Theme Issue Article
Classic thrombophilic gene variants
Pier Mannuccio Mannucci1; Massimo Franchini2
1Scientific
Direction, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation, Milan, Italy; 2Department of Transfusion Medicine and Hematology, Carlo Poma Hospital,
Mantova, Italy
Summary
Thrombophilia is defined as a condition predisposing to the develop-
ment of venous thromboembolism (VTE) on the basis of a hypercoagu-
lable state. Over the past decades, great advances in the pathogenesis
of VTE have been made and nowadays it is well established that a
thrombophilic state may be associated with acquired and/or inherited
factors. The rare loss-of-function mutations of the genes encoding
natural anticoagulant proteins (i. e. protein C, protein S and antithrom-
bin) and the more common gain-of-function polymorphisms factor V
Correspondence to:
Pier Mannuccio Mannucci
Scientific Direction
IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation
Milan, Italy
E-mail: pm.mannucci@policlinico.mi.it
Introduction
Thrombophilia is defined as a hypercoagulable state leading to a
thrombotic tendency (1–3). In 1856, Rudolf Virchow conceived
the theory of the triad, i. e. vessel wall damage, blood stasis and hy-
percoagulability, in order to explain the etiology of thrombosis (4).
This concept was prophetic, because it is now well established that
all the components of the triad play important mechanistic roles in
the development of the clinical manifestations of thrombosis. Dur-
ing the past two to three decades, much progress has been made in
the identification and characterisation of the cellular and molecu-
lar mechanisms that influence the Virchow’s triad. It is now ac-
cepted that the combination of stasis and hypercoagulability, much
more than vascular endothelial damage, is crucial for the occur-
rence of venous thromboembolism (VTE), venous thrombi being
mainly constituted by fibrin and red blood cells and less by blood
platelets. In contrast, platelets are essential for primary haemo-
stasis and play a pivotal role in the development of arterial throm-
bosis (5).
With this background, the term thrombophilia is now em-
ployed to describe a tendency to develop VTE (not arterial throm-
bosis), owing to abnormalities of blood coagulation that can be in-
herited, acquired or mixed (both congenital and acquired). In-
herited thrombophilias include loss-of function mutations in the
genes that encode the natural anticoagulant proteins antithrom-
bin, protein C and protein S (▶ Figure 1), as well as gain-of-func-
tion mutations in the genes encoding factor V (factor V Leiden)
and prothrombin (prothrombin G20210A) (6). In addition, con-
sistent data have been accumulated on the association between a
very frequent biomarker such as the non-O blood types (i. e. A, B
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1
Leiden and prothrombin G20210A are the main genetic determinants
of thrombophilia. In addition, non-O blood group has been consist-
ently demonstrated to be the most frequent inherited marker of an in-
creased risk of VTE. The mechanism role of these inherited throm-
bophilia markers will be discussed in this narrative review.
Keywords
Inherited thrombophilia, natural anticoagulants, factor V Leiden,
prothrombin mutation, ABO blood group
Received: February 13, 2015
Accepted after minor revision: April 26, 2015
Epub ahead of print: May 28, 2015
http://dx.doi.org/10.1160/TH15-02-0141
Thromb Haemost 2015; 114: ■■■
and AB) and VTE (7, 8). The main risk factors of VTE will be dis-
cussed in this narrative review, focusing only on established
thrombophilic gene variants.
Loss-of-function mechanisms
Antithrombin deficiency
Antithrombin, a single chain glycoprotein member of the serine
protease inhibitor (serpin) superfamily synthesised by the liver, is
the major inhibitor of coagulation serine proteases, in particular
thrombin and activated factor X (FXa) (9, 10). The result of this
anticoagulant activity is a reduction in both the generation and
half-life of thrombin, the final enzyme of blood coagulation. In ad-
dition to the active site responsible for coagulation factor inacti-
vation, the antithrombin molecule contains a heparin-binding site
(10). When exogenous heparin or endogenous heparan sulphate
bind to this site, the ability of antithrombin to inactivate activated
coagulation factors is greatly enhanced. Currently, more than 250
loss-of-function mutations have been identified in the antithrom-
bin gene (SERPIN1) located at chromosome 1q 23–25, including
missense and nonsense mutations, insertions and deletions (11,
12). Most mutations, that lead to a reduction of plasma antithrom-
bin levels or to a decreased ability of this anticoagulant protein to
interact with the activated coagulation factors or heparin, lead to
an increased risk of VTE (13).
