Paternal endothelial protein C receptor 219Gly variant as a mild and limited risk factor for deep vein thrombosis during pregnancy

Summary. Background: Half of all venous thromboembolism (VTE) cases during pregnancy are associated with a maternal thrombophilia. The influence of paternal genotype on the placenta and in the genesis of VTE has not been described. Objectives: To determine if the maternal and paternal Ser219Gly dimorphism of the endothelial protein C receptor (EPCR), evaluated through detection of the PROCR 6936G allele, is a risk factor for VTE during pregnancy. Methods: Using a case‐control study nested in the NOHA first cohort of primigravidae, 66 patient couples with a first episode of gestational VTE and randomly selected non‐thrombotic control couples were investigated. For each couple, factor V gene (F5) G1691A, factor II gene (F2) G20210A, factor XII gene (F12) C46T and PROCR A6936G polymorphisms were determined. Results: Only maternal F5 1691A, F2 20210A and F12 46T alleles were independently associated with iliac and infra‐iliac deep vein thromboses (DVT). The maternal PROCR 6936G allele was a mild risk factor for iliac DVT (OR = 5.5 [2.3–13.0]). The paternal PROCR 6936G allele was also a mild independent risk factor for iliac DVT (OR = 2.6 [1.1–6.2]) and only during pregnancy (rather than postpartum) among maternal carriers of the F5 1691A allele (OR = 77.6 [4.2 to > 999.9]). Conclusions: The paternal PROCR 6936G allele could be a risk factor for maternal iliac DVT. Its impact was milder than the F5 1691A and F2 20210A polymorphisms in mothers. We hypothesize that the prothrombotic effect of the paternal PROCR 6936G allele is localized. Therefore, DVT during pregnancy may be influenced by trophoblastic cell‐surface proteins inherited from both maternal and paternal alleles.     

The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A

Background : The risk of venous thromboembolism (VTE) during pregnancy in double heterozygous carriers of factor (F) V Leiden and prothrombin G20210A is not established. Hence, whether or not these women deserve antithrombotic prophylaxis when pregnant is unknown. Patients and methods : In the frame of a multicenter family study, 52 double heterozygous carriers of FV Leiden and prothrombin G20210A who had remained pregnant at least once before knowledge of thrombophilia, were retrospectively investigated with respect to the occurrence of first VTE during pregnancy and puerperium. They were compared with 104 heterozygous carriers of FV Leiden, 104 of prothrombin G20210A and 104 women without thrombophilia. Results : Double heterozygotes were similar to single heterozygous carriers and non-carriers for the age at first pregnancy, age at testing and rate of full-term pregnancies. No VTE during pregnancy was observed in the four groups of women, whereas in the puerperium it occurred in two double carriers (1.8% of pregnancies, 95% CI: 0.5–6.3), three single FV Leiden carriers (1.5%, 0.5–4.3), two single prothrombin G20210A carriers (1%, 0.2–3.6) and one non-carrier (0.4%, 0–2.5). Conclusions : The risk of first VTE during pregnancy and puerperium in double heterozygous carriers of FV Leiden and prothrombin G20210A is low and similar to that of single carriers. As for single heterozygotes, antithrombotic prophylaxis in asymptomatic double heterozygous carriers appears to be justified only in puerperium.     

Impact of environmental and hereditary risk factors on the clinical manifestation of thrombophilia in homozygous carriers of factor V:G1691A

