Protein Z.

Protein Z is a vitamin K-dependent protein. The first cases of protein Z deficiency were described in patients suffering from a bleeding tendency from otherwise unknown origin. Today, diminutions of protein Z seem to play a role not only in bleeding patients but also in patients with factor V Leiden mutation: Patients presenting with factor V Leiden mutation and low protein Z levels show earlier onset and higher frequency of thromboembolic events than do patients presenting with factor V Leiden mutation and normal protein Z levels. Thus, protein Z is a good example for the--at first sight--paradox action of coagulation proteins.     

Factor V Leiden and prothrombin gene mutation in inflammatory bowel disease in a Mediterranean area.

BACKGROUND: Thromboembolism has been reported to be associated with inflammatory bowel disease. AIM: To evaluate the association of factor V Leiden and prothrombin gene mutation with inflammatory bowel disease in a population of patients with thromboembolic events and inflammatory bowel disease and in a control population of patients with inflammatory bowel disease without thromboembolic events. PATIENTS AND METHODS: A series of 18 patients with inflammatory bowel disease and a history of arterial or venous thrombosis and 45 patients with inflammatory bowel disease without thromboembolic events were evaluated for the presence of factor V Leiden and prothrombin gene mutation. Frequency of gene mutation was compared with its occurrence in 100 healthy controls. RESULTS: One patient with inflammatory bowel disease without thromboembolic events was heterozygous for factor V Leiden mutation. whereas no patient with a thromboembolic event had factor V Leiden mutation. No patients (either cases or controls) had prothrombin gene mutation. In the healthy population the frequency of factor V Leiden and prothrombin mutation was 5% and 2%, respectively. CONCLUSIONS: Data emerging from the present study do not support any role of factor V Leiden and prothrombin gene mutation as the cause of thromboembolism in inflammatory bowel disease.     

Factor V Leiden and prothrombin gene mutation in inflammatory bowel disease in Mediterranean area

Background. Thromboembolism has been reported to be associated with inflammatory bowel disease.Aim. To evaluate the association of factor V Leiden and prothrombin gene mutation with inflammatory bowel disease in a population of patients with thromboembolic events and inflammatory bowel disease and in a control population of patients with inflammatory bowel disease without thromboembolic events.Patients and methods. A series of 18 patients with inflammatory bowel disease and a history of arterial or venous thrombosis and 45 patients with inflammatory bowel disease without thromboembolic events were evaluated for the presence of factor V Leiden and prothrombin gene mutation. Frequency of gene mutation was compared with its occurrence in 100 healthy controls.Results. One patient with inflammatory bowel disease without thromboembolic events was heterozygous for factor V Leiden mutation. whereas no patient with a thromboembolic event had factor V Leiden mutation. No patients (either cases or controls) had prothrombin gene mutation. In the healthy population the frequency of factor V Leiden and prothrombin mutation was 5% and 2%, respectively.Conclusions. Data emerging from the present study do not support any role of factor V Leiden and prothrombin gene mutation as the cause of thromboembolism in inflammatory bowel disease.     

Activated protein C resistance and factor V Leiden mutation are independent risk factors for venous thromboembolism

