Homozygous factor V Leiden and double heterozygosity for factor V Leiden and prothrombin mutation

The most common forms of familial thrombophilia are factor V Leiden (FVL) and prothrombin mutation (PTM). Homozygous FVL and PTM have long been feared conditions thought to cause high rates of morbidity and mortality. To analyse clinical features in patients with homozygous FVL and PTM, as well as patients with double heterozygosity for FVL and PTM. All patients with homozygous FVL, PTM or double heterozygosity in the MATS database of 1465 consecutive unselected patients were analysed regarding age at inclusion venous thromboembolism (VTE), age at first thrombosis, recurrence, clinical course and acquired risk factors. We found 36 patients homozygous for FVL. Patients homozygous for FVL were younger than controls at group level (56 ± 18 vs. 63 ± 17, p < 0.02). Homozygous women were younger than female controls (50 ± 19 vs. 63 ± 18, p < 0.002). No difference was observed when comparing male subjects. Women were younger than men at inclusion thrombosis (50 ± 19 vs. 65 ± 14, p < 0.02) and at first thrombosis (47 ± 19 vs. 64 ± 14, p < 0.01). Deep venous thrombosis (DVT) was seen in 33 patients (92 %), 6 (17 %) had pulmonary embolism (PE) and 3 (8 %) had combined DVT and PE. PE was less frequent in homozygous FVL women compared to female controls (p < 0.03). VTE recurred in 3 subjects during the duration of the study. Odds ratio for VTE in homozygous FVL patients compared to controls was 13.9 (95 % CI 9.9–19.7). We found no subjects with homozygous PTM. Double heterozygosity for FVL and PTM was seen in 12 subjects. There was no difference in age at inclusion VTE between double heterozygotes and controls (59 ± 16 vs. 63 ± 17, ns.). DVT was seen in 92 % at inclusion, 8 % had PE. Mean age at first VTE was 52 ± 17 (27–82). Consecutive homozygous FVL patients had a higher age at first thrombosis than previously described. Homozygous females are affected at an earlier age than homozygous men and female controls. It seems that thrombi in homozygous FVL have a different pattern compared to controls i.e. more prone for thrombosis in the lower extremity. The odds ratio for thrombosis among homozygous FVL seems to be lower than previously described.     

Thrombophilia: 2009 update

As venous thrombosis is mostly caused by disturbances in the plasma coagulation system, abnormalities of coagulation factors are mostly risk factors for venous thromboembolism (VTE). Relatively little is known about thrombophilias that predispose to arterial thromboembolism. Although some abnormalities in the fibrinolytic pathway appear to predispose to arterial thrombosis, the associations are weak and often inconsistent between studies. At present, there is not enough consistent and clinically meaningful information to include fibrinolytic parameters in a clinical thrombophilia workup. Controversy exists as to which patients and family members to test for thrombophilia. Several testing guidelines exist. Routine screening for inherited thrombophilias is not indicated in patients with VTE provoked by immobility, surgery, and malignancy, or in those with arterial thrombosis with arteriosclerosis risk factors. Heterozygous factor V Leiden (FVL) and prothrombin 20210 mutations increase the risk for recurrent VTE only slightly once anticoagulation is stopped. Therefore, decisions regarding the length of anticoagulant therapy typically are not influenced by finding one of these heterozygous mutations. The main reason to perform thrombophilia testing in a patient is to detect a strong thrombophilia (ie, antithrombin deficiency, antiphospholipid antibody syndrome, homozygous FVL, double-heterozygous FVL plus prothrombin 20210 mutation, protein C deficiency, and maybe protein S deficiency). The finding of a strong thrombophilia has several clinical consequences: it decreases the threshold to recommend long-term anticoagulation in a patient with unprovoked VTE; facilitates discussion regarding whether anticoagulant or antiplatelet therapy is the preferred empiric treatment for a patient who had an unexplained arterial, nonarteriosclerotic thromboembolic event; and leads to the consideration of testing asymptomatic female family members for the identified thrombophilia(s) so they can be counseled on their risk of thromboembolism, the use of hormonal therapies, and the potential benefit of pre- and postpartum anticoagulant therapy.     