Summary.  Background : Limited data exist on the clinical manifestations of homozygous factor (F)V:G1691A mutation (FV Leiden) and the impact of environmental and genetic risk factors. Objectives : To assess the contribution of these factors on the thrombophilic phenotype. Patients and methods : In a retrospective multicenter cohort study 165 individuals with homozygous FV:G1691A mutation, of whom 129 had previous venous thromboembolism (VTE), were included. To study the role of environmental risk factors, patients were compared by the use of a standardized questionnaire to 165 sex- and age-matched individuals (reference group A); of these, two had previous VTE. To assess the role of genetic risk factors, factor (F)II:G20210A and MTHFR:C677T were determined in individuals homozygous for FV:G1691A and in 177 healthy individuals without previous VTE (reference group B). Results : The first VTE occurred significantly earlier in women (median age 25 years) than men (35.5 years). In 81% of women and 29% of men an environmental risk factor was present before first VTE. Oral contraceptives increased the risk of thrombosis 4-fold [odds ratio (OR) 4.0, 95% confidence interval (CI) 1.7, 10.4] in women with homozygous FV:G1691A. Postoperative and post-traumatic VTE as first manifestation occurred in 13% and 15% of surgical/traumatic events in patients and in 0.7% and 1.8% in reference group A, respectively (OR 19.7, 95% CI 2.5, 154 and OR 9.2, 95% CI 1.1, 79.4). Heterozygous FII:G20210A was more prevalent in symptomatic patients (11.7%) compared with reference group B (2.8%, OR 4.6, 95% CI 1.6, 13.2). The prevalence of homozygous MTHFR:C677T genotype was similar in patients and reference group B. Conclusions : Our study supports the concept of thrombophilia as a multifactorial disorder. The knowledge of coexisting factors predisposing to VTE is useful for medical advice for primary and secondary prophylaxis in these patients.     

Prothrombin A19911G polymorphism and the risk of venous thromboembolism

BACKGROUND: The A > G polymorphism at position 19911 of the prothrombin gene is associated with increased plasma prothrombin levels but its role as a risk factor for venous thromboembolism (VTE) is not established. OBJECTIVE: To investigate the role of prothrombin 19911 A > G polymorphism in the risk of VTE in patients with heterozygous prothrombin 20210GA or factor (F) V Leiden and in those without thrombophilia. PATIENTS AND METHODS: Case-control study of 793 patients with prothrombin 20210 GA (n = 167) or FV Leiden (n = 198), and without thrombophilia (n = 428), and of 795 healthy individuals with the corresponding coagulation profile, investigated for the presence of prothrombin 19911 A > G. Plasma prothrombin levels were measured in 342 individuals. RESULTS: Prothrombin 19911 A > G did not increase the risk of VTE in carriers of prothrombin 20210 GA [odds ratio (OR) 1.2, 95% CI (95% CI) 0.8-1.8] but significantly increased the risk in carriers of FV Leiden (OR 2.1, 95% CI 1.3-3.4) and in patients without thrombophilia (OR 1.5, 95% CI 1.0-2.2). Higher plasma prothrombin levels in carriers of prothrombin 19911 A > G polymorphism than in non-carriers were found among individuals without thrombophilia (P =0.05) and with FV Leiden (P = 0.07), but not in carriers of prothrombin 20210 GA (P = 0.2). CONCLUSIONS: Prothrombin 19911 A > G polymorphism was independently associated with a 1.5-fold increased risk of VTE and increased 2-fold the risk of VTE associated with FV Leiden, both increases statistically significant. No effect was observed in carriers of prothrombin 20210 GA, perhaps because this polymorphism has a stronger influence on plasma prothrombin levels than the prothrombin 19911 polymorphism.     

The G20210A prothrombin variant and the risk of venous thromboembolism or fetal loss in pregnant women: a family study

BACKGROUND: The relationship between the G20210A prothrombin variant (PT-G20210A) and adverse pregnancy outcome has been studied by several groups in the last few years. However, because of the different design and sample sizes of these studies the estimated risks have varied. OBJECTIVE: In this retrospective, multi-center, cohort study we assessed the risk of thromboembolic or obstetric complications in women belonging to families of probands with isolated PT-G20210A and that were symptomatic for venous thromboembolism (VTE). METHODS: Two hundred and eighty-three female family members that had been pregnant at least once were enrolled. The occurrence of VTE and obstetric complications during pregnancy and postpartum were assessed in carriers of PT-G20210A and compared with non- carriers. RESULTS: One thromboembolic event occurred during the postpartum period in the carriers group. In the same group, 48 out of 359 pregnancies resulted in unexplained fetal loss as compared with 50 out of 357 pregnancies in the non-carriers (RR 0.9; 95% CI: 0.7-1.4). After adjustment, carriers of PT-G20210A showed a trend towards a higher risk of late fetal loss as compared with non-carriers (RR 2.2; 95% CI: 0.8-6.2). Furthermore, in pregnancies subsequent to those with previous fetal loss there was not a different risk of adverse outcome regardless of the carrier status. CONCLUSIONS: Female family members who are heterozygous carriers of isolated PT-G20210A do not seem to be at significant increased risk for fetal loss as compared with non-carriers. Screening for PT-G20210A of fertile age women belonging to these families is not warranted in this situation.     