BACKGROUND: Resistance to activated protein C due to the factor V R506Q (Leiden) mutation is the most common clotting abnormality in patients with venous thromboembolism. OBJECTIVE: To evaluate the risk for venous thromboembolism associated with the factor V Leiden mutation or with resistance to activated protein C in the general population. DESIGN: Cross-sectional survey. SETTING: General community of Vicenza, Italy. PATIENTS: A population-based sample of 15,109 white persons 18 to 65 years of age who were randomly selected from the census list. MEASUREMENTS: Sequential validated approach based on participants' reports and Doppler ultrasonography. Resistance to activated protein C was investigated in all participants; 2134 participants with resistance to activated protein C were screened for the factor V Leiden mutation. RESULTS: Carriers of the factor V Leiden mutation had a relative risk of 3.3 (95% CI, 1.7 to 6.1) for venous thromboembolism before 65 years of age. The fraction of cases attributable to the factor V Leiden mutation was 6.6%. By 65 years of age, 5.7% of carriers of the mutation had had venous thromboembolism, mostly after surgery. Participants with a reduced response to activated protein C were at higher risk even if they did not carry the mutation (odds ratio, 1.7 [CI, 1.0 to 2.7]); the attributable risk for venous thromboembolism was 5.1%. CONCLUSIONS: The factor V Leiden mutation and resistance to activated protein C are important, independent risk factors for venous thromboembolism. Screening strategies for the factor V Leiden mutation in patients undergoing surgery or experiencing major trauma cannot be recommended, but phenotypic evaluation of resistance to activated protein C should be encouraged in patients with venous thromboembolism.     

Lack of association between factor V Leiden and thromboembolism in patients with prosthetic heart valves.

Thromboembolism represents the most serious complication in patients with prosthetic heart valves, and causes significant mortality and morbidity. Many risk factors for the condition have been identified. However, many patients who have a therapeutic level of anticoagulation and no obvious risk factors develop thromboembolism. Factor V Leiden, found in 3-7% of the normal population, is the most common inherited factor associated with thrombosis. Whether or not this factor is associated with thromboembolism in this setting has not been explored. This study compares the prevalence of factor V Leiden in patients with prosthetic heart valves, with and without thromboembolic complications. A total of 148 patients were studied. Thirty had documented thromboembolic complications and none exhibited the factor V mutation. Of the 118 patients without thromboembolic complications, seven (5.9%) were heterozygous for factor V Leiden (P = 0.345, by Fisher's two-tailed exact test; odds ratio 0, 95% confidence interval 0.0-4.34). We conclude that until future data shows otherwise, routine testing for factor V Leiden in patients with prosthetic heart valves is not warranted, except as part of ongoing research.     

Acquired activated protein C resistance is common in cancer patients and is associated with venous thromboembolism

PURPOSE: Cancer patients have an increased risk for venous thromboembolism. Because activated protein C resistance is a common risk factor for venous thromboembolism, we prospectively evaluated the activated protein C sensitivity ratio and factor V Leiden mutation in cancer patients with and without venous thromboembolism. SUBJECTS AND METHODS: We studied 55 consecutive cancer patients with deep vein thrombosis, 58 cancer patients with no history of venous thromboembolism, 54 patients with venous thromboembolism without malignancy, and 56 healthy controls. The presence of factor V Leiden mutation was determined by polymerase chain reaction and allele specific restriction digestion. The activated protein C sensitivity ratio was expressed as the ratio of activated partial thromboplastin times measured in the presence and absence of activated protein C; a ratio <2.0 in patients who did not have factor V Leiden was considered to indicate acquired activated protein C resistance. RESULTS: The prevalence of factor V Leiden mutation in cancer patients with thromboembolism (1 of 55, 2%) did not differ significantly from those in cancer patients without thromboembolism (4 of 58, 7%) or normal controls (2 of 56, 4%), but was significantly lower than that of patients with thromboembolism without cancer (18 of 54, 33%, P <0.001). The prevalence of acquired activated protein C resistance was significantly greater in cancer patients with thromboembolism (29 of 54, 54%, P = 0.001) compared with the other groups: 9 of 54 (17%) in cancer patients without thromboembolism, 7 of 36 (19%) in patients with thromboembolism without cancer, and none of the normal controls. CONCLUSION: Although factor V Leiden is not a major risk factor for thrombosis in cancer patients, acquired activated protein C resistance is common and may contribute to the thrombotic tendency in these patients.     

Factor V Leiden in women: a thrombotic risk factor or an evolutionary advantage?