The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies

Factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) are the two most common genetic polymorphisms known to predispose to a first episode of venous thromboembolism (VTE). However, whether these thrombophilic abnormalities are also risk factors for recurrent VTE is unclear. We conducted a systematic review of prospective studies to assess the risk of recurrent VTE associated with heterozygous carriage of each of these mutations. All randomized controlled trials and prospective cohort studies that reported the incidence of recurrent VTE in patients with and without FVL and PTM after discontinuation of anticoagulant treatment were collected and analyzed. The risk ratios (RR) and their 95% confidence intervals (CI) for recurrent VTE were calculated in heterozygous carriers of FVL or PTM and compared to those of non-carriers. Eleven studies fulfilled the inclusion criteria. Recurrent VTE occurred in 114 out of 557 heterozygous carriers of FVL (20.5%) as compared to 382 out of 2,646 non-carriers (14.4%); and in 38 out of 212 heterozygous carriers of PTM (17.9%) compared to 428 of 2,996 non-carriers (14.3%). The RR of VTE recurrence conferred by the heterozygous carriage of FVL and PTM was 1.39 (95% CI, range 1.15 to 1.67) and 1.20 (range 0.89 to 1.61), respectively, using the Mantel-Haenszel fixed-effects model; 1.45 (1.13 to 1.85) and 1.36 (1.02 to 1.82), respectively, using the Der Simonian and Laird random effects method. In symptomatic patients with VTE, heterozygous carriage of FVL is clearly associated with a definitely increased risk of recurrent thromboembolism. The risk is lower with PTM and is difficult to interpret since it varies according to the assessment method used.     

Factor V Leiden: the venous thrombotic risk in thrombophilic families

Factor V Leiden (FVL) leads to a sevenfold increased risk of venous thrombosis and is present in 50% of individuals from families referred because of unexplained familial thrombophilia. We assessed the association of FVL with venous thromboembolism (VTE) in 12 thrombophilic families of symptomatic probands with FVL in a retrospective follow-up study. We screened 182 first- and second-degree relatives of the 12 unrelated propositi for the FVL mutation and the occurrence of VTE. The incidence rate of VTE in carriers of FVL (0.56%/year) was about six times the incidence for the Dutch population (0.1%/year). The incidence rate in non-carriers also appeared to be higher (0.15% per year). At the age of 50 years, the probability of not being affected by VTE was reduced to 75% for carriers and to 93% for non-carriers (P = 0.009). Identification of carriers of FV Leiden may be worthwhile in young symptomatic individuals and their relatives with a strong positive family history of venous thromboembolism or a history of recurrent venous thrombosis who may be at risk (e.g. pregnancy, use of oral contraceptives). After adjustment for prothrombin G20210A (present in two families), even higher thrombotic incidence rates were found in carriers and non-carriers of FVL. This makes the presence of other unknown prothrombotic risk factors more probable in these families.     

High factor VIII levels contribute to the thrombotic risk in families with factor V Leiden

Factor V Leiden (FVL)-carrying relatives of selected patients with venous thromboembolism (VTE) have much higher venous thrombotic risks than FVL-carrying relatives of unselected consecutive patients with VTE. To find an explanation for this, we explored other risk factors of VTE, in particular the presence of high factor VIII levels, in a retrospective follow-up study. We assessed levels of factor VIII, factor IX, fibrinogen, protein C, protein S, antithrombin, the presence of prothrombin 20210A, and the occurrence of VTE in 61 first-degree relatives of 12 selected thrombophilic families harbouring FVL, and 183 first-degree relatives of 47 unselected families of FVL carriers with a first VTE. In all families, FVL appeared to be an independent risk factor for VTE. Higher thrombosis incidence rates were found in carriers of both FVL and high factor VIII levels (> or = 150 IU/dl), while high levels of factor VIII appeared to be an independent thrombotic risk factor only in selected thrombophilic families. The fraction of individuals with more than one prothrombotic coagulation disorder was 10% higher in selected families. These results and the higher thrombotic risks we found in the thrombophilic families favour the hypothesis that other unknown co-existing genetic defects contribute to thrombophilia.     