LP-a升高为静脉栓塞的一种独立危险因子

目的　评估脂蛋白 a(LP a)在遗传性凝血酶原缺陷的静脉血栓栓塞 (VTE)病人组中所起的作用。方法　研究对象包括至少发生一次静脉血栓栓塞的病人共 6 85例和 2 6 6例性别和年龄相当 ,并排除存在活化蛋白C(APC)抵抗 ,蛋白C、蛋白S及抗凝血酶缺陷 ,血清LP a升高 ,因子 (F)VG16 91A、二甲基四水叶酸还原酶 (methylenetetrahydrofolatereductase ,MTHFR)C6 77T和凝血酶原 (PT)G2 0 2 10A基因突变等因素的健康人对照组。将其LP a升高及FVG16 91A因子突变作比较。结果　病人组中LP a>0 .30g/L的占 2 0 % ,明显高于对照组 (P <0 .0 0 1,OR3.2 ,95 %CI 1.9～ 5 .3) ;LP a升高 ,同时存在FVG16 91A因子 ,在VTE病人中明显多于对照组 (P <0 .0 0 1,OR9.8,95 %CI2 .4～ 4 0 .7)。结论　LP a >0 .30g/L为VTE的一种常见独立危险因子。此外 ,LP a水平可能与由于受其它凝血因子缺陷 ,如FVG16 91A突变影响的VTE疾病的外显率有关     

Prediction of recurrent venous thromboembolism by the activated partial thromboplastin time

BACKGROUND: Venous thromboembolism (VTE) is a multi-factorial disease. Extensive thrombophilia screening is costly and often inconclusive. Simple laboratory methods are required to predict the risk of recurrence. OBJECTIVE: To assess if measurement of activated partial thromboplastin time (APTT) allows stratification of patients with VTE into high- and low-risk categories with regard to recurrence. PATIENTS AND METHODS: We prospectively followed 918 patients with a first unprovoked VTE and studied the relationship between recurrence and an APTT after discontinuation of anticoagulation. APTT was expressed as a ratio of test to reference coagulation times. Study endpoint was symptomatic recurrent VTE. RESULTS: Venous thromboembolism recurred in 101 (11%) patients. Patients without recurrence had a greater APTT ratio than those with recurrence (0.97 +/- 0.09 vs. 0.93 +/- 0.09, P = 0.001). After 4 years, probability of recurrent VTE was 8.5% (95% CI: 5.5-11.5%) among patients with a ratio equal to or > 0.95 and 15.6% (95% CI: 11.4-19.9%) among patients with a lower ratio (P = 0.005). Compared with patients with an APTT ratio < 0.95, the relative risk (RR) of recurrence among patients with a ratio equal to or > 0.95 was 0.56 (95% CI: 0.38-0.84, P = 0.005) before and 0.58 (95% CI: 0.39-0.87, P = 0.009) after adjustment for sex, age, factor V Leiden, and factor II G20210A. CONCLUSIONS: Measurement of APTT allows stratification of patients with VTE into high- and low-risk categories with regard to recurrence.     

ABO blood groups and risk of venous thromboembolism during pregnancy and the puerperium. A population-based, nested case-control study.