Antithrombin deficiency is transmitted as an autosomal domi-
nant trait and the penetrance of this disease is very high, since
most affected family members experience a thrombotic event by
the age of 45–50 years (14). In the general population, the esti-
Thrombosis and Haemostasis 114.4/2015
2 Mannucci, Franchini: Genetics of thrombophilia
mated prevalence of antithrombin deficiency is extremely low,
ranging between 0.02 and 0.2 %, and in unselected patients with
VTE is around 1 % (15–17) (▶ Table 1). This deficiency is the most
severe among the inherited thrombophilias, causing more than
50-fold increased risk for VTE compared to that of individuals not
carrying this defect (12).
On the basis of functional and immunological assays, two types
of antithrombin deficiency can be distinguished. Type I, due to a
wide variety of DNA mutations, is a quantitative defect characte-
rised by reduced functional and antigen levels; type II, due to mis-
sense mutations, is a qualitative defect characterised by normal
antithrombin antigen with an impaired inhibitory activity due to
the production of a variant protein (18). Type I is associated clini-
cally with premature recurrent VTE, whereas in type II the risk of
thrombosis is closely related to the position of the amino acid sub-
stitution within the protein. Thus, carriers of heterozygous mu-
tations within the heparin binding domain of antithrombin have a
low or absent risk of thrombosis, at variance with those with mu-
tations at or close to the reactive site of the protein (3, 5). The only
individuals homozygous for antithrombin deficiency described so
far carry heparin-binding site defects, suggesting that the other
subtypes are associated with embryonic lethality (19).
Protein C deficiency
Protein C, described for the first time in 1979 (20), is a vitamin-
K–dependent glycoprotein synthesised in the liver in an inactive
form. Protein C is activated by thrombin and this process is accel-
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Figure 1: Simplified
scheme of the coagu-
lation and anticoagu-
lation system. TF, tissue
factor; AT, antithrombin;
PC, protein C, APC, acti-
vated protein C, PS, pro-
tein S.
erated by the complex formed by thrombin with the endothelial
protein C receptor (EPCR) and thrombomodulin. Together with
protein S, activated protein C (APC) quenches thrombin gener-
ation by inactivating activated coagulation factors V (FVa) and
VIII (FVIIIa).
Inherited protein C deficiency is transmitted as a dominant
autosomal trait (21, 22) and more than 200 loss-of-function mu-
tations in the protein C gene (PROC), located at chromosome
2q13-q14, have been reported (23). Protein C deficiency is very
rare in the general population (around 0.2 %) and its frequency in
unselected patients with VTE is 3 % (17) (▶ Table 1). The pen-
etrance of the disease is lower than that of antithrombin deficien-
cy, and heterozygotes have a 15-fold increased risk for premature
VTE compared to the general population (12, 21). Homozygotes
have a more severe clinical picture, not infrequently leading to
neonatal purpura fulminans, a potentially fatal condition characte-
rised by microvascular thrombosis and skin necrosis (17).
Protein C deficiency is classified on the basis of the plasma lev-
els of the enzymatic activity and antigen and, similarly to anti-
thrombin deficiency, can be divided in two subtypes. Type I, the
most common, is characterised by a parallel reduction in plasma
antigen and activity, reflecting a reduced synthesis of a functional
protein. The rarer type II is characterised by normal antigen re-
duced functional activity, reflecting normal synthesis of a dysfunc-
tional protein. In type I, the majority of mutations are of the mis-
sense variety, leading to premature termination of synthesis or dis-
ruption of protein folding, deletions and insertions occurring with
a much lower frequency (~10 %). In type II deficiency, missense
© Schattauer 2015
 Mannucci, Franchini: Genetics of thrombophilia 3

mutations are located mainly in the γ–carboxyglutamic acid and Table 1: Prevalence of thrombophilia abnormalities and relative risk
protease domains (23, 24). of venous thromboembolism (VTE).

