Haemophilia (2008), 14, 1159–1163
DOI: 10.1111/j.1365-2516.2008.01832.x
ORIGINAL ARTICLE
Abnormalities of prothrombin: a review of the
pathophysiology, diagnosis, and treatment
S. L. MEEKS and T. C. ABSHIRE
Aflac Cancer Center and Blood Disorders Service, ChildrenÕs Healthcare of Atlanta and Emory University, Atlanta, GA, USA
Summary. Prothrombin (factor II) deficiency is a rare
autosomal recessive coagulation disorder that occurs
in approximately 1 in 1–2 million people. Prothrombin is activated to thrombin, which in turn proteolytically cleaves fibrinogen to fibrin and contributes
to forming a stable fibrin clot. The haemostatic level
of prothrombin is thought to be between 20 and
40%, and the half-life is approximately 3 days.
There are more than 40 known mutations in
prothrombin. Both hypoprothrombinemia and dysprothrombinemia have been described. Low prothrombin activity typically prolongs both the
activated partial thromboplastin time and prothrombin time. Clinical manifestations are predominantly
mucosal or surgical- or trauma-associated bleeding,
but joint bleeding and intracranial haemorrhages
have been reported. No purified prothrombin products are available for replacement therapy. Both fresh
frozen plasma and prothrombin complex concentrates contain prothrombin and may be used for
treatment.
Introduction
Materials and methods
Prothrombin (factor II) deficiency is a rare coagulation disorder first reported by Quick in 1947 and
further described in 1955 and 1962. In 1969, Shapiro
reported the first prothrombin abnormality, prothrombin Cardeza, in [1]. We now know that the
zymogen prothrombin, when activated to thrombin,
is instrumental in converting fibrinogen to fibrin and
forming a stable fibrin clot. Homozygous prothrombin deficiency is exceedingly rare, occurring in
approximately 1 in 1–2 million people. This review
summarizes our current knowledge of the pathophysiology, diagnosis, and treatment of prothrombin
deficiency (Fig. 1). Also included is a brief review of
the prothrombin 20210 mutation, an abnormality
associated with thrombosis rather than bleeding.
A systematic review of the PubMed database was
undertaken using ÔprothrombinÕ and Ôfactor IIÕ as the
initial keywords searched. Review articles and
original reports were included. An internet-based
search was also performed.
Correspondence: Shannon L. Meeks, MD, Aflac Cancer Center
and Blood Disorders Service, ChildrenÕs Healthcare of Atlanta/
Emory University, 2015 Uppergate Dr. NE, 4th Floor, Atlanta, GA
30322, USA.
Tel.: 404-727-1608; fax: 404-727-4451;
e-mail: shannon.meeks@choa.org
Accepted after revision 5 July 2008
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
Keywords: bleeding, coagulation, factor II, haemostasis, prothrombin, thrombophilia
Incidence, racial/ethnic predilection
Like most autosomal recessive disorders, prothrombin deficiency is reportedly higher in regions and
ethnic groups with increased rates of consanguinity
[2]. Indeed, many of the patients who have been
genotyped are homozygous for the same mutation
rather than being compound heterozygotes. In the
North American Rare Bleeding Disorder Registry,
62% of the patients with heterozygous or homozygous factor II deficiency were Latinos, 25% Caucasian, and 12% other [3]. This increase in Latino
patients was not accounted for by the baseline
percentage of Latinos in the overall study population.
Pathophysiology
Thrombin, which is derived from the Greek word
thrombos, meaning Ôto clotÕ, is a serine protease
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S. L. MEEKS and T. C. ABSHIRE
Prothrombin (factor ll) deficiency
Clinical
Mucosal bleeding
Surgical- or trauma-related bleeding
Rare-joint bleeding, ICH
Laboratory
FII level <10%
↑ aPTT; ↑↑ PT
Treatment
FFP
PCC
Fig. 1. Summary of prothrombin deficiency.
synthesized in the liver as the inactive zymogen
prothrombin. Prothrombin is a 72-kDa, vitamin Kdependent glycoprotein with a plasma concentration
of approximately 100 lg mL)1. In the coagulation
cascade, factor Xa is made as a product of both the
tissue factor and the contact factor pathways. In
the presence of calcium, factor Xa, as part of the
prothrombinase complex with factor Va and phospholipid, sequentially cleaves two peptide bonds in
prothrombin to form thrombin [4]. Thrombin in turn
proteolytically cleaves fibrinogen to fibrin and contributes to forming a stable fibrin clot. Thrombin
also acts on a variety of other substances in the
haemostatic pathway. It promotes platelet activation, activates factor XIII to cross-link the fibrin clot,
enhances clot stability by activating thrombin-activatable fibrinolysis inhibitor (TAFI), and up-regulates its own production by activating factors IX,
VIII, and V [5–7].