Factor V Leiden is a common gain-of-function gene mutation resulting in a genetic predisposition to thromboembolic complications. Growing evidence in the literature indicates an interaction between factor V Leiden thrombophilia and acquired prothrombotic conditions such as contraceptive use or hormone replacement therapy, resulting in an increased risk of venous thromboembolism (VTE). Similarly, when combined with the prothrombotic influence of pregnancy, women who are carriers of factor V Leiden are faced with an increased risk of adverse pregnancy outcomes, including VTE, pre-eclampsia, fetal loss, placental abruption, and fetal growth restriction. The results of the most important meta-analyses on the relationship between inherited (factor V Leiden) and acquired thrombophilia in women are analyzed in this review, along with the possible evolutionary role of this mutation.     

Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis

Carriers of a mutation in the prothrombin (clotting factor II) or factor V gene have a 2- to 4-fold greater risk for venous thromboembolism than subjects without the mutations. Whether both mutations also predispose to recurrent venous thromboembolism is unclear. Outpatients who had a first episode of proven symptomatic deep-vein thrombosis and a long-term follow-up were studied. The outcome measure was the cumulative incidence of confirmed venous thromboembolic complications. Two hundred fifty-one patients were enrolled in the study. Mean duration of follow-up was 8.3 years. The prothrombin gene mutation was demonstrated in 27 patients (prevalence, 10.8%; 95% CI, 6.9 to 14.6), and the factor V gene mutation was demonstrated in 41 patients (prevalence, 16.3%; 95% CI, 11.8 to 20.9). The cumulative incidence of venous thromboembolic complications after 10 years was 61.3% (95% CI, 35.7 to 87.9), and the hazard ratio was 2.4 (95% CI, 1.3 to 4.7; P =.004) in patients with the prothrombin gene mutation); the cumulative incidence of venous thromboembolic complications after 10 years was 55.2% (95% CI, 36.4 to 74.0), and the hazard ratio was 2.4 (95% CI, 1.4 to 4.1; P =.001) in patients with the factor V gene mutation. In comparison, the cumulative incidence of venous thromboembolic complications after 10 years was 23.1% (95% CI, 16.2 to 30.1) in patients without the mutations. Prothrombin and factor V gene mutations occur frequently in patients with venous thrombosis and are associated with an increased risk for recurrent venous thromboembolic complications.     

Factor XIII Val34Leu and the risk of venous thromboembolism in factor V Leiden carriers

A mutation in factor XIII (Val34Leu) was reported to protect against venous thromboembolism. We evaluated the effect of Val34Leu on thrombotic risk in 352 factor V Leiden carriers who were first-degree relatives of 132 thrombotic propositi carrying factor V Leiden. The total observation period was 2,594 years in 92 Val34Leu carriers and 7,444 years in 260 non-carriers. The annual incidence of a first episode of venous thromboembolism was 0.31% in Val34Leu carriers and 0.44% in non-carriers [relative risk (RR) for venous thromboembolism: 0.7, 95% CI 0.3-1.5]. Age-specific RR for venous thromboembolism were (for Val34Leu carriers and non-carriers respectively): 1.0 (95% CI 0.3-3.2) in the age group of 15-30 years, 0.4 (95%, CI 0.05-3.0) in the age group of 30-45 years, 0.6 (95% CI 0.1-2.9) in the group aged 45-60 years and 0.5 (95% CI 0.06-4.5) in relatives older than 60 years. In conclusion, the impact of FXIII Val34Leu on the venous thromboembolic risk is modest, suggesting that screening for this mutation in factor V Leiden carriers is not justified.     

Protein Z: a new factor of thrombophilia?

