The incidence of venous thromboembolism among Factor V Leiden carriers: a community-based cohort study

While Factor V (FV) Leiden is a risk factor for venous thromboembolism (VTE), the incidence of VTE among FV Leiden carriers is uncertain. The objective of the study was to estimate the overall age-specific and pregnancy-related VTE incidence and the relative risk among FV Leiden carriers. In a community-based sample of 3424 south-eastern Minnesota residents, 230 (6.7%) were genotyped as FV Leiden carriers; 220 carriers (mean age = 68 years) could be matched to a non-carrier on age, gender, ethnicity and length of medical history. We performed a retrospective cohort study of carriers and non-carriers by reviewing the complete medical records in the community for demographic and baseline characteristics, pregnancies and live births, and first lifetime VTE. Over 14 722 person-years, 24 (10.9%) carriers developed VTE [overall incidence = 163 (95% CI 104, 242) per 100,000 person-years]. VTE incidence rates for ages 15-29, 30-44, 45-59 and > or = 60 years were 0, 61, 244 and 764 per 100,000 person-years, respectively (cumulative VTE incidence at age 65 years = 6.3%). VTE incidence for carriers did not differ significantly from that for non-carriers except for those > or = 60 years old (relative risk = 3.6; 95% CI 2.0, 6.0). There were 311 live births among 130 women carriers; no VTE events occurred during pregnancy or postpartum [incidence = 0 (95% CI 0, 1186) per 100,000 women-years]. Most FV Leiden carriers do not develop VTE. Among all carriers, those > or = 60 years old are at the highest risk for VTE. The incidence of VTE among asymptomatic women carriers during pregnancy is low and insufficient to warrant prophylaxis.     

Determinants of the APTT- and ETP-based APC sensitivity tests

BACKGROUND: A reduced sensitivity for activated protein C (APC) is associated with an increased risk of venous thrombosis even in the absence of the factor (F)V Leiden mutation. This risk has been demonstrated with two APC sensitivity tests, which quantify the effects of APC on the activated partial thromboplastin time (APTT) and the endogenous thrombin potential (ETP), respectively. OBJECTIVES: We examined determinants of both APC sensitivity tests in the control group of the Leiden Thrombophilia Study (LETS). METHODS: Multiple linear regression analysis was performed with normalized APC-SR(APTT) or APC-SR(ETP) as dependent variable and putative determinants [levels of FII, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII A subunit, FXIII B subunit, protein S total, protein S free, protein C, tissue factor pathway inhibitor (TFPI) total, TFPI free, antithrombin and fibrinogen] as independent variables. RESULTS AND CONCLUSIONS: The major determinant of the APTT-based test was FVIII level, followed by FII level. The ETP-based test was influenced most by free protein S and free TFPI levels. In both tests FXa formation plays a major role, as the effect of FVIII and TFPI on the tests seems to be executed via FXa. The ETP-based test was also strongly influenced by oral contraceptive use, even when we adjusted for all the clotting factors listed above. This means that the effect of oral contraceptives on the ETP-based test is not fully explained by the changes of coagulation factor levels investigated in this study, and that the molecular basis of acquired APC resistance during use of oral contraceptives remains to be established.     

Knowledge and educational needs of individuals with the factor V Leiden mutation

Summary.  Background : Genetic testing for factor (F)V Leiden is widely performed in an effort to prevent thrombosis-related morbidity. The implications of a positive test for patients' health perception and the extent of patients' understanding of results are not known. Objectives : This study examined patient experience of genetic testing for FV Leiden. Patients and methods : The study was a cross-sectional, mailed survey of 110 patients who tested positive for the FV Leiden gene mutation at an academic medical center between 1995 and 2001. Patient knowledge about FV Leiden, satisfaction with available information, and psychosocial reactions to testing were assessed and the influence of demographic and clinical characteristics on outcome measured. Results : The magnitude of thrombosis risk associated with FV Leiden was incorrectly estimated by 79% of participants. Many patients (64%) stated that they had not been given much information about FV Leiden and 68% still had many questions. Most patients (53%) felt that their healthcare providers do not understand FV Leiden. Patients who had been seen by a hematologist or in a specialized thrombosis clinic were more knowledgeable and had less information need. Most patients (88%) were glad to know genetic test results, despite negative psychosocial implications such as increased worry (43%). Conclusions : Knowledge of genetic status increases awareness of thrombosis risk among patients, but magnitude of risk is often overestimated. Affected individuals indicate that there is a lack of available information about FV Leiden and that additional educational resources are needed.     