OBJECTIVES: To examine possible associations of ABO blood types with the risk of venous thromboembolism (VTE) in pregnancy and the puerperium. PATIENTS AND METHODS: We conducted a nested case-control study within a cohort of 71,729 women who gave birth to 126,783 children in the North Jutland County, Denmark, from 1980 to 2001. We identified 129 cases with VTE in pregnancy (n = 61) or the puerperium (n = 68), and 258 controls with no VTE. We collected information on ABO blood groups and possible maternal confounding factors and estimated the relative risk [odds ratio (OR)]. RESULTS: Women with an A or AB blood group had elevated risk estimates of VTE in pregnancy or the puerperium compared with women with a O blood group [adjusted ORs 2.4, 95% confidence interval (CI) 1.3, 4.3, and 2.0, 95% CI 0.7, 5.8, respectively]. No increased risk estimate was found for group B (adjusted OR 1.2, 95% CI 0.5, 3.0). The increased risk estimates of VTE for blood groups A and AB appeared present in both pregnancy (adjusted ORs of 3.9, 95% CI 1.5, 9.7, and 2.2, 95% CI 0.4, 12.5) and in the puerperium (adjusted ORs of 2.4, 95% CI 1.0, 4.9 and 2.7, 95% CI 0.8, 9.3). Furthermore, blood groups A and AB appeared to be associated with increased risk estimates for both DVT and pulmonary embolism. CONCLUSION: Keeping the modest statistical precision of our study in mind, blood groups A and AB may be associated with increased risk estimates for VTE in pregnancy and the puerperium.     

Plasminogen activator inhibitor 1 4G/5G polymorphism and coagulation factor XIII Val34Leu polymorphism: impaired fibrinolysis and early pregnancy loss

BACKGROUND: A successful outcome of pregnancy depends on proper placental formation. In the very beginning of this process, trophoblast invasion and fibrin deposition into the wall of the decidual veins play an important part. Two polymorphisms, coagulation factor XIII (FXIII) Val34Leu and plasminogen activator inhibitor 1 (PAI-1) 4G/5G, interfere with fibrin cross-linking and regulation of fibrinolysis and may therefore contribute to early pregnancy loss. METHODS: We enrolled 49 unrelated Caucasian women with a history of two consecutive or three to six nonconsecutive early pregnancy losses and 48 unrelated parous healthy controls without a history of pregnancy loss and evaluated them for the following genetic variants: the factor V Leiden and prothrombin G20210A gene mutations, the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms, and the PAI-1 4G/5G and FXIII Val34Leu polymorphisms. RESULTS: For the isolated occurrence of PAI-1 4G/5G or FXIII Val34Leu, we found no statistically significant difference between cases and controls. For homozygosity of either or compound carrier status of both mutations, the overall relative risk for early pregnancy loss was significantly increased (odds ratio = 2.4; 95% confidence interval, 1.1-5.5; P = 0.032). We observed no statistically relevant association of any of the other tested mutations with early pregnancy loss. CONCLUSION: Homozygosity for PAI-1 4G or FXIII 34Leu polymorphisms as well as compound carrier status is associated with early pregnancy loss.     

Thrombophilic risk factors in patients with severe carotid atherosclerosis.

Carotid stenosis and atrial fibrillation are the strongest risk factors for ischemic stroke. Ongoing prevention efforts include the identification of novel factors that increase the risk for carotid atherosclerosis. The aim of this study was to determine the thrombophilic risk profile of patients with severe carotid stenosis by evaluating a number of genetic and metabolic risk factors [factor (F)II G20210A, factor V Leiden, MTHFR C677T polymorphisms, anticardiolipin antibodies (aCL), lipoprotein(a) (Lp(a)), and homocysteine (Hcy)]. The study population consisted of 615 patients [(410 M/205 F; median age 73 (26-94) years] with severe (> 70%) carotid stenosis, and 615 apparently healthy subjects [(410 M/205 F; age 73 (31-92) years]. On multivariate analysis, independent risk factors were elevated Hcy [odds ratio (OR) 7.6, 95% confidence interval (CI) 4.8, 11.8] and Lp(a) levels (OR 2.9, 95% CI 2.1, 3.9), the presence of aCL (OR 5.7, 95% CI 3.1, 10.4) and heterozygosity for FII G20210A polymorphism (OR 2.8, 95% CI 1.3, 5.9). In the subgroup of women, independent risk factors for severe carotid atherosclerosis were: high levels of Hcy and Lp(a) and the presence of aCL, whereas hyperhomocysteinemia, elevated Lp(a) levels, aCL, FII G20210A and MTHFR 677TT polymorphisms remained independent risk factors in the subgroup of men. The results of the present study demonstrate that the prevalence of the thrombophilic risk factors is increased in patients with severe carotid atherosclerosis.     

Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations

BACKGROUND: The factor V Leiden (FVL) and prothrombin 20210A (PTm) mutations are associated with single late pregnancy loss and recurrent early pregnancy loss. The prognosis after an initial loss in women with thrombophilia is uncertain. OBJECTIVE: To assess the pregnancy outcome of the second pregnancy after a first loss in women with and without either FVL or PTm mutations. METHODS: We selected women with a first pregnancy loss out of two family cohorts of first degree relatives of probands with FVL or PTm mutations and a history of documented venous thromboembolism or premature atherosclerosis. RESULTS: Ninety-three women had had a first pregnancy loss and became pregnant a second time. Their risk of loss of the subsequent pregnancy was higher than in 825 women with a successful first pregnancy [25 vs. 12%, relative risk (RR) 2.0, 95% CI 1.4-3.0]. The live birth rate of the second pregnancy after an early first loss ( 12 weeks), the live birth rates were 68% (95% CI 46-85) and 80% (95% CI 49-94) for carriers and non-carriers, respectively (RR 0.9, 95% CI 0.5-1.3). CONCLUSIONS: Women with a first pregnancy loss have a 2-fold increased risk of loss of the subsequent pregnancy, regardless of their carrier status. More importantly, the outcome of the second pregnancy is rather favorable in absolute terms, even for those with thrombophilia and a late loss, which raises concern regarding the risks and presumed benefits of anticoagulant therapy in these women.     

Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms

Background: Pregnancy is associated with a 10‐fold increased risk of venous thrombosis (VT), with different risk profiles for the antenatal and postnatal periods. The purpose of this study was to assess the risk of pregnancy‐related VT associated with the factor (F)V Leiden and prothrombin gene G20210A polymorphisms. Materials and Methods: The study comprised 377 155 women with 613 232 pregnancies at 18 Norwegian hospitals from 1 January 1990 to 31 December 2003. Of a total 559 cases with a validated first lifetime diagnosis of VT in pregnancy or within 14 weeks postpartum, and 1229 controls naive for VT, 313 cases and 353 controls donated biological material. Results: The odds ratios for VT during pregnancy or puerperium were 5.0 [95% confidence interval (CI) 3.1–8.3] and 9.4 (95% CI 2.1–42.4) for heterozygous carriers of the FV Leiden and the prothrombin gene polymorphisms, respectively. All homozygous carriers of the FV Leiden polymorphism (n = 8) and the prothrombin polymorphism (n = 1) developed VT, indicating a very high risk of VT. We estimated that pregnancy‐related VT occurred in 1.1/1000 non‐carriers, in 5.4/1000 heterozygous carriers of the FV Leiden polymorphism, and in 9.4/1000 heterozygous carriers of the prothrombin polymorphism. To avoid one VT, the number of pregnant women needed to be screened for these two polymorphisms and the number needed to be given thromboprophylaxis were 2015 and 157, respectively. Conclusions: Although the relative risk for VT during pregnancy and after delivery was increased among carriers of the FV Leiden and the prothrombin polymorphisms, the overall probability for pregnancy‐related VT was low.     

C677T mutation in methylentetrahydrofolatereductase gene in patients with venous thromboses from the central region of Russia correlates with a high risk of pulmonary artery thromboembolism