Regulation of thrombinÕs procoagulant activity is
necessary to generate enough fibrin to stop bleeding
but at the same time prevent excessive clot formation. When bound to thrombomodulin, thrombin
down-regulates the coagulation cascade by activating
protein C, which in turn inactivates factors VIIIa and
Va. In addition, antithrombin, heparin cofactor II,
and protease nexin I, all members of the serine
protease inhibitor (serpin) superfamily, inhibit the
catalytic activity of thrombin, thus limiting clot
formation. The activity of these serpins is increased
in the presence of glycosaminoglycans such as
heparin [6]. Thrombin interacts via proteinase-activated receptors on endothelial cells, leading to tissue
plasminogen activator (tPA) release and up-regulation of cell surface molecules, which increase the rate
of tPA conversion of plasminogen to plasmin and
Haemophilia (2008), 14, 1159–1163
thus enhances thrombolysis [8]. There are additional
effects of thrombin on cytokine production and
vessel wall biology, including regulation of vessel
tone, smooth muscle cell proliferation, angiogenesis,
atherogenesis, and vascular development [9–11].
There are two types of inherited prothrombin
deficiency. Type I or hypoprothrombinemia occurs
when there is a decreased level of normally functioning protein, characterized by a proportional
decrease in protein antigen and activity. Type II or
dysprothrombinemia occurs when there is a normal
antigen level but a decreased level of activity. The
haemostatic level of prothrombin is thought to be
between 20 and 40%. The half-life is approximately
3 days [2,12]. No reports are in the literature of
aprothrombinemia, and complete deficiency is
thought to be incompatible with life. In a murine
factor II knock-out model, complete prothrombin
deficiency resulted in either embryonic or neonatal
death [13]. Acquired prothrombin deficiency can
occur in vitamin K deficiency, liver disease, and
warfarin therapy and in the presence of inhibitors
similar to those seen with the lupus anticoagulant.
Genetics
The prothrombin gene is composed of 20.3 kb and
found on chromosome 11p11.2. The deficiency is
inherited in an autosomal recessive fashion, either as
a single or a combination of defects within the
prothrombin gene. Combined deficiencies of the
vitamin K-dependent proteins, factors II, VII, IX,
and X, can occur when there is an abnormality in the
gamma-glutamyl carboxylase gene or the vitamin K
epoxide reductase complex [14]. More than 40
different mutations have been identified in patients
with prothrombin deficiency [1,15,16]. The Human
Gene Mutation Database at the Institute of Medical
Genetics in Cardiff contains a large collection of
mutations, leading to prothrombin deficiency, including 35 missense/nonsense, 2 splicing, 4 small deletion,
and 1 small insertion [17].
The mutations associated with dysprothrombinemia can be divided into two groups: those that
produce defects in prothrombin activation and those
with defects in the thrombin molecule that is
formed. In the first group, prothrombin activation
by factor Xa in the prothrombinase complex is
diminished, but the thrombin that is generated is
fully functional. In the second group, the function
of the thrombin produced is abnormal either
because of altered interactions with fibrinogen or
abnormalities in the catalytic region of thrombin
itself [1,18].
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
ABNORMALITIES OF PROTHROMBIN
Clinical manifestations
Patients who are homozygous or compound heterozygous for defects in the prothrombin gene can have
moderate to severe bleeding symptoms. Given the
small number of cases reported in the literature, the
genotype/phenotype correlation is difficult to ascertain, but in general, the lower the levels of protein, the
more severe the bleeding. A spectrum of bleeding
symptoms have been reported, including easy bruising, mucosal bleeding, surgical bleeding, traumarelated bleeding, haemarthroses, and intracranial
haemorrhage [2,3,19]. In the newborn period, patients
can present with haematomas, bleeding after circumcision, and umbilical cord bleeding. Heterozygotes are
typically asymptomatic; however, bleeding has been
reported after tonsillectomy and tooth extraction
[1,2]. In the North American Registry, most heterozygotes who had their conditions diagnosed after
haemorrhage or abnormal preoperative screening
laboratory test results reported bleeding symptoms
entirely in the skin or mucous membranes [3].
In terms of prognosis and chronic disease-related
complications, the North American Registry
reported that 49% of the patients with homozygous
prothrombin deficiency had anaemia, 17% had
musculoskeletal complications such as target joints
or muscle contractures, and 11% had central nervous
system complications, including intracranial bleeding
and stoke [3]. Chronic arthropathy was also reported
in a series of patients from Iran and Italy [15,16].
Diagnosis
Patients with prothrombin deficiency typically demonstrate both a prolonged prothrombin time and
partial thromboplastin time from a screening laboratory panel often drawn as part of a preoperative
evaluation. However, the increase may be minimal
and reagent-dependent. If the index of suspicion for
prothrombin deficiency is high, a factor II assay
(usually a functional or activity level) should be
checked. Activity testing is most often performed
using a one-stage assay, which uses a tissue thromboplastin as the activating agent and a prothrombinfree substrate. Factor II antigen testing can be
performed using an immunoassay. When considering
a dysprothrombinemia, it is important to consider
that the different prothrombin-activating agents,
including tissue thromboplastin and various snake
venoms, all demonstrate varying requirements for
the presence of factor V, phospholipid, and calcium
in the activation of prothrombin to thrombin and
2008 The Authors
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will manifest different activity levels, depending on
where the defect in prothrombin is located [1,18]. In
the first months of life, prothrombin deficiency must
be differentiated from haemorrhagic disease of the
newborn, in which all of the vitamin K-dependent
factors are low.
