Bertina, R.M.

Morelli, V.M.

Rosendaal, F.R.

Visser, M.C.H. de

Vos, H.L.

Leiden University Scholary Publications

ABO blood group genotypes and the risk of venous thrombosis:effect of factor V Leiden1V. M. MORELL I , * M. C . H . DE V ISSER ,* H . L . VOS ,* R . M. BERT INA* and F . R . ROSENDAAL**Hemostasis and Thrombosis Research Center, Department of Hematology and Department of Clinical Epidemiology, Leiden University MedicalCenter, Leiden, the NetherlandsTo cite this article: Morelli VM, De Visser MCH, Vos HL, Bertina RM, Rosendaal FR. ABO blood group genotypes and the risk of venousthrombosis: effect of factor V Leiden. J Thromb Haemost 2005; 3: 183–5.ABO blood group and more recently high von Willebrandfactor (VWF) and factor (F)VIII levels have been associatedwith thrombotic disease. An excess of non-O blood group haslong been recognized in patients with ischemic heart disease [1]and venous thrombosis [2]. In 1995, we demonstrated that non-O blood group, high VWF levels and high FVIII levels allincreased the risk of deep vein thrombosis [3]. In multivariateanalysis only FVIII remained a risk factor, whereas thethrombosis risk associated with VWF and ABO blood grouplargely disappeared. Since then, several other studies haveidentified high FVIII levels as a risk factor for venousthrombosis [4–7].Usually blood group phenotypes are used to study theassociationbetweenbloodgroupandvenous thrombosis.Bloodgroup genotypes may be more informative since genotypes candistinguish between heterozygous and homozygous carriers ofA, B and O alleles and between A1 and A2 alleles. Therefore westudied the effect ofABOgenotype on thrombosis risk in a largepopulation-based case–control study of venous thrombosis(Leiden Thrombophilia Study, LETS). This study, whichincluded 474 patients and 474 control subjects, has beenpreviously described [3]. For the present study DNA wasavailable for 471 patients and 471 control subjects.Blood was collected into 0.1 volume 0.106 mol L)1 tri-sodium citrate. Plasma was prepared by centrifugation for10 min at 2000 · g at room temperature and stored at )70 C.FVIII coagulant activity (FVIII:C), FVIII:Ag, VWF:Ag andblood group phenotype were measured as previously reported[3–5].High-molecular-weight DNA was isolated from leukocytesand stored at 4 C. Polymerase chain reaction (PCR) wasdesigned to amplify exons 6 and 7 of the ABO blood groupgene in two separate reactions. The sequences of the primershave been described previously [8]. The amplified DNAfragments corresponding to exons 6 and 7 were digested withAcc65I (MBI Fermentas) or MspI (MBI Fermentas), respect-ively, in two separate reactions and separated by electrophor-esis on 3.5% agarose gels. With this method we discriminatedA1, A2, B, O1 and O2 alleles. There was 99% agreementbetween ABO blood group phenotype and genotypes in allpatients and controls.Table 1 (upper part) shows the frequency of the ABO bloodgroup genotypes in patients and controls. Odds ratios (OR)were calculated as estimates of the relative risk by anunmatchedmethod. Ninety-five percent confidence intervals were assessedaccording to Woolf [9]. All non-OO genotypes except A2homozygotes or A2–O combinations, i.e. A2O1/A2O2/A2A2,were associated with an increased thrombosis risk whencompared with OO genotypes. This reinforces the concept thatblood group exerts its thrombotic risk largely via FVIII levels,since A2O/A2A2 genotypes correspond to the lowest FVIIIlevels among non-OO genotypes (data not shown). Adjustmentfor age and sex did not alter the risk estimates.Because blood group is known to affect plasma levels ofVWF and FVIII and because VWF and FVIII levels influencethrombosis risk, we adjusted the thrombosis risk associatedTable 1 Thrombosis risk for ABO blood group genotypesGenotypesNo. ofpatients (%)n ¼ 471No. ofcontrols (%)n ¼ 471 OR 95% CIO1O1/O1O2 137 (29.1) 202 (42.9) 1*Non-OO 334 (70.9) 269 (57.1) 1.8 (1.4-2.4)A1A1 29 (6.2) 20 (4.2) 2.1 (1.2-3.9)A1A2 19 (4.0) 15 (3.2) 1.9 (0.9-3.8)A1O1/A1O2 177 (37.6) 130 (27.6) 2.0 (1.5-2.7)A2O1/A2O2/A2A2 34 (7.2) 41 (8.7) 1.2 (0.7-2.0)BB/BO1/BO2 52 (11.0) 47 (10.0) 1.6 (1.0-2.6)A1B/A2B 23 (4.9) 16 (3.4) 2.1 (1.1-4.1)OO and FVL (–) 113 (24.0) 193 (41.0) 1*OO and FVL (+) 24 (5.1) 9 (1.9) 4.6 (2.0-10.1)Non-OO and FVL (–) 266 (56.5) 264 (56.0) 1.7 (1.3-2.3)Non-OO and FVL (+) 68 (14.4) 5 (1.1) 23.2 (9.1-59.3)Number of subjects composing the genotypes with lower frequency:patients, A1O2 (n ¼ 3), A2A2 (n ¼ 2), BB (n ¼ 4), BO2 (n ¼ 3), A2B(n ¼ 4), O1O2 (n ¼ 3). A2O2 genotype was not observed amongpatients; controls, A1O2 (n ¼ 4), A2O2 (n ¼ 1), A2A2 (n ¼ 1), BB (n ¼1), BO2 (n ¼ 1), A2B (n ¼ 3), O1O2 (n ¼ 11). FVL, Heterozygous(1691AG) and homozygous (1691AA). *Reference category.Correspondence: F. R. Rosendaal, Hemostasis and ThrombosisResearch Center, Department of Hematology, Leiden UniversityMedical Center, C2-R, PO Box 9600, 2300 RC, Leiden, theNetherlands.Tel.: +31 71 526 4037; fax: +31 71 526 6994; e-mail: f.r.rosendaal@lumc.nlReceived 6 September 2004, accepted 13 September 2004Letters to the Editor 183 2005 International Society on Thrombosis and Haemostasiswith blood group non-OO genotypes for VWF and FVIII in alogistic regression model (see also Koster et al. [3]). The aim ofthis analysis was to assess whether a blood group effect on riskwas present that did not act via levels of VWF and FVIII.VWF:Ag and FVIII:C had been measured in 301 patients and299 controls in whom ABO genotypes were also determined.The crude thrombosis risk for non-OO carriers compared withOO carriers [OR 2.0; 95% confidence interval (CI) 1.4-2.8]decreased after adjustment for FVIII:C only (OR 1.5; 95% CI1.0-2.1), for VWF:Ag only (OR 1.6; 95% CI 1.1-2.3), or forboth FVIII:C and VWF:Ag (OR 1.4; 95%CI 1.0-2.1). For thisanalysis we stratified FVIII:C and VWF:Ag levels intoapproximate quartiles. Similar results were obtained whenFVIII:Ag was used instead of FVIII:C and when FVIII:C andVWF:Ag were entered into the model as continuous variables.So, even after extensive adjustment for VWF and FVIII levels,some risk-enhancing effect of blood group remained present.One explanation is that, due tomeasurement error, wewere notable to adjust completely for VWF and FVIII levels. The otherexplanation is that there is an additional effect of blood groupon thrombosis risk. It is unlikely that this effect also acts viaVWF (e.g. via its effect on platelet adhesion and aggregation),since adjustment for FVIII only and for FVIII and VWFtogether reduced the risk associated with non-OO blood groupto the same extent.Among the 471 patients, 92 (19.5%) carried factor (F)VLeiden compared with 14 (3.0%) of the 471 controls, yieldingan OR for venous thrombosis of 7.9 (95%CI 4.4, 14.1) [10]. Incarriers of FVLeiden, non-OO genotypes were present in 68/92(74%) patients vs. 5/14 (36%) controls. Table 1 (lower part)shows separate and combined effects of ABO blood group andFV Leiden on thrombosis risk. The risk of the combination ofnon-OO blood group genotypes and FV Leiden, comparedwith subjects with OO genotypes and without FV Leiden was23-fold increased. This is higher than expected on the basis ofthe effects of non-OO genotype (OR 1.7) and FV Leiden (OR4.6) separately. Adjustment for age and sex did not influencethese risk estimates. Similar results were obtained when welimited the analysis to carriers of the risk-enhancing A1 and Balleles (because A2O/A2A2 genotypes were not associated withrisk). This finding extends previous observations [11,12]. In onestudy, among 28 subjects with FV Leiden and venousthrombosis, 96% possessed non-O blood group, while in asecond study [12] among carriers of FV Leiden the thrombosisrisk for subjects with non-O blood group was increased 4-foldcompared with those with O blood group. Also, our previousobservation that in selected thrombophilic families with FVLeiden elevated FVIII levels (¼ 150 IU dL)1) contributesubstantially to the incidence rate of thrombosis in FV Leidencarriers, explains the higher frequency of non-O blood group inthese families [13].The mechanism by which non-O blood group contributes tothe thrombosis risk in carriers of the FV Leiden mutation ismainly explained by its effect on FVIII levels. High FVIII levelsare associated with a decreased responsiveness to activatedprotein C (APC) in the absence of FV Leiden [14]. In FVLeiden carriers this small additional effect on the APCsensitivity might result in an exponential increase in thrombosisrisk. In a similar way the small additional effect of oralcontraceptive use on the APC sensitivity ratio in FV Leidencarriers results in amore than