INTRODUCTION: Sometimes, in front of a clinical setting of thrombophilia, the biological findings are helpless. Therefore we suggest to test a protein Z deficiency. EXEGESIS: Protein Z is a vitamin-K dependent protein forming a complex with the Z protein-dependent protease inhibitor for inhibiting the activated factor X; so protein Z acts as a "natural low molecular weight heparin". The prothrombotic phenotype associated with protein Z deficiency includes early fetal losses (before the 20th week of gestation), early and relapsing venous thrombosis in patients with factor V Leiden mutation and somehow ischaemic stroke in young people. CONCLUSION: The protein Z deficiency seems to be associated with a particular prothrombotic phenotype including early fetal losses as well as early and relapsing venous thromboses in patients carrying the factor V Leiden mutation. It is unclear whether or not it plays a role as a thrombophilic factor especially in the arterial vascular field.     

The prothrombin 20210A allele and the factor V Leiden are associated with venous thrombosis but not with early coronary artery disease.

This study was performed in order to establish the role of the prothrombin 20210 G/A and factor V Leiden (R506Q) polymorphisms in the susceptibility to develop venous thromboembolism and early coronary artery disease (CAD). These polymorphisms were determined in 82 consecutive patients with venous thromboembolism, 175 male patients with early CAD, and 200 healthy controls from the same Caucasian population (Asturias, Northern Spain). DNA was amplified using polymerase chain reactions and digested with the appropriate restriction enzymes in order to define the prothrombin and factor V genotypes. The prevalence of the heterozygous for the prothrombin A allele was 3.5% in the general population and 15.8% in patients with venous thrombosis (P = 0.0007); the frequency was 4% in patients with early CAD. No sex-related differences in the prevalence of the A allele were observed, and the average age at the first venous thromboembolic event was similar between GG and AG patients. The frequency of carriers of the factor V Leiden polymorphism was 9.75% among patients with venous thromboembolism, compared with 3.5% among controls, and 3.4% in the patients with CAD. Our data showed an association between venous thromboembolism and the AG genotype at the prothrombin 20210 G/A polymorphism. This polymorphism was not related to an increased risk for early CAD in our population of male patients.     

A comparison of polymorphism in the 3'-untranslated region of the prothrombin gene between Chinese and Caucasians in Australia

The 20210G-->A mutation in the 3'-untranslated (UT) region of the prothrombin gene is extremely rare or absent in the Chinese population (0 in 449 subjects, 140 with a history of thromboembolism). This is in contrast to the results from 302 Caucasians from Australia in our study (4.6% in 153 patients with a thromboembolic history and 1.3% in 149 patients with no history). This rarity implies that the variant of the prothrombin gene is probably not the main cause of venous thromboembolism in the Chinese population. Even among Caucasians this mutation accounts for only a minor percentage of all patients with thromboembolism. The relatively low incidence of venous thromboembolism in the Chinese population compared with Caucasians is probably as a result of the low prevalence of factor V Leiden or other environmental or genetic factors.     

Risk of venous thromboembolism in carriers of factor V Leiden with a concomitant inherited thrombophilic defect: a retrospective analysis.

Factor V Leiden is the most common genetic defect associated with venous thromboembolism. Its clinical expression is limited and shows a wide intrafamilial and interfamilial variation, which might be explained by the influence of other genetic risk factors. We retrospectively studied 226 patients with factor V Leiden and documented venous thromboembolism (probands) and 400 first-degree carrier relatives to assess the contribution of concomitant genetic risk factors to the occurrence of venous thromboembolism. The prothrombin G20210A mutation was found in 8.3%, homozygosity of factor V Leiden in 7.2%, and inherited deficiencies of antithrombin, protein C or protein S in 4.7% of symptomatic carriers (probands and relatives), as compared with 6.0, 3.4 and 0.9% of asymptomatic carriers, respectively. The total follow-up time in relatives was 11 049 years. Prevalences of venous thromboembolism were 10.8% in single heterozygous factor V Leiden carrier relatives, 16.0% in double-heterozygotes for factor V Leiden and the prothrombin mutation, 36.8% in homozygotes for factor V Leiden, and 40.0% in double-heterozygotes for factor V Leiden and an inherited deficiency of protein C or protein S. Annual incidences in these groups were 0.39, 0.57, 1.41, and 4.76%, respectively. Multivariate analysis showed a small, non-significant additional effect of the prothrombin mutation on the risk of venous thromboembolism in heterozygotes for factor V Leiden [adjusted hazard ratio, 1.3; 95% confidence interval (CI), 0.5-3.8]. This effect was more pronounced for homozygosity of factor V Leiden (adjusted hazard ratio, 3.9; 95% CI, 1.7-9.0) and inherited protein C or protein S deficiencies (adjusted hazard ratio, 17.5; 95% CI, 3.8-81.2). Our data provide evidence of clustering of the evaluated genetic thrombophilic defects in symptomatic factor V Leiden carriers and support the assumption that the clinical expression of factor V Leiden depends on clustering in a part of carriers.     