Increased Factor V Leiden frequency is associated with venous thrombotic events among young Brazilian patients

Introduction Of the inherited thrombophilias, the Factor V Leiden (FVL) and the prothrombin mutant (FII G20210A) are associated with increased risk of venous thromboembolism (VTE). The C677T mutation of the methylenetetrahydrofolate reductase gene, which may lead to hyperhomocysteinemia, is also considered a risk factor for VTE in some studies. However, the frequency of these genetic risk factors may vary significantly among different populations. Material and methods The FVL, FII G20210A and C677T mutations were investigated by PCR-RFLP in 275 young VTE Brazilian patients as well as in 324 biologically unrelated individuals selected to compose the control group. Results The C677T mutation in the MTHFR gene was detected in 135 (49.1%) patients, of which 117 (42.5%) were identified as heterozygous and 18 (6.5%) as homozygous. The G20210A mutation was detected in 14 (5.1%) patients in heterozygosis. In both cases, no significant difference was observed when these results were compared to the frequencies observed in the control group. FVL was detected in heterozygosis in 19 (6.9%) patients, corresponding to a significantly increased frequency when compared to that observed for the control group (1.2%) (OR 5.9; 95% CI 2.08–16.79; p < 0.001). Conclusions The data indicated that FVL is significantly associated with VTE among young Brazilian patients, but also supported previous evidence that VTE is a multi-factorial disease, resulting from the interaction of genetic and acquired risk factors.     

Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family

We analysed the clinical and analytical features of 18 subjects from a Spanish family who bear several combinations of two prothrombotic mutations, factor V Leiden (FVL) and prothrombin 20210A. We identified three subjects homozygous for the 20210A prothrombin mutation which additionally were heterozygous for FVL. The combination of both mutations increases the risk of developing venous thrombotic episodes at the earlier age. However, even in association with FVL, the homozygous condition of the prothrombin 20210A mutation requires additional risk factors to induce a thrombotic event. Finally, the plasma level of factor II showed a significant relationship with the prothrombin genotype.     

High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]

Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.     

Factor V Leiden mutation in venous thrombosis in southeast Turkey

Venous thrombosis (VT) is a common disease, with an annual incidence in the general population of approximately 1 per 1,000. Factor V Leiden mutation (G1691A) (FVL) is the most common risk factor in venous thrombosis. The prevalence of FVL for thrombosis varies greatly in different regions of the world. FVL mutation has been identified both by conventional method and fluorescence resonance energy transfer (FRET) with the LightCycler. Sixty-one patients with VT, different in age and sex, were consecutively entered into this study to assess the prevalence of FVL in VT in southeast Turkey. FVL mutation was found in 24.6% (15/61). Fourteen individuals were heterozygous and 1 homozygous, a rate of 22.9% and 1.6%, respectively. In conclusion, the authors suggest that FVL mutation is common in patients with venous thrombosis in southeast Turkey.     