Thrombophilia Prevalence (%) Relative risk

Protein S deficiency abnormality General Patients First Recur-
Protein S, which derives its name from the city of Seattle where it population with VTE VTE rent VTE
was discovered (25), is a vitamin-K–dependent protein of liver Antithrombin deficiency 0.02–0.2 1 50 2.5
synthesis circulating in plasma in a free functionally active form Protein C deficiency 0.2–0.4 3 15 2.5
(approximately 40 %) and an inactive form bound to the Protein S deficiency 0.03–0.1 2 10 2.5
C4b-binding complement protein (approximately 60 %) (26). Pro-
tein S functions as a cofactor of APC for the degradation of acti- Factor V Leiden 5 20 7 1.5
(heterozygous)
vated factors Va and VIIIa and as a cofactor of tissue factor path-
way inhibitor in the inhibition of factor Xa (26). Factor V Leiden 0.02 1.5 80 -
Inherited protein S deficiency is transmitted as an autosomal (homozygous)
dominant trait and its gene (PROS1) is located at 3q11.2 chromo- Prothrombin G20210A 2 6 3–4 1.5
some. Almost 200 loss-of-function mutations have been identified (heterozygous)
in the PROS1 gene so far, the majority being missense mutations Prothrombin G20210A 0.02 <1 30 -
or short deletions or insertions (27), although large deletions were (homozygous)
relatively common in recent studies (28–30). The prevalence of Non-O blood group 55–57 75 2 2
protein S deficiency in the general population is estimated at
0.03–0.1%, while its prevalence in patients with VTE is around
2 %, similar to that of protein C deficiency (▶ Table 1) (17). In-
herited protein S deficiency has a clinical presentation very similar tween wild-type factor V and factor V Leiden, and are usually as-
to that observed for protein C deficiency (25). Thus, heterozygotes sociated with a lower VTE risk than that of factor V Leiden (35).
experience early and recurrent episodes of VTE and sometimes The factor V Leiden mutation has a dominant autosomal trans-
skin necrosis, while the very rare homozygotes exhibit a more se- mission and in heterozygosis is the most common prothrombotic
vere clinical picture with neonatal purpura fulminans. The risk of gene mutation in the Caucasian population, with a prevalence of
VTE is 10-fold higher in carriers than in non-carriers. Three types about 5 %, ranging from 2-10 % with a positive gradient from
of protein S defects have been described: type I is a quantitative Southern to Northern Europe (36). This prevalence rises up to
deficiency with decreased plasma levels of functional and immu- 20 % in non-selected VTE patients. The risk of VTE is increased
noreactive total and free protein S; type II is a qualitative deficien- approximately seven-fold in heterozygous and 80-fold in homozy-
cy with decreased cofactor activity but normal total and free pro- gous carriers of the mutation compared to non-carriers (▶ Table
tein S levels; type III is a quantitative deficiency, with reduced 1) (37, 38). Homozygosity for factor V Leiden mutation occurs in
functional activity and free protein S antigen levels but normal approximately in one in 1,000 individuals in the general popu-
total protein S levels (12). lation and in 1 % of non-selected patients with VTE.