additive effect on thrombosis risk[15]. There is also evidence that FV Leiden is a defectivecofactor in the inactivation of FVIIIa by APC [16], in whichcase the combination of poor inactivation of FVIIIa and highFVIII levels associated with non-O blood groupmight result ina more pronounced reduction in the sensitivity for APC.Our data indicate that carriers of blood group alleles A1 andB have a 2-fold increased risk of a first deep vein thrombosisand that the non-OO genotypes strongly influence the risk ofthrombosis in FV Leiden carriers. Therefore information onblood group genotype may play a role in the management ofthrombophilia patients, especially when they are carriers of FVLeiden.AcknowledgementsThe study was supported by grants of the Fundação deAmparo à Pesquisa do Estado de São Paulo (no 02/04262-5),the Netherlands Organization for Scientific Research (NWO)(912-02-036) and the Dutch Heart Foundation (NHS 89.063).References1 Bronte-Stewart B, Botha MC, Krut LH. ABO blood groups in rela-tion to ischaemic heart disease. BMJ 1962; 1: 1646–50.2 Jick H, Slone D, Westerholm B, Inman WH, Versey MP, Shapiro S,Lewis GP, Worcester J. Venous thromboembolic disease and ABOblood type. Lancet 1969; 1: 539–42.3 Koster T, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR.Role of clotting factor VIII in effect of von Willebrand factor onoccurrence of deep-vein thrombosis. Lancet 1995; 345: 152–5.4 O’Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, John-son D, Laffan M. High prevalence of elevated factor VIII levels inpatients referred for thrombophilia screening: role of increased syn-thesis and relationship to the acute phase reaction. Thromb Haemost1997; 77: 825–8.5 Kamphuisen PW, Eikenboom JC, Rosendaal FR, Koster T, BlannAD, Vos HL, Bertina RM. High factor VIII levels increase the risk ofvenous thrombosis but are not associated with polymorphisms in thevon Willebrand factor and factor VIII gene. Br J Haematol 2001; 115:156–8.6 Kraaijenhagen RA, in’t Anker PS, KoopmanMM,Reitsma PH, PrinsMH, van den EndeA, Büller HR.High plasma concentration of factorVIIIc is a major risk factor for venous thromboembolism. ThrombHaemost 2000; 83: 5–9.7 Tsai AW, Cushman M, Rosamond WD, Heckbert SR, Tracy RP,Aleksic N, Folsom AR. Coagulation factors, inflammation markers,and venous thromboembolism: the longitudinal investigation ofthromboembolism etiology (LITE). Am J Med 2002; 113: 636–42.8 OlssonML, ChesterMA.A rapid and simple ABO genotype screeningmethod using a novel B/O2 versus A/O2 discriminating nucleotidesubstitution at the ABO locus. Vox Sang 1995; 69: 242–7.9 Woolf B. On estimating the relation between blood group and disease.Ann Hum Genet 1955; 19: 251–3.10 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High riskof thrombosis in patients homozygous for factor V Leiden (activatedprotein C resistance). Blood 1995; 85: 1504–8.184 Letters to the Editor 2005 International Society on Thrombosis and Haemostasis11 González Ordóñez AJ, Medina Rodriguez JM, Martı́n L, Alvarez V,Coto E. TheO blood group protects against venous thromboembolismin individuals with the factor VLeiden but not the prothrombin (factorII G20210A) mutation. Blood Coagul Fibrinolysis 1999; 10: 303–7.12 Robert A, Aillaud MF, Eschwege V, Randrianjohany A, Scarabin Y,Juhan-Vague I. ABO blood group and risk of venous thrombosis inheterozygous carriers of factor V Leiden. Thromb Haemost 2000; 83:630–1.13 Lensen R, Bertina RM, Vandenbroucke JP, Rosendaal FR. Highfactor VIII levels contribute to the thrombotic risk in families withfactor V Leiden. Br J Haematol 2001; 114: 380–6.14 de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity foractivated protein C in the absence of factor V Leiden increases the riskof venous thrombosis. Blood 1999; 93: 1271–6.15 Vandenbroucke JP, Koster T, Briët E, Reitsma PH, Bertina RM,Rosendaal FR. Increased risk of venous thrombosis in oral-contra-ceptive users who are carriers of factor V Leiden mutation. Lancet1994; 344: 1453–7.16 Varadi K, Rosing J, Tans G, Pabinger I, Keil B, Schwarz HP. FactorV enhances the cofactor function of protein S in the APC-mediatedinactivation of factor VIII: influence of the factor VR506Q mutation.Thromb Haemost 1996; 76: 208–4.Symptomatic deep vein thrombosis and immobilization afterday-care arthroscopy of the knee1M. R . HOPPENER , H . B . ETTEMA, C . P . HENNY,* C . C . P . M. VERHEYEN and H . B . B ÜLLERDepartments of Vascular Medicine and *Anaesthesiology, Academic Medical Center, University of Amsterdam, the Netherlands; andDepartment of Orthopaedic Surgery and Traumatology, Isala Clinics (De Weezenlanden Hospital), Zwolle, the NetherlandsTo cite this article: Hoppener MR, Ettema HB, Henny CP, Verheyen CCPM, Büller HB. Symptomatic deep vein thrombosis and immobilization afterday-care arthroscopy of the knee. J Thromb Haemost 2005; 3: 185–7.Deep vein thrombosis (DVT) and pulmonary embolism (PE)are common and clinically important complications of majorsurgery. Without thromboprophylaxis, the risk of venograph-ically detected DVT ranges from 50 to 58% of patientsfollowing total hip and 57 to 74% following total kneereplacement surgery [1]. At present it is standard practise to useperioperative thromboprophylaxis. In the last decades, therehas been a major shift from the full clinical approaches to day-care surgery. In North America two-thirds of all surgery isperformed in day-care practice [2] compared with about 30%in the Netherlands [3]. There are few studies describing theincidence of postoperative venous thromboembolism (VTE)after day-care surgery. Arthroscopy of the knee seems to carrya relatively high risk of VTE in this setting [4,5]. In contrast tofull clinical surgical approaches, inmany institutions patients inday-care surgery do not receive perioperative thromboproph-ylaxis [6]. Until now it seems there has been no consensusregarding a thromboprophylactic regime. In the Netherlands,about 60% of all patients undergoing knee arthroscopy in aday-care setting receive a single injection of low-molecular-weight heparin (LMWH) postoperatively, while the remainderdo not receive any form of thromboprophylaxis [6]. Thepotential for VTE increases with the duration and extent of thesurgery performed [7]. Hence, the main rationale not to usethromboprophylaxis in day-care surgery is the idea that theoperations performed in this setting are less invasive, leading toan earlier resumption of normal physical activities. At present,however, surprisingly little is known about postoperativemobilization after day-care surgery. The aim of this studywas to assess the incidence of symptomatic VTE and theduration of immobilization after arthroscopy of the knee in aday-care setting.A questionnaire was developed focusing on postoperativesymptomatic VTE and duration of immobilization, within afollow-up of 6 weeks, after arthroscopy of the knee in a day-care setting. All consecutive patients who underwent anarthroscopy of the knee in day-care in the Academic MedicalCenter (AMC) in Amsterdam during 1 year were sent aquestionnaire. Surgeons at the AMC operated a large part oftheir patients also in the Jan van Gooyen clinic (JvG) inAmsterdam. If no reply was received, a second package wasmailed. To the remaining non-responders the general practi-tioner (GP) was sent a questionnaire. All data followingarthroscopy in day-care were analyzed for the AMC and theJvG separately.Categorical data and dichotomous variables were summar-ized as percentages when applicable. Continuous variables werecompared using Student’s t-test or in case of an abnormaldistribution the Mann–Whitney U-test. Categorical data werecompared with cross tabulation (v2 or Fischer’s exact test).In the year 2000, 270 patients underwent a unilateralarthroscopy of the knee, 88 in the AMC and 182 in the JvG.Replies were received from 173 patients (64%). Of theremaining 97, the GP returned 74 questionnaires (76%). Theoverall response rate was therefore 91% (247 out of 270), 93%and 91%, respectively, for the AMC and JvG. The patients’Correspondence: M. R. Hoppener, AMC, Department of VascularMedicine, Amsterdam, the Netherlands.Tel.: +31 20 5665976; fax: +31 20 6968833;3 e-mail: m.r.hoppener@amc.uva.nlReceived 15 September 2004, accepted 16 September 2004Letters to the Editor 185 2005 International Society on Thrombosis and Haemostasis

ABO blood group genotypes and the risk of venous thrombosis: effect of factor V Leiden

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ABO blood group genotypes and the risk of venous thrombosis: effect of factor V Leiden

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