delayed bleeding after haemostatic
challenges such as trauma or surgery to more severe joint
bleeds. The combined deficiency of factor V and FVIII,
commonly known as F5F8D, is a recessive disorder not
attributable to the association of isolated factor V and FVIII
deficiencies, but rather to defective intracellular processing
of both proteins due to mutations involving the LMAN1 and
MCFD2 genes, which encode two proteins forming an
essential cargo receptor complex. Overall, patients affected
by F5F8D do not bleed more in terms of both frequency and
severity than those carrying specific deficiencies of both
factors and the bleeding phenotype is generally mild.
Although now increasingly rare, inhibitors directed against
factor V may also develop in individuals of any age and are
Biochemistry and function of factor V
The clotting factor V, historically known as proaccelerin
or labile factor, is a 2224 amino acid protein with a
theoretical molecular weight of 251.7 kDa synthesized
by the liver and is also contained in the megakaryocytes
(the amount present in the alpha-granules of the platelets
accounts for 25% of the total circulating factor V). The
relatively low platelet pool is, however, important inas-
much as patients with undetectable plasma factor V may
contain functional factor V in their platelets which, in
combination with low tissue factor pathway inhibitor
(TFPI) level, allows sufficient thrombin generation to
rescue these patients from fatal bleeding. Factor V is
characterized by a typical domain structure A1-A2-B-A3-
C1-C2 [1,2] and is synthesized by the F5 gene, which is
located on the long (q) arm of chromosome 1 at position
23. The gene is related to the family of multicopper
oxidases and displays a high degree of homology with
factor VIII (FVIII) and ceruloplasmin. Both F5 and F8
genes have probably arisen by duplication of a cerulo-
plasmin-like gene that already contained three A
domains, after which this gene acquired the exons for
the B and C domains. Then this gene duplicated again to
give separate F5 and F8 genes. The entire gene spans
0957-5235 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
characterized by a very heterogeneous clinical phenotype.
The aim of the current review is to provide an overview on
the physiopathology, diagnostics, and clinical management
of both inherited and acquired factor V deficiency. Blood
Coagul Fibrinolysis 22:160–166 ß 2011 Wolters Kluwer
Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2011, 22:160–166
Keywords: bleeding, coagulation, deficiency, factor V, hemorrhage
a
U.O. di Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di
Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy,
b
Department of Haematology, Institute of Clinical Pathology and Medical
Research (ICPMR), Westmead Hospital, Westmead, Australia, cSezione di
Chimica Clinica, Dipartimento di Scienze Morfologico-Biomediche, Azienda
Ospedaliera-Universitaria di Verona, Verona, dLaboratorio Patologia Clinica,
Azienda Ospedaliera ‘Carlo Poma’, Mantova and eServizio di Immunoematologia
e Trasfusione, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
Correspondence to Professor Giuseppe Lippi, U.O. Diagnostica Ematochimica,
Azienda Ospedaliero-Universitaria di Parma, Strada Abbeveratoia 14, 43126
Parma, Italy
Tel: +39 0521 703050, þ39 0521 703054;
e-mail: glippi@ao.pr.it, giuseppe.lippi@univr.it
Received 4 August 2010 Revised 15 September 2010
Accepted 27 October 2010
70 kb, consists of 25 exons, and codes for a leader
sequence of 28 amino acids and a mature protein of
2196 amino acids [3]. At variance with other clotting
factors, factor V is a nonenzymatically active protein,
which exerts its main biological function as a cofactor.
In normal conditions, factor V circulates in an inactive
form, which can be activated (to FVa) by thrombin-
mediated or activated factor X (FXa)-mediated cleavage
of peptide bonds at three arginine residues (Arg709,
Arg1018, and Arg1545), thereby producing a heavy chain,
a connecting fragment(s), and a light chain [1]. As such,
the resulting FVa lacks the entire B domain and com-
prehends a 105-kDa heavy chain (A1-A2 domains) and a
74-kDa or 71-kDa light chain (A3-C1-C2 domains) non-
covalently linked by a single calcium ion. The amino acid
sequence of the light chain is partially homologous to that
of the carboxyl-terminal fragment of human FVIII. Inter-
estingly, although both sequences have an analogous
domain structure that includes a single ceruloplasmin-
related domain followed by two ‘C’ domains, the carboxyl
terminus of the interconnecting region has no significant
amino acid sequence homology with that of FVIII. The
two C domains of human factor V have a 30–50%
homology with each other and with the C domains of
DOI:10.1097/MBC.0b013e3283424883
 Inherited and acquired factor V deficiency Lippi et al. 161

human FVIII. Another interesting feature in the structure Fig. 1

of factor V is that the carboxyl terminus of the connecting

fragment of FVa contains at least 20 repeats of a nine
amino acid sequence.