Gain-of-function mechanisms
Factor V Leiden
In 1993, a poor anticoagulant response to APC was associated
with an increased risk of VTE (31, 32). The following year, a gain-
of-function mutation in the F5 gene (chromosome 1q23) was first
described in the city of Leiden (33, 34) as being responsible for the
majority of cases of APC resistance. The factor V Leiden mutation,
which results from a substitution of adenine to guanine at the 1691
position (G1691A) in exon 10 of the F5 gene, is located in the part
of the gene encoding one of the cleavage sites of the factor
(Arg506) involved in the inactivation of activated factor V (6). As a
consequence, the mutant activated factor V molecule (factor V
Leiden) is resistant to proteolytic inactivation by APC and retains
full procoagulant activity (33). Another point mutation in the F5
gene occurs at Arg306, another APC cleavage site, and the result-
ing factor V variants (factor V Hong Kong and factor V Cam-
bridge) cause varying degrees of APC resistance, intermediate be-
Prothrombin G20210A
This mutation in the prothrombin gene (located on chromosome
11p11-q12), first described in 1996 by the Leiden group (39), con-
sists of a guanine to adenine substitution at the nucleotide 20210
within the 3’ untranslated region of the gene that results in an ap-
proximately 30 % increase of prothrombin plasma levels (39). Like
factor V Leiden, prothrombin G20210A has a dominant autoso-
mal transmission and is the second most common thrombophilia
abnormality, with a prevalence of heterozygotes in populations of
Caucasian origin of 2–3 %, that increases to 6 % in patients with
VTE (▶ Table 1) (40). The mutation is more common in Southern
than in Northern Europe, with a gradient opposite to that of factor
V Leiden. Heterozygosity for prothrombin G20210A mutation
confers an approximately three- to four-fold increased risk of de-
veloping VTE. Thus these individuals exhibit a relatively low
thrombotic risk, and most of them will not develop a premature
thrombotic episode. In contrast, homozygosity for the prothrom-
bin gene mutation which is much rarer and occurs in four out of

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4 Mannucci, Franchini: Genetics of thrombophilia
10,000 people, causes an approximately 30-fold increased VTE
risk. The risk of VTE recurrence is similar to that of factor V
Leiden (1.4-fold) (12).
The case of blood groups
The antigens of the ABO blood group system (i. e., A, B, and H
antigens) are complex carbohydrate molecules expressed on the
extracellular surface of the red blood cell membranes (41). The
molecular basis of the ABO blood group system was elucidated in
1990 by Yamamoto et al. (42, 43): the codominant A and B alleles
at the ABO locus encode slightly different glycosyltransferases that
add N-acetylgalactosamine and D-galactose, to a common precur-
sor side chain, the H determinant, converting it into A or B
antigens. By contrast, the silent recessive allele O does not encode a
functional enzyme and thus OO carriers, who lack transferase
enzymes, continue to express the unaltered H structure, with a
solitary terminal fucose moiety attached to the precursor oligosac-
charide chain, i. e. the phenotypic marker of the O blood group
(44). Beside red blood cells, ABO antigens are widely expressed in
human cells and tissues, extending their biological importance
beyond transfusion medicine (45–47).
ABO blood group system exerts a profound influence on hae-
mosstasis, mostly on von Willebrand factor (VWF) and conse-
quently on factor VIII (FVIII) plasma levels, because individuals of
non-O blood group have VWF and FVIII plasma levels approxi-
mately 25 % higher than those of O blood group (48). The molecu-
lar basis of this phenomenon is provided by the presence of ABH
antigenic structures on circulating VWF, which are able to modu-
late VWF half-life in plasma through the different degrees of gly-
cosylation (the VWF plasma half-life is 10 hours for group O and
25 hours for non-O subjects) (49, 50). The subjects with the very
rare Bombay blood group phenotype, characterised by the com-
plete inability to produce the H determinant, lack the ABH
antigens and have the lowest plasma VWF levels (51).
A number of studies have investigated whether or not non-O
blood type is associated with the development of VTE, considering
that increased VWF and FVIII levels are important risk factors for
VTE (52). Two recent systematic reviews and meta-analyses have
consistently demonstrated that non-O blood type carries an ap-
proximately two-fold increased risk of VTE (6, 53, 54). Non-O
blood type has also been associated with an increase risk of recur-
rent VTE (▶ Table 1) (55, 56). Even thought the magnitude of the
risk increase is lower than for the other inherited thrombophilia
markers, it must be borne in mind that this marker is much more
frequent in the general population.