History of non-fatal cardiovascular disease in a cohort of Dutch and British patients with haemophilia

Protein C (PC) deficiency is an autosomal dominant inherited disorder associated with spontaneous and recurrent thrombotic events. Factor V Leiden (FVL) increases the risk of thrombosis in PC-deficient type I families. We have investigated the relationship between PC deficiency genotype and clinical phenotype in a large four-degree Italian family followed since 1988. Methods: PC activity and antigen levels were quantified; sequencing of PC DNA was performed to identify polymorphism. FVL and factor II (G20210A) polymorphism were screened. Results: PC activity ranged from 5% to 9%, and PC antigen levels were 5,3% in two homozygous for PROC missense mutation Arg32Cys; PC activity ranged from 18% to 60% and antigen levels from 21% to 64%, respectively, in 11 heterozygous for Arg32Cys; PC activity was 99% and 120% in two wild type. Of 15, eight were heterozygous for FVL. The two subjects with PC < 6%, homozygous for Arg32Cys and heterozygous for FVL, suffered from thrombosis during childhood. Of 11, six subjects with PC deficiency and heterozygous for FVL showed the first thrombosis at an age between 21 and 54. None of the five PC-deficient subjects, who were wild type for FVL, showed thrombosis. Two subjects with PC > 70%, both heterozygous for FVL developed thrombosis in the presence of another risk factor. This study suggests that FVL and PROC mutations increase the risk of thrombosis in subjects with PC deficiency, which could be considered as a 'variable' risk factor. The thrombosis-prone PC-deficient families carry additional risk factors for thrombosis.     

Prevalence of Factor V Leiden in a healthy population in Santa Catarina,Southern Brazil

Thrombophilic disorders are found in 50% of patients with venous thromboembolism, and factor V Leiden (FVL) is the most common genetic risk factor for the development of these conditions. FVL prevalence varies according to population group. In Europe, many countries have a high prevalence of the mutation, including Portugal, Germany, and Italy. Santa Catarina State, southern Brazil, was colonized by different European nations; most inhabitants are descendants of Portuguese, Italian, and German immigrants. There are, however, no data on the prevalence of FVL in the state. This study aimed to determine FVL prevalence in a healthy population in Santa Catarina and assess whether there is an association between the mutation and demographic characteristics, thereby contributing to the understanding of the heterogeneity of prevalence of this important VTE risk factor and racial or geographical differences in the incidence of thrombotic diseases. Analysis of the FVL mutation was performed on 400 blood donors using the PCR technique followed by enzymatic digestion. The findings show that 2.5% of the participants were heterozygous for FVL, and none were homozygous. No association was found between the presence of FVL in heterozygosis and individual characteristics. In conclusion, this study found a prevalence of FVL in heterozygosis of 2.5% among healthy individuals in Santa Catarina, Brazil. Further studies are needed to assess the prevalence of FVL in other regions of the country, determine the distribution of the mutation among population groups, and evaluate how these factors affect the incidence of thrombotic diseases.     

The frequency of anticardiolipin antibodies and genetic mutations associated with hypercoagulability among patients with Wegener's granulomatosis with and without history of a thrombotic event

OBJECTIVE: Venous thrombotic events (VTE), including both deep venous thrombosis and pulmonary emboli, are now recognized as an important complication of Wegener's granulomatosis (WG), but the mechanism(s) of this occurrence is unclear. The frequency of anticardiolipin antibodies (aCL), anti-beta2-glycoprotein antibodies (anti-beta2-GP), and several genetic hypercoagulable factors were examined in a large cohort of patients with WG. METHODS: One hundred eighty patients with active WG had serum and DNA samples collected upon entry into a clinical trial. Of the 180 patients, 29 patients had VTE -- 13 before trial entry, 16 during trial. aCL (IgG, IgM, and IgA) and anti-beta2-GP (IgG and IgM) were evaluated in 176 patients. Factor V Leiden (FVL), the prothrombin gene mutation (G20210A, PGM), and methylenetetrahydrofolate reductase (MTHFR) gene mutation were tested in the 29 patients with thrombotic events, and 36 patients without. RESULTS: aCL occurred with increased frequencies in patients with WG when compared to the general population (1%-5%): 12% had aCL and 3% had anti-beta2-GP. There was no difference in the prevalences of aCL or anti-beta2-GP based on clotting status. The prevalence of the genetic hypercoagulable factors examined in patients with WG was comparable to the reported rates in the general population. CONCLUSION: Although the incidence of clinically significant VTE is increased in patients with WG, this increased risk is not explained by increased prevalences of aCL, anti-beta2-GP, FVL, or mutations in PGM or MTHFR. These observations suggest a need to search for new genetic or acquired prothrombotic abnormalities to account for the increased thrombotic event rate in patients with active WG.     