Platelet factor V is contained in the alpha-granules bound
to the soluble protein multimerin 1 (MMRN1) and most
likely originates from the plasma pool after endocytosis
by bone marrow megakaryocytes, a process that causes
posttranslational re-tailoring of the protein and that,
therefore, confers structural and functional peculiarities
that distinguish it from the plasma counterpart [4]. Basi-
cally, platelet factor V is activated by FXa 50–100 times
more efficiently than by thrombin; is present in a partially
proteolyzed form already expressing FXa-cofactor
activity before being converted to FVa by FXa or throm-
bin; presents a O-glycosylated at Thr402; is resistant to
phosphorylation of the heavy chain at Ser692; and is Activated protein C and thrombin cleavage sites on coagulation factor
V. APC, activated protein C.
proteolyzed more slowly by activated protein C (APC)
and, thus, cannot be completely inactivated.
Factor V exerts its main biological function as a cofactor
of the prothrombinase complex (FVa-FXa), which con- tendency [6]. In 1994, a genetic basis was demonstrated
verts prothrombin to thrombin at the surface of the when a GA missense mutation at position 1691 in the
platelet membrane (the presence of FVa in this complex factor V cDNA was identified to result in the replacement
enhances the rate of prothrombin activation by several of Arg506 by Gln (factor V Leiden) and that this was
orders of magnitude). Upon platelet activation, the plate- associated with APC resistance [7]. Additional allelic
let factor V also dissociates from MMRN1 to be exposed variants of the F5 gene have been identified in patients
on the surface membrane as a fully activated cofactor, with venous thromboembolism, namely, factor V
thereby promoting the assembly and activity of the Arg306Thr (factor V Cambridge) [8] and factor V Arg306-
prothrombinase complex. The downregulation of the Gly (factor V Hong Kong) [9]. A recently identified
procoagulant activity of FVa is mediated by APC- polymorphism in the F5 gene H1299R (also known as
mediated proteolysis of FVa at positions Arg306, HR2) has been reported to be another potential risk
Arg506, and Arg679. In the presence of thrombomodulin, factor for venous thromboembolism, although a meta-
thrombin activates protein C, which in turn suppresses analysis by Castaman et al. [10] suggested that factor V
FVa cofactor and clotting activity. Although the cleavage HR2 might be a very mild prothrombotic factor and its
site at Arg506 seems to prevail under low concentrations association with factor V Leiden does not increase sig-
of both APC and FVa, it does not determine a complete nificantly the risk of venous thromboembolism carried by
inactivation of the protein, and the additional cleavage at isolated heterozygosity for factor V Leiden.
Arg306 is thereby necessary for the complete inactivation
of FVa activity (Fig. 1) [2]. Fig. 2

A major breakthrough in understanding the biological

role of factor V arose, however, when it was finally
discovered that apart from its procoagulant potential,
intact factor V has an important anticoagulant cofactor
capacity in synergy with protein S and APC in the APC-
catalyzed inactivation of the activated form of FVIII
(FVIIIa) [5]. This evidence led Nicolaes and Dahlback
[2] to define factor V as a Janus-faced protein, inasmuch
as factor V has the potential to function in both proco-
agulant and anticoagulant pathways, its functional pro-
perties being modulated by proteolysis exerted by proco-
agulant and anticoagulant enzymes (Fig. 2).