Conclusions
Our knowledge on the genetic basis of thrombophilia has dramati-
cally improved in the last few decades, leading to a much improved
understanding of the mechanisms of VTE. All in all, inherited
thrombophilia helps to explain the pathogenesis in approximately
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40 % of VTE episodes, and the contribution of each different ab-
normality varies greatly according to their different frequency and
clinical penetrance (57). Thus, while the rarest abnormalities
(natural anticoagulant deficiencies, homozygous factor V Leiden
and prothrombin G20210A, combined defects) result in a severe
thrombophilia phenotype, other more common genetic variants
(non-O blood type, heterozygous factor V Leiden and prothrom-
bin G20210A) are associated with a smaller risk of VTE, that often
develops only in association with triggering factors. Considering
that thrombophilic abnormalities are stronger risk factors for pri-
mary than for secondary (recurrent) thrombosis (▶ Table 1),
screening of asymptomatic relatives of patients with severe throm-
bophilia may be useful. Furthermore, because of the multifactorial
pathogenesis of VTE, the assessment of the thrombotic risk should
be individualised, being the result of the additive (or supra-addi-
tive) effect of inherited and acquired risk factors (i. e. pregnancy,
oral contraceptive, confinement to bed, trauma, surgery, cancer,
inflammatory states). Most importantly, patients’ age should be
taken into strong account, as the thromboembolic risk dramati-
cally increases during the decades of life. Finally, some believe that
gain-of-function polymorphisms (i. e. A and B antigens, factor V
Leiden and prothrombin G20210A), by inducing a greater propen-
sity toward blood clot formation and a lower risk of bleeding, may
have conferred a survival advantage to early humans (58).
Are new genetic abnormalities associated with thrombophilia
going to be identified? Genome-wide association studies have
identified a few additional relatively common variants consistently
but weakly associated with VTE (for more information see [3]), so
that they are of limited clinical value. However, the developing and
improving methods of DNA sequencing might help to identify a
few very rare variants endowed with a high risk of thrombosis.
Finally, inherited thrombophilia is likely to be explained in a few
cases by epigenetic changes that influence gene expression and
regulation.
Conflicts of interest
None declared.
References
1. Martinelli I, Bucciarelli P, Mannucci PM. Thrombotic risk factors: basic patho-
physiology. Crit Care Med 2010; 38 (Suppl 2): S3-S9.
2. Previtali E, Bucciarelli P, Passamonti SM, et al. Risk factors for venous and arter-
ial thrombosis. Bloood Transfus 2011; 9: 120–138.
3. Martinelli I, De Stefano V, Mannucci PM. Inherited risk factors for venous
thromboembolism. Nat Rev Cardiol 2014; 11: 140–156.
4. Virchow R. Phlogose und Thrombose im Gefäßsystem; Gesammelte Abhand-
lungen zur Wissenschaftlichen Medizin. Frankfurt, Staatsdruckerei, 1856.
5. Lippi G, Franchini M, Targher G. Arterial thrombus formation in cardiovascu-
lar disease. Nat Rev Cardiol 2011; 8: 502–512.
6. Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost
2009; 7 (Suppl 1): 301–304.
7. Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood groups and vascular
disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6:
62–69.
8. Franchini M, Mannucci PM. ABO blood group and thrombotic vascular dis-
ease. Thromb Haemost 2014; 112: 1103–1109.
© Schattauer 2015

9. Mammen EF. Antithrombin: its physiological importance and role in DIC.
Semin. Thromb Haemost 1998; 24: 19–25.
10. Roemisch J, Gray E, Hoffmann JN, et al. Antithrombin: a new look at the ac-
tions of a serine protease inhibitor. Blood Coagul Fibrinolysis 2002; 13:
657–670.
11. Lane DA, Kunz G, Olds RJ, et al. Molecular genetics of antithrombin deficiency.
Blood Rev 1996; 10: 59–74.
12. Franchini M, Veneri D, Salvagno GL, et al. Inherited thrombophilia. Crit Rev
Clin Lab Sci 2006; 43: 249–290.