A study of the lecithin/sphingomyelin ratio of amniotic fluid.

1. There is a significant correlation between lecithin/sphingomyelin (L/S) ratios based on densitometry (L/S)D and L/S ratios based on phosphorus determinations ((L/S)P). 2. The fetal lung is mature when the (L/S)D, determined according to Verhoeven, A.G.J. and Merkus, H.M.W.M. (1974) Clin. Chim. Acta 53, 229--232, is 1.2. This value is equivalent to an (L/S)P of 1.8. 3. The acetone precipitation procedure, introduced by Gluck, L., Kulovich, M.V., Borer, R.C. and Keidel, W.N. (1974) Am. J. Obstet. Gynecol. 120, 142--155, is a necessary step for isolating surface-active lecithin. 4. Standardization of the (L/S)D test is feasible and should permit different laboratories to use the same transition point.     

High density lipoprotein cholesterol and apolipoprotein A-I levels in 32–33-year-old women on steroid contraceptives—differences between two frequently used low-estrogen pills

High density lipoprotein cholesterol and apolipoprotein A-I levels were measured in about one thousand 32–33-year-old women taking part in a cardiovascular screening programme. After corrections for differences in smoking habits and use of alcoholic drinks women on various types of steroid contraceptives had widely different levels of high density lipoprotein cholesterol and apolipoprotein A-I. Lowest levels were found in users of lynestrenol-containing minipills (progestagen-only pills) and highest levels in lynestrenol-containing low-estrogen pills. Of the two commonly used low-estrogen pills (“sub-50 pills”) one type (containing levonorgestrel) was associated with elevated and the other (containing lynestrenol) with depressed levels of high density lipoprotein cholesterol and apolipoprotein A-I as compared with the reference group of non-users of oral contraceptives.     

Homozygous factor V Leiden mutation in type IV Ehlers-Danlos patient

Ehlers-Danlos syndrome (EDS) is a group of inherited connective tissue disorders caused by collagen synthesis defects. Several hemostatic abnormalities have been described in EDS patients that increase the bleeding tendencies of these patients. This case report illustrates a patient with an unusual presentation of a patient with type IV EDS, platelet δ-storage pool disease and factor V Leiden mutation. Young woman having previous bilateral deep vein thrombosis and pulmonary emboli coexisting with ruptured splenic aneurysm and multiple other aneurysms now presented with myocardial infarction. Presence of factor V Leiden mutation raises the possibility that the infarct was due to acute coronary thrombosis, although coronary artery aneurysm and dissection with myocardial infarction is known to occur in vascular type EDS. This is the first report in the medical literature of factor V Leiden mutation in an EDS patient which made the management of our patient challenging with propensity to both bleeding and clotting.     

The epidemiology of venous thromboembolism in Caucasians and African‐Americans: the GATE Study1

Summary. The aim of this study was to assess, comprehensively, medical and genetic attributes of venous thromboembolism (VTE) in a multiracial American population. The Genetic Attributes and Thrombosis Epidemiology (GATE) study is an ongoing case–control study in Atlanta, Georgia, designed to examine racial differences in VTE etiology and pathogenesis. Between 1998 and 2001, 370 inpatients with confirmed VTE, and 250 control subjects were enrolled. Data collected included blood specimens for DNA and plasma analysis and a medical lifestyle history questionnaire. Comparing VTE cases, cancer, recent surgery, and immobilization were more common in caucasian cases, while hypertension, diabetes, and kidney disease were more prevalent in African‐American cases. Family history of VTE was reported with equal frequency by cases of both races (28–29%). Race‐adjusted odds ratios for the associations of factor V Leiden and prothrombin G20210A mutations were 3.1 (1.5, 6.7) and 1.9 (0.8, 4.4), respectively. Using a larger external comparison group, the odds ratio for the prothrombin mutation among Caucasians was a statistically significant 2.5 (1.4, 4.3). A case‐only analysis revealed a near significant interaction between the two mutations among Caucasians. We found that clinical characteristics of VTE patients differed across race groups. Family history of VTE was common in white and black patients, yet known genetic risk factors for VTE are rare in African‐American populations. Our findings underscore the need to determine gene polymorphisms associated with VTE in African‐Americans.     