Although inherited factor V deficiencies are usually
Activation and inactivation of coagulation factor V as regards its
associated with a bleeding phenotype, an inherited procoagulant and anticoagulant function. APC, activated protein C; FV,
defective anticoagulant function of factor V has been factor V.
consistently associated with an increased prothrombotic

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 162 Blood Coagulation and Fibrinolysis 2011, Vol 22 No 3
Inherited factor V deficiency
Isolated factor V deficiency is a rare inherited coagulo-
pathy transmitted with autosomal recessive inheritance,
with an estimated prevalence in the general population
in heterozygotes and homozygous form of 1 : 1000 and
1 : 1 000 000, respectively (8.3% of all rare inherited
bleeding disorders) [11–14]. Individuals affected in a
homozygous state or those with compound heterozygos-
ity usually have factor V plasma levels lower than 10%,
whereas heterozygous individuals with mild or moderate
factor V deficiencies have factor V plasma levels typically
around 50% [14]. Basically, these defects can be classified
as quantitative (type I, characterized by concordantly low
or immeasurable antigen and functional plasma levels) or
qualitative (type II, characterized by normal or mildly
reduced antigen plasma levels associated with a reduced
coagulant activity). Several deficiency-causing mutations
(n ¼ 65) and polymorphisms (n ¼ 700) have been
described in the FV gene so far, involving patients with
a hemorrhagic diathesis or pseudohomozygotes for APC
resistance (i.e., heterozygous carriers of factor V Leiden
who also carry factor V deficiency). Most of these
mutations modify the sequence of factor V [15–22]. As
reviewed by Vos [15], protein-truncating nonsense and
frameshift mutations are fairly homogeneously distribu-
ted, whereas missense mutations are mostly located in
the A2 and C2 domains and virtually lacking from the B
domain. Interestingly, the FVNewBrunswick mutation
(Ala221Val) was the first to be reported, but is the only
genetic defect to be associated with type II deficiency as
yet [23].
The Québec platelet disorder (QPD) is an inherited
bleeding disorder transmitted as an autosomal dominant
trait and caused by decrease/degradation of most platelet
alpha-granule proteins, including factor V, but normal or
low-normal plasma factor V levels. Although the typical
hallmark of this disorder is delayed bleeding after hemo-
static challenges such as trauma or surgery, affected
patients may experience a wide spectrum of bleeding
symptoms, ranging from easy bruising to joint bleeds.
Despite this, the major cause of the bleeding phenotype
is now recognized to be related to a more than 100-fold
increased expression of the urokinase-type plasminogen
activator (u-PA), which causes proteolysis of alpha-gran-
ule and triggers plasmin generation and thereby acceler-
ated fibrinolysis [24].
Inherited factor V deficiency, also known as Owren
disease or parahemophilia, was first described by Paul
Owren in 1943 [25], who identified this defect in a young
Norwegian woman who had suffered from nosebleeds
and menorrhagia for most of her life and was found to
have a prolonged prothrombin time (PT). This disorder
was further defined as ‘parahemophilia’ because – like-
wise hemophilia – factor V deficiency in the most severe
form can be associated with hemarthrosis and other life-
threatening hemorrhages. Since the original description
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
by Owren, several other cases of inherited factor V
deficiency have been reported.
Although the clinical phenotype has a limited correlation
with the residual activity of factor V in plasma (e.g.,
individuals with identical mutations or factor V plasma
levels differ widely in their bleeding diathesis), severely
affected patients (i.e., factor V activity in plasma <5–
10%) are more predisposed to severe bleeding episodes
than those with mild or moderate deficits [26]. As such,
the disease can range, therefore, from a mild bleeding
tendency in carriers of mild-to-moderate deficits, up to
severe bleeding episodes in severely affected individuals.
In this last category of patients, the onset of the bleeding
phenotype usually occurs in the childhood and encom-
passes umbilical stump bleeding, skin, and mucosal tract
hemorrhages (e.g., epistaxis and menorrhagia). Never-
theless, severe hemorrhages such as hematomas, hemar-
throses, central nervous system, and gastrointestinal tract
bleedings are reportedly infrequent, if not rare (i.e.
<20%) [14]. The main laboratory finding is a variable
prolongation of both the PT and the activated partial
thromboplastin time (APTT), which correlates with the
residual factor activity in plasma. In the inherited form,
both abnormalities are corrected by mixing the patient
plasma with a normal plasma pool. The final diagnosis is
made by the demonstration of an isolated reduction of
factor V levels in plasma using a specific PT-based factor
V assay. Nevertheless, the recent results of three External
Quality Assessment exercises with respect to factor V
clotting (factor V:C) assays undertaken by 192–225 par-
ticipating laboratories performed over a 2-year period
showed remarkable differences, up to 20%, between
results obtained using different reference plasmas and
different thromboplastins. Additional in-house studies
confirmed the finding that the choice of commercial
reference plasma might significantly affect the results
of the individual factor V:C methods, thereby highlight-
ing an urgent need for developing an international stan-
dard for this assay [27]. Interestingly, an International
factor V coagulation reference standard was developed by
the National Institute for Biological Standards and Con-
trol (NIBSC) in the same year.