The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation

The G20210A mutation in the prothrombin gene is associated with an increased risk of a first venous thromboembolic episode; few data are available about the long-term risk for recurrent venous thromboembolism and it is not known whether or not carriers of the mutation should be recommended lifelong anticoagulant treatment after the first thrombosis. We investigated 624 patients, referred for previous objectively documented deep venous thrombosis of the legs or pulmonary embolism, to determine the risk of recurrent thromboembolism in heterozygous carriers of the G20210A mutation in the prothrombin gene after the first episode of venous thromboembolism. After exclusion of other inherited (anti-thrombin, protein C, protein S deficiency and factor V Leiden) or acquired (anti-phospholipid antibody syndrome) causes of thrombophilia, 52 heterozygous carriers of the prothrombin mutation were compared with 283 patients with normal genotype. The relative risk for recurrent venous thromboembolism was calculated between groups using a Cox's proportional hazard model. The patients with the prothrombin mutation had a risk for spontaneous recurrent venous thromboembolism similar to that of patients with normal genotype (hazard ratio 1.3; 95% CI, 0.7-2.3). The circumstances of the first event (spontaneous or secondary) did not produce any substantial variation in the risk for recurrence. In conclusion, the carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype.     

Review article: inherited thrombophilia in inflammatory bowel disease

Individuals with inflammatory bowel disease frequently experience increased systemic thromboembolic complications, which represent an important cause of morbidity and mortality. Risk factors for thrombosis can be inherited or acquired. The most common inherited risk factors for thromboembolism are factor V Leiden mutation, G20210A mutation in the prothrombin gene, and homozygous C677T mutation in the methylenetetrahydrofolate reductase gene. In the last few years, a great amount of literature has focused on the prevalence of such genetic mutations and their role in determining thrombosis in IBD patients. In this review, we summarize the results of these studies.     

A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism

BACKGROUND: The factor V Leiden mutation is a common genetic defect associated with an increased risk for venous thromboembolism. The clinical implications for asymptomatic carriers of this mutation and, consequently, the usefulness of screening families in which a proband has both the mutation and venous thromboembolism are unclear. OBJECTIVE: To determine the incidence of venous thromboembolism in asymptomatic carriers of the factor V Leiden mutation. DESIGN: Prospective cohort study. SETTING: University hospitals in the Netherlands. PARTICIPANTS: 470 asymptomatic carriers of the factor V Leiden mutation (234 men, 236 women; mean age, 43 years [range, 15 to 88 years]), 12 of whom were homozygous. Carriers were identified by screening the first-degree relatives (>15 years of age) of 247 symptomatic probands. MEASUREMENTS: Objectively diagnosed episodes of venous thromboembolism and the relationship between incidence and exposure to high-risk situations. RESULTS: Nine venous thromboembolic events were observed in 1564 observation-years, resulting in an annual incidence of 0.58% (95% CI, 0.26% to 1.10%). The incidence of spontaneous venous thromboembolism was 0.26% (CI, 0.07% to 0.65%) per year; 3.5% (CI, 0.1% to 17.8%) per episode of surgery, trauma, or immobilization; 0.0% (CI, 0.0% to 19.5%) per pregnancy; 1.8% (CI, 0.4% to 5.2%) per year of oral contraceptive use; and 2.9% (CI, 0.8% to 15.3%) per year of use of hormone replacement therapy. CONCLUSIONS: The absolute annual incidence of spontaneous venous thromboembolism in asymptomatic carriers of the factor V Leiden mutation is low and does not justify routine screening of the families of symptomatic patients.     