13. Mammen EF. Clinical relevance of antithrombin deficiencies. Semin. Hematol
1995; 32 (4 Suppl 2): 2–6.
14. Buchanan GS, Rodgers GM, Branch DW. The inherited thrombophilias: gen-
etics, epidemiology, and laboratory evaluation. Best Pract Res Clin Obst Gyne-
col 2003; 17: 397–411.
15. Wells PS, Blajchman MA, Henderson P, et al. Prevalence of antithrombin defi-
ciency in healthy blood donors: a cross-sectional study. Am J Hematol 1994; 45:
321–324.
16. Tait RC, Walker ID, Perry DJ, et al. Prevalence of antithrombin deficiency in the
healthy population. Br J Haematol 1994; 87: 106–112.
17. De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis,
clinical syndromes, and management. Blood 1996; 87: 3531–3544.
18. Lane DA, Mannucci PM, Bauer KA, et al. Inherited thrombophilia: part 1.
Thromb Haemost 1996; 76: 651–662.
19. Finazzi G, Caccia R, Barbui T. Different prevalence of thromboembolism in the
subtypes of congenital antithrombin III deficiency: review of 404 cases. Thromb
Haemost 1987; 58: 1094.
20. Kisiel W. Human plasma protein C. Isolation, characterization and mechanism
of activation by alpha-thrombin. J Clin Invest 1979; 64: 761–769.
21. Simioni P. The molecular genetics of familial venous thrombosis. Bailliere’s Clin
Haematol 1999; 12: 479–503.
22. Griffin JH, Evatt B, Zimmerman TS, et al. Deficiency of protein C in congenital
thrombotic disease. J Clin Invest 1981, 68: 1370–1373.
23. Reitsma PH, Bernardi F, Doig RG, et al. Protein C deficiency: a database of mu-
tations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation In-
hibitors of the Scientific and Standardization Committee of the ISTH. Thromb
Haemost 1995; 73: 876–889.
24. Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Gen
2001; 109: 369–384.
25. Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a
partial deficiency of protein S. N Engl J Med 1984; 311: 1525–1528.
26. Borgel D, Gandrille S, Aiach M. Protein S deficiency. Thromb Haemost 1997;
78: 351–356.
27. García de Frutos P, Fuentes-Prior P, Hurtado B, et al. Molecular basis of protein
S deficiency. Thromb Haemost 2007; 98: 543–556.
28. Lind-Halldén C, Dahlen A, Hillarp A, et al. Small and large PROS1 deletions but
no other types of rearrangements detected in patients with protein S deficiency.
Thromb Haemost 2012; 108: 94–100.
29. Pintao MC, Garcia AA, Borgel D, et al. Gross deletions/duplications in PROS1
are relatively common in point mutation-negative hereditary protein S deficien-
cy. Hum Genet 2009; 126: 449–456.
30. Johansson AM, Hillarp A, Säll T, et al. Large deletions of the PROS1 gene in a
large fraction of mutation-negative patients with protein S deficiency. Thromb
Haemost 2005; 94: 951–957.
31. Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a pre-
viously unrecognized mechanism characterized by poor anticoagulant response
to activated protein C: prediction of a cofactor to activated protein C. Proc Natl
Acad Sci USA 1993; 90: 1004–1008.
32. Koster T, Rosendaal FR, Bertina RM. Venous thrombosis due to poor antico-
agulant response to activated protein C: Leiden Thrombophilia Study. Lancet
1993; 342: 1503–1506.
33. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation fac-
tor V associated with resistance to activated protein C. Nature 1994; 369: 64–67.
© Schattauer 2015
Downloaded from www.thrombosis-online.com on 2015-06-02 | IP: 134.129.120.3
Note: Uncorrected proof, epub ahead of print online
For personal or educational use only. No other uses without permission. All rights reserved.
Mannucci, Franchini: Genetics of thrombophilia 5
34. Voorberg J, Roelse J, Koopman R, et al. Association of idiopathic venous throm-
boembolism with a single point-mutation at Arg506 of factor V. Lancet 1994;
343: 1535–1536.