Arterial and venous thrombosis in two Italian families with the factor V Arg506→ Gln mutation

Abstract: APC resistance, due to a point mutation in factor V at amino acid position Arg⁵⁰⁶, has been identified as a major cause of inherited thrombophilia. Here we report the presence of the factor V Arg⁵⁰⁶→Gln mutation in 2 Italian families. In 1 family 3 subjects heterozygous and 2 subjects homozygous for the factor V Arg⁵⁰⁶→ Gln mutation were identified. The only subject who developed a thrombotic event was a 20-yr-old girl who was found to be homozygous for the factor V Arg⁵⁰⁶→Gln mutation. In the second family 10 subjects were identified to be heterozygous for the factor V Arg⁵⁰⁶ →Gln mutation; among them 2 developed a thrombotic event. In the same family 2 individuals were found to be homozygous for the mutation: the first had a myocardial infarction at age 25 yr and the second suffered from multiple episodes of deep venous thrombosis and had a stroke at age 24 yr. These data show that the risk of developing deep venous thrombosis for the carriers of the factor V Arg⁵⁰⁶→Gln mutation is high in the families investigated. Furthermore our data imply that the factor V Arg⁵⁰⁶ →Gln mutation in its homozygous form may relate to myocardial infarction and stroke.     

Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis

It is remarkable that certain patients with heterozygous protein C (PC) deficiency manifest venous thromboembolism (VTE), whereas others, particularly those belonging to families with homozygous PC deficiency, remain asymptomatic. The goals of the present study of a family, in which the proband had homozygous PC deficiency, were to identify members with and without VTE, to determine the mutation causing PC deficiency, and to search for the R506Q mutation of factor V (FV) causing activated PC resistance. Heterozygosity for a T298M mutation in exon 9 of the PC gene was found in the father of the homozygous proband who died of massive thrombosis. Based on analysis of a three- dimensional molecular model of PC, we speculate that this mutation causes type I deficiency due to disruption of packing of hydrophobic side chains and loss of an H-bond between Q184 and T298. Forty-six family members were examined for the T298M mutation by polymerase chain reaction (PCR) amplification of exon 9 and restriction analysis using Mae III and for the FV R506Q mutation by PCR amplification of exon 10 and restriction analysis using Mnl I. VTE was observed in five of 11 members who were heterozygous for both PC and FV mutations. In contrast, VTE was not observed for the PC mutation in 13 heterozygotes who had normal FV, including the parents of the deceased proband, 10 heterozygotes for the FV mutation who had normal PC, and 12 individuals bearing neither mutation. These observations extend recent evidence of an increased thrombotic risk conferred by the coexistence of heterozygous PC deficiency and heterozygous activated PC resistance and support the paradigm in which hereditary thrombophilia is often a multigenic disease.     

Clinical evaluation of a functional prothrombin time-based assay for identification of factor V Leiden carriers in a group of Italian patients with venous thrombosis.