AIM: To investigate genetic factors of risk (RF) to develop venous thrombosis and pulmonary artery thromboembolism (PATE) in population of central Russia. MATERIAL AND METHODS: We studied polymorphism of the genes of coagulation factor II (G20210A), factor V (G1691A) and methylentetrahydrofolatereductase (MTHFR) with polymerase chain reaction and restriction analysis of DNA amplified sites. We estimated prevalence of the mutations in healthy population and in patients with flebothrombosis as well as effects of the mutations on a PATE rate in patients with thrombosis. We examined 97 patients with documented flebothrombosis. PATE was detected in 54 of them. The control group consisted of 56 healthy volunteers matched by age and gender. RESULTS: G1691A mutation in the gene of coagulation factor V (Leiden mutation of factor V--LMFV) in healthy population occurred in 3.6%, in patients with flebothromboses--in 19.6% (OR = 6.58; 95% CI from 1.47 to 29.42; p = 0.006). Heterozygous mutation G20210A in prothrombine gene was detected in 8 (8.2%) patients (p = 0.027), while this mutation was registered in none controls. Polymorphism of MTHFR gene (C677T) was seen both in the control and patients (60.7 and 52.6%, respectively). LMFV occurrence in patients with flebothrombosis and PATE is less than in patients with flebothrombosis without TEPA (16.7 and 23%, respectively). The PATE risk is significantly higher in carriers of mutant allele 677CT and 677TT of MTHFR compared to patients free of this mutation (OR = 3.11; CI 95% from 1.35 to 7.15; p = 0.006). Homozygous inheritance of this mutation in males combined with PATE in 100% cases. Of 8 carriers of heterozygous mutation G20210A in prothrombin gene PATE was detected in 5 carriers. CONCLUSION: LMFV and mutation G20210A in prothrombin gene are genetic risk factors of venous thrombosis. LMFV is not a PATE risk factor. Mutation C677T in MTHFR gene has no influence on the risk of venous thromboses but makes PATE much more probable. This suggests that it may be a genetic risk factor of PATE in this disease.     

Thrombophilias and adverse pregnancy outcomes: results from the Danish National Birth Cohort

Summary. Background: Inherited thrombophilias have inconsistently been linked to adverse pregnancy outcomes. Differences in study design, size and population could explain this heterogeneity. Objective: The aim of the present study was to evaluate if factor (F)V Leiden G1691A, prothrombin mutation G20210A (PTM) and methylenetetrahydrofolate reductase C677T (MTHFR) increased the risk of severe preeclampsia, fetal growth restriction, very preterm delivery, placental abruption and a composite of these outcomes also including stillbirth. Patients and methods: In a nested case–cohort study of pregnant women in Denmark, we genotyped 2032 cases and 1851 random controls. Each of the medical records of the cases was validated. We calculated both genomic and allelic models, and present both models. We also performed sensitivity analyses adjusting for parity, age, smoking, body mass index and socioeconomic status. Results: In the allelic models, FV Leiden increased the risk of the composite outcome (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.1–1.8), severe preeclampsia (OR 1.6, 95% CI 1.1–2.4), fetal growth restriction (OR 1.4, 95% CI 1.1–1.8) and placental abruption (OR=1.7 (95% CI 1.2–2.4). In the sensitivity analyses, adjustment diminished these estimates slightly. PTM was not significantly associated with any of the outcomes, and MTHFR was only significantly associated with severe preeclampsia (OR 1.3, 95% CI 1.1–1.6). Conclusion: FV Leiden predisposes to adverse pregnancy outcomes in a setting of Scandinavian women.     

Factor V Leiden and prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case–control ''NOHA first'' study

Factor V Leiden (FVL) and prothrombin G20210A (FIIG20210A) mutations are associated with a higher risk of miscarriage: we sought to understand whether this association differs by clinical time of unexplained miscarriage, and by ethnic origin, among women with no previous thrombotic episode, during the first intended pregnancy. We performed a case-control study nested in a cohort of 32 683 women. We analyzed 3496 pairs of women matched for classical confounding factors. The FVL and FIIG20210A mutations were associated with an increased risk of miscarriage in Caucasian women [odds ratio (OR) 3.19, 95% confidence interval (CI) 2.37-4.30, P < 0.001 and OR 2.36, 95% CI, 1.72-3.24, P < 0.001, respectively]. Among non-Caucasian women, the mutations were rare and the associations with risk of miscarriage less clear. FVL and FIIG20210A mutations were independent risk factors for miscarriages only for women with related clinical signs occurring from the 10th week of gestation on (OR 3.46, 95% CI 2.53-4.72, P < 0.001 and OR 2.60, 95% CI 1.86-3.64, P < 0.001, respectively). These results indicate that FVL and FIIG20210A mutations are associated with a significant risk of spontaneous abortion which clinical signs occur from the 10th week on of the first intended pregnancy.     

Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome

Summary.  To learn more about the frequencies of congenital prothrombotic disorders in pediatric venous thromboembolism (VTE) and the outcome of this disease, we evaluated consecutive patients from 0 to 18 years with objectively diagnosed VTE at a single tertiary center over a 12-year period. We included 100 patients, with a median age at diagnosis of 1.0 year (range 2 days to 17 years). At least one underlying clinical condition was present in 96% of the patients. Factor (F)V G1691A mutation was present in 13%, FII G20210A mutation in 3%, antithrombin deficiency in 1%, protein C deficiency in 1% and protein S deficiency in 1% of the tested patients. Combined defects were present in 2.6% of the 77 patients with a complete work-up. Positive family history appeared to be the only predictor for positive testing for congenital disorders (OR 14.9, 95% CI 1.9–113). The overall mortality rate was 20%. The cumulative recurrence-free survival was 92% after 1 year of follow-up, and 82% after 7 years. The incidence and severity of the post-thrombotic syndrome was analyzed in a subgroup of 33 patients with VTE of the lower extremities. Twenty-three (70%) patients developed PTS: moderate in three and mild in 20 patients. In conclusion, congenital prothrombotic disorders seem to play a role in the development of pediatric VTE, and the risk of complications of this disease is high.     

Low protein Z levels and risk of occurrence of deep vein thrombosis

BACKGROUND: Protein Z (PZ) serves as a cofactor for activated factor X inhibition by the PZ-dependent protease inhibitor. In vivo and in vitro studies aimed at investigating the role of PZ levels in venous thombosis have produced conflicting results. OBJECTIVES: We investigated whether reduced PZ levels and PZ gene common variants are associated deep vein thrombosis (DVT). PATIENTS AND METHODS: In 197 patients with DVT and in 197 age-matched and sex-matched controls, PZ plasma levels and gene polymorphisms were evaluated by means of an enzyme-linked immunosorbent assay and direct cycle sequence analysis. RESULTS: Similar PZ levels were found in controls (1.44; SD 0.63 microg mL-1) and in patients (1.44; SD 0.96 microg mL-1). The incidence of PZ levels below the 5.0 (0.52 microg mL-1) or the 2.5 percentile of controls (0.47 microg mL-1) was higher in patients (10.2% and 8.7%, respectively) than in controls {4.1% [odds ratio (OR) 2.7, 95% confidence interval (CI) 1.2-7.3], and 2.0% (OR 4.6, 95% CI 1.5-13.9), respectively}. This relationship was independent of the effect of age, sex, and factor V Leiden and FII A(20210) alleles [OR 2.8 (95% CI 1.1-7.3), and OR 4.9 (95% CI 1.4-17.3)]. PZ levels were associated with the intron C G-42A and the intron F G79A polymorphisms in cases (r2=0.129) and in controls (r2=0.140). However, frequencies of the PZ gene polymorphisms were similar in the two groups and were not associated with very low PZ levels. CONCLUSIONS: The present data suggest an association between very low PZ plasma levels and the occurrence of DVT, with PZ gene polymorphisms contributing little to this relationship.     

Type and location of venous thromboembolism in patients with factor V Leiden or prothrombin G20210A and in those with no thrombophilia

BACKGROUND: Patients with factor (F) V Leiden or the prothrombin G20210A polymorphism are at increased risk of developing deep vein thrombosis (DVT). On the other hand, the risk of developing pulmonary embolism (PE) appears to be low in carriers of FV Leiden, perhaps because of a lower tendency to develop iliofemoral DVT than non-carriers. For prothrombin G20210A, data are scanty and controversial. METHODS: The clinical manifestations (isolated DVT, DVT and PE, and isolated PE), the extension of DVT, and the presence of transient risk factors were retrospectively investigated in 115 patients with heterozygous FV Leiden, 87 with prothrombin G20210A and 200 with no thrombophilia marker. RESULTS: Isolated symptomatic PE was less prevalent in patients with FV Leiden (6%) than in those with prothrombin G20210A (21%) and no thrombophilia (23%) (P > 0.0001). The rate of distal DVT was higher in patients with no thrombophilia (16% vs. 7% for FV Leiden and 6% for prothrombin G20210A) (P = 0.02). No difference in the incidence of PE from distal and proximal DVT, the extension of proximal DVT and the type of transient risk factors for venous thromboembolism (VTE) was found in the three groups. Patients with prothrombin G20210A had a younger age at their first VTE (24 years, P < 0.0001) and a higher rate of DVT accompanying PE (P = 0.04) than those with FV Leiden or no thrombophilia. CONCLUSIONS: Carriers of prothrombin G20210A, unlike those of FV Leiden, have an increased risk of developing isolated PE. This difference was not explained by a different rate of distal DVT, extension of proximal DVT, or distribution of transient risk factors in the two groups. Patients with prothrombin G20210A have more severe clinical manifestations than those with FV Leiden or no thrombophilia.     