35. Norstrøm E, Thorelli E, Dahlbäck B. Functional characterization of recombi-
nant FV Hong Kong and FV Cambridge. Blood 2002; 100: 524–530.
36. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;
346: 1133–1134.
37. Rosendaal FR, Koster T, Vandenbroucke JP, et al. High risk of thrombosis in pa-
tients homozygous for factor V Leiden. Blood 1995; 85: 1504–1508.
38. Cushman M, Tsai AW, White RH, et al. Deep vein thrombosis and pulmonary
embolism in two cohorts: The Longitudinal Investigation of Thromboembolism
Etiology. Am J Med 2004; 117: 19–25.
39. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the
3’-untranslated region of the prothrombin gene is associated with elevated plas-
ma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88:
3698–3703.
40. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210
G to A prothrombin variant. Thromb Haemost 1998; 79: 706–708.
41. Storry JR, Olsson ML: The ABO blood group system revisited: a review and up-
date. Immunohematology 2009; 25: 48–59.
42. Yamamoto F, Clausen H, White T, et al. Molecular genetic basis of the histo-
blood group ABO system. Nature 1990; 345: 229–233.
43. Yamamoto F, Cid E, Yamamoto M, et al. ABO research in the modern era of ge-
nomics. Transfus Med Rev 2012; 26: 103–118.
44. Lowe J. The blood group-specific human glycosyltransferases. Baillieres Clin
Haematol 1993; 6: 465–490.
45. Liumbruno GM, Franchini M. Beyond immunohaematology: the role of the
ABO blood group in human diseases. Blood Transfus 2013; 11: 491–499.
46. Garratty G. Blood groups and disease: a historical perspective. Transfus Med
Rev 2000; 14: 291–301.
47. Anstee DJ. The relationship between blood groups and disease. Blood 2010; 115:
4635–4643.
48. Gill JC, Endres-Brooks J, Bauer PJ, et al. The effect of ABO blood group on the
diagnosis of von Willebrand disease. Blood 1987; 69: 1691–1695.
49. Jenkins PV, O’Donnell JS. ABO blood group determines plasma von Willebrand
factor levels: a biologic function after all? Transfusion 2006; 46: 1836–1844.
50. Gallinaro L, Cattini MG, Sztukowska M, et al. A shorter von Willebrand factor
survival in O blood group subjects explains how ABO determinants influence
plasma von Willebrand factor. Blood 2008; 111: 3540–3545.
51. O’Donnell JS, McKinnon TA, Crawley JT, et al. Bombay phenotype is associated
with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13
proteolysis. Blood 2005; 106: 1988–1991.
52. Franchini M, Mannucci PM. ABO blood group and thrombotic vascular dis-
ease. Thromb Haemost 2014; 112: 1103–1109.
53. Wu O, Bayoumi N, Vickers MA, et al. ABO(H) blood groups and vascular dis-
ease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6: 62–69.
54. Dentali F, Sironi AP, Ageno W, et al. Non-O blood type is the commonest gen-
etic risk factor for VTE: results from a meta-analysis of the literature. Semin
Thromb Haemost 2012; 38: 535–548.
55. Dentali F, Franchini M. Recurrent venous thromboembolism: a role for ABO
blood group? Thromb Haemost 2013; 110: 1110–1111.
56. Gandara E, Kovacs MJ, Kahn KR, et al. Non-OO blood type influences the risk
of recurrent venous thromboembolism. A cohort study. Thromb Haemost 2013;
110: 1172–1179.
57. Coppola A, Tufano A, Cerbone AM, et al. Inherited thrombophilia: implications
for prevention and treatment of venous thromboembolism. Semin Thromb
Haemost 2009; 35: 683–694.
58. Franchini M, Lippi G. The intriguing relationship between ABO blood group,
cardiovascular disease and cancer. BMC Med 2015; 13: 7.
Thrombosis and Haemostasis 114.4/2015