Because factor V-containing concentrates are still una-
vailable and factor V is not contained in cryoprecipitate or
prothrombin complex concentrates, the clinical manage-
ment of patients with inherited factor V deficiency is
based on replacement therapy with fresh-frozen plasma
(FFP). In the cases of severe hemorrhages or as a pro-
phylaxis before surgery, the minimum factor V plasma
level is 20–25% [14].
Combined deficiency of factor V and VIII
The combined deficiency of factor V and FVIII (F5F8D)
is a rare autosomal recessive bleeding disorder with an
estimated prevalence of less than one in 1 000 000 in the
general population, and a peak of prevalence among

middle eastern Jewish and non-Jewish Iranians (one in
100 000) [28]. The overall prevalence among the rare
bleeding disorders is, however, low and estimated at
2.7% [13]. The hallmark of this condition is the presence
of concomitantly low levels, usually consisted between 5
and 20%, of both factor V and FVIII. F5F8D is, however,
an autonomous condition, separate from the combination
in the same individual of an isolated factor V deficiency
with an isolated FVIII deficiency. The molecular mech-
anism of this inherited disorder is in fact a defective
intracellular processing affecting both factor V and FVIII,
which is attributable in 70% of the cases to mutations
involving the ERGIC-53 gene [also known as lectin
mannose-binding protein (LMAN1)], and in nearly 15%
of the cases to mutations in multiple coagulation factor
deficiency 2 gene (MCFD2), which encodes a cofactor
of LMAN1.
LMAN1 is a 53 kDa transmembrane protein localized in
the endoplasmic reticulum-Golgi intermediate compart-
ment (ERGIC), whose function is essential for the trans-
portation of both clotting factors out of the ERGIC.
The function of LMAN1 depends on the formation of
a 1 : 1 calcium-dependent stoichiometric complex with
MCFD2 (a 146-residue soluble protein with a molecular
weight of 16 kDa), to form the specific cargo receptor
complex for the endoplasmic reticulum-to-Golgi trans-
port of the proteins [29]. Although several other ‘cargo’
proteins have been identified thus far, the activity of
MCFD2 seems limited to the transportation of blood
coagulation factors. As such, inactivating mutations in
both LMAN1 and MCFD2 cause a nearly indistinguish-
able F5F8D phenotype [28].
LMAN1 is a gene 29-kb long located on chromosome
18q21 and composed of 13 exons. Thirty-two mutations
(virtually all are null mutations) in the LMAN1 gene have
been identified thus far and associated with the F5F8D
phenotype. The gene encoding for MCFD2 is located on
chromosome 2p21 and contains four exons. Sixteen null
and missense mutations have been described in this gene
in patients with F5F8D, five of which alter LMAN1
binding.
Overall, the combined deficiency of factor V and FVIII
does not seem to cause more bleeding than if only one or
the other of the factors were affected, and the symptoms
are generally mild. The most common symptoms include
skin bleeding, menorrhagia, hemorrhages in the mouth,
especially after dental surgery or tooth extraction, epi-
staxis, bleeding after circumcision and abnormal bleeding
during or after trauma, surgery, or childbirth. Hemarthro-
sis and muscle bleeds are very rare in F5F8D patients.