The association of factor V Leiden with myocardial infarction is replicated in 1880 patients with premature disease

See also Tosetto A. Thrombophilic mutations and cardiovascular disease: the case is still open. This issue, pp 2113–5. Summary. Aims: Gain‐of‐function variants of genes encoding coagulation factor V (F5 G1691A) and prothrombin (F2 G20210A) cause hypercoagulability and are established risk factors for venous thrombosis. A meta‐analysis of 66 155 cases and 91 307 controls found that either polymorphism is associated with a moderately increased risk of coronary artery disease (CAD). Because genetic factors play a particularly important role when acute myocardial infarction (AMI) occurs in the young, we chose to replicate these results by investigating, in the frame of a case‐control study, a large cohort of Italian patients who had AMI before the age of 45 years. Methods and Results: In 1880 patients with AMI (1680 men and 210 women) and an equal number of controls, the minor A allele of F5 G1691A (2.6% frequency in cases and 1.7% in controls) was associated with an increased risk of AMI, the association remaining significant after adjustment for traditional risk factors (OR, 1.66; 95% CI, 1.15–2.38; P = 0.006). The positive association with AMI for the minor A allele of F2 G20210A (2.5% frequency in cases and 1.9% in controls) did not reach statistical significance (OR, 1.32; 95% CI, 0.96–1.80; P = 0.159). Conclusions: In a large cohort of young AMI patients the gain‐of‐function variant F5 G1691A was associated with an increased risk of AMI. The findings on the variant F2 G20210A confirmed the previously reported results, but the association was statistically not significant. These data suggest that a number of young patients with AMI carry gene variants associated with a procoagulant phenotype.     

Risk of obstetric and thromboembolic complications in family members of women with previous adverse obstetric outcomes carrying common inherited thombophilias

Summary. Background: Factor (F)V Leiden and the prothrombin 20210A mutation (PTm) are associated with the occurrence of obstetric complications, including pregnancy‐related venous thromboembolism (VTE). It is not known whether family members of women with FV Leiden or PTm and previous obstetric complications have a higher risk of VTE or adverse obstetric outcomes. Methods: A retrospective family study including 563 relatives of 177 women with previous adverse outcomes carrying FV Leiden or PTm, referred between April 1993 and June 2010. A history of obstetric complications and VTE was obtained. Prevalence of VTE and obstetric complications in relatives with and without inherited thrombophilias was compared. Adjusted odd ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models that controlled for predictors (age, FV Leiden and PTm). Results: Relatives carrying FV Leiden had a significant and independent risk for obstetric complications (OR: 1.98, 95% CI 1.03–3.83); this risk was not observed in the presence of PTm (OR: 1.03, 95% CI 0.46–2.32). The presence of FV Leiden or PTm in heterozygosis was significantly and independently associated with the occurrence of VTE (OR: 5.2, 95% CI: 1.70–15.91). Severe thrombophilias were strong risk factors for VTE (OR: 23.2, 95% CI: 6.0–89.85). Male gender was a significant and independent risk factor for VTE (OR: 3.49, 95% CI: 1.51–8.05). The risk did not change when relatives of women with a previous pregnancy‐related VTE were excluded (OR: 3.49, 95% CI: 1.51–8.05). Conclusions: Knowledge of thrombophilia status may help to better define the obstetric and thromboembolic risks in asymptomatic family members of women who suffered from obstetric complications.