血栓栓塞症患者抗活化的蛋白C的研究

目的 探讨抗活化的蛋白Ｃ（ＡＰＣＲ）现象在中国人血栓栓塞症发病中的作用。方法 用ＡＰＴＴ法检测ＡＰＣＲ敏感比率（ＡＰＣＲ－ＳＲ）来研究４０例深静脉血栓症（ＤＶＴ）患者、５２例脑血栓形成患者和１００例正常人的ＡＰＣＲ发生率;用多聚酶链反应－限制性内切酶长度多态性（ＰＣＲ－ＲＦＬＰ）来检测ＦＶ Ｌｅｉｄｅｎ突变;用免疫火箭电泳测血浆总蛋白Ｓ和游离蛋白Ｓ。结果 正常人的正常化ＡＰＣＲ－ＳＲ（ｎ－ＡＰＣＲ     

Increased sperm count may account for high population frequency of factor V Leiden

Summary. Background: Factor V Leiden (FVL) increases the risk of venous thrombosis and pregnancy loss in carriers. Nevertheless, this relatively old mutation is prevalent in Caucasion populations, which could be explained by positive selection pressure. Men with FVL have previously been found to have higher fecundity (the time between marriage and first pregnancy). Whether this is caused by increased sperm counts in men with FVL is unknown. Objectives: To assess whether men with factor V Leiden have increased sperm counts. Patients/methods: We performed a prospective cohort study among 1139 consecutively included male partners of subfertile couples presenting at our university hospital for fertility workup between January 2000 and July 2007. All potential candidates who gave informed consent were included, irrespective of their fertility workup. In this retrospective analysis, we excluded participants with known causes of spermatogenic function or azoospermia. Subsequently, we genotyped all participants and compared sperm counts between FVL carriers and non‐carriers. Results: We identified 37 FVL carriers and 921 non‐carriers. FVL carriers had higher total sperm counts and total motile sperm counts than non‐carriers: 236 × 10⁶ (95% CI 158–292 × 10⁶) vs. 163 × 10⁶ (95% CI 147–178 × 10⁶) and 81 × 10⁶ (95% CI 54–105 × 10⁶) vs. 52 × 10⁶ (95% CI 48–57 × 10⁶), respectively. Conclusions: To our knowledge, this is the first study that indicates that an increased incidence of a genotype may be controlled by increased sperm counts. However, the finding that men with FVL had higher total (motile) sperm counts was not statistically significant and needs confirmation in other studies.     

中国脑血栓患者活化蛋白C抵抗的检测

目的 由凝血因子V Arg506→Gln突变（FV Leiden突变）引起的活化蛋白C抵抗（APCR）是深静脉血栓形成的主要危险因素，然而它与缺血性脑卒中的相关性尚不明确。本研究为探讨APCR和FV Leiden突变在中国人群中脑血栓形成中的作用。方法应用以活化部分凝血酶时间为基础的APCR测定方法对61例急性脑血栓的住院病人和39例正常健康人进行检测。APC敏感性比率（APC-SR）=（APTT＋ARC）／（ATIT-APC），并计算出正常化APC-SR。用多聚酶链反应-限制性内切酶长度多态性（PCR-RFLP）分析检测FV Leiden突变。结果61例脑血栓患者中有2例（3．3％）存在APCR现象，但对照组中未发现APCR。在正常健康人和脑血栓患者中均未发现有FV Leiden突变。结论在中国人群中，低发病率的非FV Leiden突变的APCR可能参与了脑血栓的形成。     

Frequency of Factor V Leiden in Juvenile Migraine With Aura

Patients with migraine are known to be at risk for stroke. It has been reported that in a group of patients with cerebral ischemia and the Leiden mutation of factor V, 67% had classical migraine. We have studied the frequency of this mutation in a group of Italian children and adolescents affected by migraine with aura.
The Leiden mutation was detected in 2 (3.5%) of 57 patients and in 8 (3.7%) of 219 controls. The 2 patients carrying the mutation had no peculiar characteristics as compared with the rest of the migrainous population. In our study, the frequency of the Leiden mutation in patients was not different from that of controls. These data contrast with those collected in the Finnish population and in a group of northwestern Italian adult patients, but agree with results previously reported from The Netherlands.     