The efficiency of a new prothrombin-based activated protein C (APC) resistance test to detect factor V Leiden (FVL) was clinically evaluated in 150 Italian patients with deep venous thrombosis. Patient samples are diluted in factor-V-deficient plasma, an APC-containing reagent, and specific factor V activator; after incubation, clotting is initiated by addition of activated-factor-FV-dependent prothrombin activator. Two prothrombin time determinations were performed under identical assay conditions except that no APC was added to one. A ratio over 4.2 for normal individuals and under 2.0 for FVL patients is expected: between 1.3 and 1.9 for FVL heterozygotes, and between 1.0 and 1.1 for FVL homozygotes. Using a predefined cut-off ratio of 2.0, a specificity and a sensitivity of 1.00 for detection of FVL mutation were found. With a cut-off ratio of 1.1, a specificity of 0.98 and a sensitivity of 1.00 were found for discrimination between FVL heterozygous (n = 60) and homozygous (n = 6). No interferences by heparins, oral contraceptives, oral anticoagulant therapy, protein C, protein S, D-dimer, homocysteine, MTHFR mutations and antiphospholipid autoantibodies were detected. In our experience, this new prothrombin time-based APC resistance assay provides improved discrimination between normal individuals and FVL carriers compared with the classical methods. Moreover, this new assay allows good discrimination between homozygous and heterozygous FVL carriers. In the authors' experience this prothrombin time-based method was not influenced by many factors compared with the classical activated partial thromboplastin time-based method.     

Prevalence of factor V Leiden in south Tunisian blood donors

Venous thrombosis (VT) is a common disease with multifactorial pathogenesis. Factor V Leiden mutation (G1691A) (FVL) is the most common risk factor in venous thrombosis. The prevalence of FVL varies according to geography and ethnicity. Hence, in several countries there is a difference in the frequency of this mutation between the southern, central and north. In Tunisia, no data is available about prevalence of FVL mutation by geographical origin. For this reason, we sought the prevalence of FVL mutation in blood donor of south Tunisia population. FVL has been detected by APCR-test and confirmed by PCR-RFLP and sequencing. Two hundred fifty blood donors, different in age and sex were included in this study to determine the prevalence of FVL in blood donors. FVL mutation was found in 13.6% of the studied population. Thirty-one were heterozygous and three persons were homozygous with a rate of 12.4 and 1.2%, respectively. In conclusion, FVL mutation is very common in south Tunisian population.     

Thrombophilic conditions in the pathogenesis of venous thromboembolism

Thrombophilic conditions are congenital or acquired hemostatic disorders pathophysiologically or statistically associated with higher risk of thrombosis. Their most important clinical manifestation is venous thromboembolism. In more than 50% of persons with non-induced thrombosis, some of the known thrombophilias can be found. Persons with congenital thrombophilias have, contrary to those without any thrombophilias, most of all an increased risk of an initial thromboembolic event while the impact of congenital thrombophilic conditions on their recurrence is not so clear. In patients with idiopathic thrombosis is the risk of recurrence 7-10% a year even at the absence of known thrombophilias. The risk of a recurrent event is influenced by a set of other factors (prevailing or undetected trigger factor, proximal thrombosis and pulmonary embolism, incomplete rechanneling of a thrombotic vein, presence of some thrombophilias, high level of D-dimers after discontinuation of the anticoagulant treatment). Their identification and consequent monitoring are decisive in the choice of an optimum treatment and the duration of their administration in secondary prevention of venous thromboembolism. In the primary venous thrombosis prevention, the knowledge of general trigger factors and the individual risk characteristics of the given patient is important, which means also timely detection of thrombophilic conditions in patients who profit from it, i.e. if they display at least medium probability of detection. A universal long-term prophylaxis in so far asymptomatic carriers of congenital thrombophilias is not indicated with regard to potential complications of anticoagulant treatment. Women with thrombophilic disorders are under an increased risk of a thromboembolic event when using hormonal contraceptives and during pregnancy. There is also a higher incidence of pregnancy complications connected with disorders in blood circulation of placental vascular tree.     