The main laboratory finding in carriers of this disorder is
typically represented by a combined prolongation of first-
line coagulation tests (i.e., PT and APTT). Further
testing includes specific factor V and FVIII coagulant
activity assays, whose results are consistent with a com-
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inherited and acquired factor V deficiency Lippi et al. 163
bined deficiency of both factors (the plasma levels are
usually <20%) [28]. Factor antigen assays are unnecess-
ary for the diagnosis or clinical management of affected
patients. Platelet factor V in F5F8D patients is also
reduced to similar levels to those observed for plasma
factor V. Despite being characterized by a nearly iden-
tical bleeding phenotype, a difference exists, however, in
the plasma levels of both factor V and FVIII between
patients carrying mutations in the LMAN1 or MCFD2
genes, in that the mean levels of these clotting factors are
significantly lower in patients with MCFD2 mutations
than in those carrying LMAN1 mutations (factor V mean
plasma levels: 9.6 versus 13.7%, P < 0.001; FVIII mean
plasma levels 10.0 versus 16.0%, P < 0.001). Statistically
significant correlations between factor V and FVIII levels
were also observed in patients with MCFD2 (r ¼ 0.53,
P ¼ 0.001) and in those with LMAN1 mutations
(r ¼ 0.322, P ¼ 0.001) [30].
The main problem in the diagnosis is represented by the
differential diagnosis with isolated factor V or FVIII
deficiencies (should only isolated factor V or FVIII levels
be assessed), or with mild hemophilia associated with
factor V deficiency (i.e., as combined defects). Because
there is no simple laboratory test to ensure rapid and
appropriate distinction of these conditions, the differen-
tial diagnosis is mainly based on the pattern of inheri-
tance (hemophilia A is X-linked and affects mostly men,
whereas F5F8D is an autosomal recessive disorder affect-
ing both men and women) and on the severity of the
symptoms (hemophilia A patients typically show a more
severe bleeding tendency).
Given the mild clinical nature of the disease, F5F8D
patients do not require a regular prophylaxis and the
bleeding episodes are usually treated on demand, accord-
ing to the severity and the site of the hemorrhages, and
the residual plasma levels of the clotting factors [28].
According to the World Federation of Hemophilia, there
are three treatments available for F5F8D, which include
the administration of FVIII concentrates, FFP, and/or
desmopressin. The excessive menstrual bleeding in
women with F5F8D might also be controlled with hor-
monal contraceptives (birth control pills) or antifibrino-
lytic drugs [31]. The recommended FVIII concentrate
dosages to administer in the cases of minor bleeding
episodes and more severe bleeds are 30–50 and 50–
70 U/kg [28], respectively, whereas the hemostatic factor
V levels of 20–25% can be reached with FFP 15–20 ml/
kg [14].
Acquired factor V deficiency
Inhibitors directed against factor V occur rarely (only
approximately 150 cases have been described in the
current literature so far), may appear at any age, and
the clinical symptoms vary to a great extent [32]. Most
cases of factor V autoantibodies reported in literature
occur in the presence of an associated risk factor [33],
 164 Blood Coagulation and Fibrinolysis 2011, Vol 22 No 3

including surgical procedures, antibiotic administration
(especially of the lactam group), blood transfusions, can-
cers, and autoimmune disorders [34–38]. The majority of
the cases previously described developed after exposure
to bovine thrombin, and the use of this material may have
also given rise to heightened rates of inhibitor develop-
ment during certain historical periods according to the
product used (e.g. the procedure used for bovine throm-
bin preparation and purification). Thrombin preparations
are frequently used as topical hemostatic agents in vas-
cular, orthopedic, and neurosurgical procedures, and
bovine thrombin preparations often contained additional
bovine proteins, such as factor V [39–43]. Bovine factor V
acts as a potent immunological stimulus for development
of antibovine factor V inhibitors, which can then cross-
react against human factor V. Although the use of topic
human thrombin is considered safe with respect to the
risk of developing factor V inhibitors, one case of factor V
autoantibody after injection of human thrombin into a
bleeding peptic ulcer has been described [44]. Accord-
ingly, surgical use of thrombin now tends to be restricted
to recombinant forms, with both recombinant bovine and
recombinant human thrombin now available [45]. As a
result, the risk of factor V inhibitors due to thrombin
exposure is now low in developed countries.
The clinical phenotype of patients with acquired factor V
inhibitors may vary from asymptomatic laboratory
abnormalities to life-threatening bleeding. In some stu-
dies, the bleeding tendency has been associated with the
residual plasma factor V activity [37,46], although other
studies did not find significant differences in factor V
activity and inhibitor titer among symptomatic and
asymptomatic patients [46,47]. Most patients with bovine
thrombin-induced autoantibodies showed only coagu-
lation laboratory abnormalities without hemorrhagic com-
plications, and the antibodies were frequently transient
[32].