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.     

Thrombosis risk modification in transgenic mice containing the human fibrinogen thrombin-binding γ' chain sequence

Summary.  Background and objectives:  Thrombin binding activity in murine fibrin (Antithrombin I) is restricted to its E domains inasmuch as murine γ' chains (mu-γ') do not bind thrombin. This feature prompted us to produce a 'gain-of-function' transgenic mouse in which the wild-type (WT) C-terminal mu-γ' chain fibrinogen sequence had been replaced with the C-terminal thrombin-binding human γ' sequence. Results:  This procedure resulted in a murine fibrinogen species containing chimeric hu-γ' chains (hu-γ' fibrinogen). As anticipated, thrombin bound to WT fibrin at a single class of sites, whereas thrombin binding to heterodimeric hu-γ'-containing fibrin was increased, reflecting its content of hu-γ' chains. In an electrolytically-induced femoral vein thrombosis injury model, we found no differences in the volume of thrombus generation between WT and heterozygous hu-γ' mice. However, heterozygous factor (F) V Leiden (FVL^+/−) mice developed greater thrombus volumes than did WT controls ( P  < 0.01). In doubly heterozygous FVL^+/−, hu-γ' mice, thrombus formation was reduced to WT levels ( P  < 0.05). Conclusions:  Murine hu-γ' fibrinogen down-regulates venous thrombosis in the presence of another known thrombosis risk factor, FV Leiden. This finding indicates that hu-γ' chain-containing fibrinogen is a thrombosis risk modifier.     

Past and future of genetic research in thrombosis

Summary.  Genetic studies in thrombosis started with coining of the term thrombophilia by Jordan and Nandorff in 1956. Next, antithrombin deficiency was identified in 1965 as a simple genetic entity that increased thrombotic risk, albeit in a small subset of patients. This subset was enlarged when, in the 1980s, family studies showed that deficiency of protein C (PC) or its co-factor protein S (PS) increased thrombotic risk. Ten years later activated PC resistance and the underlying genetic trait of factor V Leiden were discovered in a family setting. This genetic risk factor was the first prothrombotic defect in a procoagulant protein and was also more prevalent than abnormalities in anticoagulant proteins. The high incidence induced a shift from family studies to case–control studies. Case–control studies became even more popular after the common prothrombin 20 210 mutation was discovered in 1996. In fact, in the last decade common genetic variations in almost all coagulation proteins were tested in association studies. These common variants impart a small risk, if any risk at all, thereby limiting their usefulness in furthering insight into the pathophysiology of thrombosis. Moreover, common risk factors for venous thrombosis fail to improve prediction models for thrombosis on which prophylactic treatment can be tailored. Now that large-scale sequencing techniques are becoming available that enable many genes to be studied in a single individual, one can expect a revival of the identification of private mutations that are associated with large risks, in particular in genes that have been only poorly studied.     

Frequency of factor V Leiden in juvenile migraine with aura

Patients with migraine are known to be at risk for stroke. It has been reported that in a group of patients with cerebral ischemia and the Leiden mutation of factor V, 67% had classical migraine. We have studied the frequency of this mutation in a group of Italian children and adolescents affected by migraine with aura. The Leiden mutation was detected in 2 (3.5%) of 57 patients and in 8 (3.7%) of 219 controls. The 2 patients carrying the mutation had no peculiar characteristics as compared with the rest of the migrainous population. In our study, the frequency of the Leiden mutation in patients was not different from that of controls. These data contrast with those collected in the Finnish population and in a group of northwestern Italian adult patients, but agree with results previously reported from The Netherlands.