Prothrombin 20210A mutation: a mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study

BACKGROUND: The prothrombin 20210A mutation has been associated with an increased risk of venous thromboembolism (VTE). Its relationship with arterial disease and pregnancy-related complications is, however, still uncertain. The aim of this study was to estimate the incidences of first venous and arterial thrombotic events and pregnancy-related complications in relatives of patients with the mutation. METHODS: After clinical classification, the presence of the mutation was determined in first-degree relatives of consecutive patients with the mutation and a history of VTE or premature atherosclerosis. Relatives with and without the mutation were compared. RESULTS: Of all relatives, 204 (50%) were heterozygous, 5 were homozygous, and 198 had a normal genotype. The annual incidence of a first episode of VTE was 0.35% and 0.18% in carriers and noncarriers, respectively (odds ratio [OR], 1.9; 95% confidence interval [CI], 0.9-4.1); the annual incidence of a first arterial thrombosis was 0.22% and 0.15% in carriers and noncarriers, respectively (OR, 2.3; 95% CI, 0.8-6.3). The annual incidence of a first myocardial infarction was 0.14% (95% CI, 0.05%-0.23%) and 0.05% (0.01%-0.14%) in carriers and noncarriers, respectively (OR, 4.7; 95% CI, 1.0-22.5; P =.06). In particular, homozygous carriers were at increased risk of VTE (OR, 6.0; 95% CI, 1.3-27.2), whereas a history of VTE in the proband influenced the risk of VTE in the relatives. Women with the mutation did not experience significantly more pregnancy-related complications than their relatives with a normal genotype. CONCLUSIONS: The prothrombin mutation is a mild risk factor for VTE within families of carriers but does not seem to play an important role in arterial thrombotic disease, with the exception of myocardial infarction, or in pregnancy-related complications.     

Hereditary protein S deficiency: clinical manifestations

To analyze the clinical manifestations of protein S deficiency, we evaluated 136 members of 12 families with the disorder. Seventy-one persons were found to be heterozygous for protein S deficiency, which is inherited as an autosomal dominant trait. Venous thrombotic events occurred in 39 patients (55%) and were recurrent in 77%. Most symptomatic patients had various combinations of deep venous thrombosis (74%), superficial thrombophlebitis (72%), and pulmonary embolism (38%), either in succession or simultaneously. On five occasions thrombosis was found at unusual sites, like the axillary, mesenteric, and cerebral veins. The age at the first thrombotic event ranged from 15 to 68 years (mean, 28 years), and at age 35 the probability to be still free of thrombosis was only 32%. Fifty-six percent of the thrombotic events were not preceded by a precipitating condition. In these respects protein S deficiency is similar to protein C deficiency.     

No evidence for an increased risk of venous thrombosis in patients with factor V Leiden by the homozygous 677 C to T mutation in the methylenetetrahydrofolate-reductase gene.

Hyperhomocysteinemia is an established risk factor for arterial and venous thrombosis. Recently, it has been shown that a C to T mutation at nt position 677 in the methylenetetrahydrofolate-reductase (MTHFR) gene is a common cause of moderately elevated levels of plasma homocysteine in adults. In order to investigate whether the newly recognized genetic alteration in the MTHFR gene potentiates the thrombotic tendency in patients with factor V Leiden, we studied 81 unrelated patients with a history of venous thrombosis and a heterozygous factor V Leiden mutation. In addition, we analyzed 111 family members of 34 families in which the proband had a heterozygous factor V Leiden mutation. In all individuals, factor V Leiden and the MTHFR mutation were tested and the occurrence of venous thrombotic events was evaluated retrospectively. Seventy-seven healthy subjects without the factor V Leiden mutation or any other known thrombotic risk factor served as a control group. The prevalence of the homozygous MTHFR mutation was similar in index patients (10 of 81, 12%) and in the control group (10 of 77, 13%). The median age at first thrombosis in index patients was 32 years (range 22-69 years) in 10 patients with heterozygous factor V Leiden and T/T MTHFR mutation, and 34 years (range 6-72 years) in 71 patients with the factor V Leiden mutation only. In the family members, the prevalence of thrombosis was not higher in patients with factor V Leiden and +/+ MTHFR genotype than in those with only the heterozygous factor V Leiden mutation. We conclude from these data that the 677 C to T mutation in the MTHFR gene does not represent a significant additional risk factor for venous thrombosis in patients with factor V Leiden mutation.