Many clinical coagulation laboratories perform
the prothrombin time-based assay for factor II
activity levels and molecular testing for the prothrombin 20210 mutation. However, molecular
testing for types I and II prothrombin deficiency is
much more complicated. Genotyping has only been
performed on a small number of patients in the rare
bleeding disorders registries. Given the small number
of known recurring mutations, complete analysis of
the prothrombin gene and flanking regions may be
necessary if a familial mutation is not already
known. This molecular analysis is currently only
available in the research setting. Prenatal diagnosis
on DNA samples obtained by chronic villous sampling or amniocentesis is feasible if the genotype of
the prothrombin abnormality is known [2,20].
Management
Treatments currently available
Acute bleeding episodes can be treated with fresh
frozen plasma (FFP) at 15–20 mL kg)1, which will
usually raise the factor level by 25%. As stated
previously, this level should be haemostatic for those
with homozygous factor II deficiency. For surgical
procedures or more severe bleeding episodes, a
loading dose of 15–20 mL kg)1 of FFP followed by
3 mL kg)1 every 12–24 h is usually adequate for
haemostasis [21]. The volume of FFP needed can be
prohibitive for patients with severe fluid restriction.
Another option is prothrombin complex concentrates (PCC) at a dose of 20–30 IU kg)1 based on
factor IX units. PCC contain factors II, VII, IX, and
X and vary in the amounts of each factor from
product-to-product and lot-to-lot. For example,
Bebulin VH (Baxter, Deerfield, IL, USA) is a PCC
with more factor X (factor X > factor II > factor IX)
and Profilnine SD (Grifols, Los Angeles, CA, USA)
has more factor II (factor II > factor IX > factor X)
[22]. However, these products are labelled based on
factor IX units, and the exact amount of factor II in
these products is unknown. The recommended dosing of 20–30 U kg)1 of factor IX usually raises the
factor II to haemostatic levels. However, as other
vitamin K-dependent factors are present in PCC,
treatment of factor II deficiency with these products
Haemophilia (2008), 14, 1159–1163
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S. L. MEEKS and T. C. ABSHIRE
may potentially lead to supertherapeutic levels of
these factors. These high factor levels may increase
the risk of thrombosis [16]. No pure factor II
concentrates are available [18,23].
Antifibrinolytic therapies such as -aminocaproic
acid or tranexamic acid can be administered orally or
intravenously to treat mucosal bleeding. Typically
antifibrinolytics are not used in conjunction with
PCC because of the risk of thrombosis. Hormonal
therapy with oestrogens and/or progesterones may
help reduce menstrual blood loss in patients with
menorrhagia [2]. Successful prophylaxis of a patient
with severe prothrombin deficiency with onceweekly home administration of PCC has been
reported [24].
both procoagulant and anticoagulant activities.
Abnormal levels of prothrombin antigen or activity
can lead to excessive bleeding or, in the case of the
20210 mutation, thrombosis. These abnormalities of
prothrombin demonstrate the delicate balance of
procoagulant and anticoagulant activities in maintaining appropriate haemostasis. Given the small
numbers of patients with prothrombin deficiency, it
is essential to continue collaborative efforts with
international registries to expand our knowledge of
this and other rare coagulation disorders.
Disclosures
The authors stated that they had no interests which
might be perceived as posing a conflict or bias.
Research
Registries for rare bleeding disorders have been
established in many countries [3,16]. The International Society of Thrombosis and Hemostasis (ISTH)
has a scientific subcommittee working group on rare
bleeding disorders and an international database has
been established [12,25]. The World Federation of
Hemophilia (WFH) also collects basic epidemiological data on patients with bleeding disorders. The
international community is working together to
standardize data collection to increase the power of
these databases. More information about rare bleeding disorders and the registries can be found at the
ISTH or WFH web sites: http://www.ISTH.org and
http://www.WFH.org.
Prothrombin and thrombosis
The prothrombin 20210 guanine to adenine mutation has been associated with an increased risk of
thrombosis. First described in 1996, this mutation, in
the 3¢ untranslated region, results in higher baseline
levels of prothrombin [26]. Studies have demonstrated a three- to fivefold increased risk of venous
thromboembolus in heterozygotes with an even
higher risk in the homozygote [26,27]. This mutation
is found in 2–3% of Caucasians and in 4–8% of
subjects presenting with a first venous thromboembolus [5,26]. The prevalence of the prothrombin
20210 mutation was also significantly higher in a
group of pregnant women with venous thromboemboli than in those without [28,29].
Conclusion
Prothrombin is the inactive zymogen that when
cleaved forms thrombin, a serine protease that has
Haemophilia (2008), 14, 1159–1163
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Links to organizations
http://www.ISTH.org – International Society of
Thrombosis and Hemostasis website;
http://www.wfh.org – World Federation of Hemophilia website;
http://www.hgmd.cf.ac.uk – The Human Gene
Mutation Database at the Institute of Medical
Genetics at Cardiff website;
http://www.rbdd.org – An international database
for rare bleeding disorders.
Haemophilia (2008), 14, 1159–1163