Although factor V inhibitors associated with thrombin use
appear to be in decline, alternative causes of factor V
inhibitor development means that laboratories and clin-
icians still need to remain vigilant of their possibility [48].
The identification of acquired factor V inhibitors usually
consists of prolonged PT and APTT, which cannot be
corrected after mixing with normal plasma, and/or an
isolated factor V deficiency in a patient with an otherwise
negative personal and familial hemorrhagic history. The
inhibitor is confirmed and titrated using the Bethesda
method. Unlike the more frequent FVIII inhibitors,
which require 1–2 h of incubation to fully inactivate
FVIII in vitro, factor V inhibitors neutralize factor V
activity almost immediately [49]. Thrombin time (TT)
is usually normal, apart from the cases of bovine throm-
bin-induced antibodies in which TT may be prolonged
due to the co-presence of antibodies against bovine
thrombin. It is important that laboratories ensure that
any factor V inhibitor identified is confirmed by repeat
testing on a fresh sample, or that EDTA contamination is
otherwise excluded, as EDTA contamination of normal
plasma can give rise to a phenotypic pattern reflective of a
false factor V inhibitor [50,51].
The prognosis of acquired factor V inhibitors is strictly
related to the underlying disease, with the drug-related
cases being those with a more favorable outcome. When-
ever possible, the triggering factor (such as the antibiotic)
should be immediately removed. The treatment of
acquired factor V inhibitors is based on two steps: the
control of the bleeding and the eradication of the auto-
antibody [26]. Although treatment is usually unnecessary
for asymptomatic patients, a number of therapeutic
options [i.e. FFP, platelet transfusions, prothrombin
complex concentrates (PCC)] have been used in bleeding
patients with varying success [52]. However, as expected,
the success rate of response to FFP used at standard dose
(15–20 ml/kg daily) was unsatisfactory (approximately
15%) because the low concentration of factor V in FFP
could be easily inactivated by circulating inhibitors. A
high percentage of responses have been reported with
platelet transfusions and PCC, ranging between 70 and
80% [48]. Administration of recombinant activated factor
VII (rFVIIa, NovoSeven; Novo Nordisk A/S, Bagsvaerd,
Denmark) may also be considered in treating patients
with a factor V inhibitor, wherever clinically indicated
[53]. Plasmapheresis and immunoadsorption can effec-
tively remove the inhibitor [54]. High dose intravenous
immunoglobulin has also been documented as rapidly
increasing factor V activity [55]. Immunosuppressive
regimens with corticosteroids and cyclophosphamide
have been used successfully to suppress autoantibody
production [56]. Finally, the anti-CD20 monoclonal anti-
body rituximab has also been used successfully in two
patients with severe and symptomatic acquired factor V
deficiency [57,58].
Conclusion
Factor V plays a central role in hemostasis, displaying
both procoagulant and anticoagulant functions. The dis-
covery of factor V Leiden and its strong association with
thromboembolic disorders has recently driven much
focus toward the prothrombotic role of factor V. The
two main forms of factor V deficiency arise from either a
defect in the F5 gene (giving rise to isolated factor V
deficiency) or defects in transport genes (giving rise to
combined factor V and FVIII deficiencies). Although
inherited and acquired factor V deficiencies represent
rare disorders, knowledge of their existence is, however,
essential for the correct diagnosis and management of
affected patients.
The prenatal diagnosis is another important issue, which
is already practiced for other hemorrhagic disorders such
as hemophilia A, hemophilia B, as well as factor VII
deficiency, factor X deficiency, and von Willebrand’s
disease. Recently, prenatal diagnosis has also been

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

carried out for factor V deficiency by chorionic villi biopsy
and allele-specific restriction enzyme analysis of the
corresponding PCR amplified products [59].
The mainstay of treatment in both conditions is to correct
the deficient factor(s). The main cause of factor V inhibi-
tors was previously the use of bovine thrombin in surgical
procedures and the contamination of bovine factor V.
Although the development of such factor V inhibitors is
now considered rare in developed countries due to pro-
gress with recombinant thrombins, laboratories and clin-
icians should not become complacent. In many regards, it
is these relatively rare conditions that provide us with the
greatest diagnostic challenge simply because most of us
encounter them only a few times within our lifetimes.
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