Phenotypic homozygous activated protein C resistance associated with compound heterozygosity for Arg506Gln (factor V Leiden) and His1299Arg substitutions in factor V

Two patients from two unrelated families with a history of thrombosis showed severe plasma activated protein C (APC) resistance. However, genotypic analysis demonstrated that the patients were heterozygous for factor V (FV) Leiden mutation. Coagulation studies revealed that FV clotting activity and antigen were similarly reduced at about 50% of normal in the patients. One brother of propositus A also showed the same abnormalities. Genetic analysis showed that, in addition to FV Leiden mutation in exon 10 of the FV gene (G1691A), these patients had a transition in exon 13 of the FV gene (A4070G; R2 allele) predicting His1299Arg substitution in the mature FV. Study by RT-PCR of platelet FV mRNA indicated that the mRNA produced by the FV gene, marked by the R2 allele, was reduced in amount in both pseudohomozygous patients of family A. The R2 allele has previously been demonstrated to be significantly associated with plasma FV deficiency in the Italian population. The presence of FV deficiency did not protect the propositi from thrombosis. These data confirm that genotypic analysis is mandatory in patients with phenotypic severe APC resistance before these patients are definitely classified as homozygotes for FV Leiden and that further genotypic analysis is advisable.     

The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both

Factor V Leiden and the G20210A mutation in the prothrombin gene are the most frequent abnormalities associated with venous thromboembolism. It is unknown whether the risks due to the presence of either mutation are of the same magnitude. We compared the prevalence and incidence rate of venous thromboembolism in relatives with either mutation or both. The finding of different rates might influence the strategies for primary prevention of thrombosis in carriers of these mutations. The study population included 1076 relatives of probands with the prothrombin gene mutation, factor V Leiden or both who underwent screening for inherited thrombophilia and were found to be carriers of single mutations or double mutations or who were non-carriers. The prevalence of venous thromboembolism was 5.7% in relatives with the prothrombin gene mutation, 7.8% in those with factor V Leiden, 17.1% in those with both mutations and 2.5% in non-carriers. Annual incidences of thrombosis were 0.13% [95% confidence interval (CI) 0.06-0.24], 0.19% (0.13-0.25), 0.42% (0.15-0.83) and 0.066% (0.03-0.11), respectively, and the relative risk of thrombosis was two times higher in carriers of the prothrombin gene mutation, three times higher in those with factor V Leiden and six times higher in double carriers than in non-carriers. The incidence of venous thromboembolism in carriers of the prothrombin gene mutation is slightly lower than that observed in carriers of factor V Leiden, whereas in carriers of both mutations it is two or three times higher. These findings suggest that lifelong primary anticoagulant prophylaxis of venous thromboembolism is not needed in asymptomatic carriers of single or double mutations. Anticoagulant prophylaxis seems to be indicated only when transient risk factors for thrombosis coexist with mutations.     

Laboratory thrombophilias and venous thromboembolism

Inherited abnormalities of coagulation are increasingly recognized in patients with venous thromboembolism. Common causes of hypercoagulability, also known as thrombophilia, include factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies. Thrombophilia should be suspected in patients who develop idiopathic venous thromboembolism at a young age, recurrent thrombosis, thromboses at unusual sites, recurrent unexplained pregnancy loss, or if there is a family history of thrombotic disorders. The most cost-effective approach is to initially screen for factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies because these are the most common defects causing thrombophilia. Long-term anticoagulation is controversial but should be considered if unprovoked venous thromboembolism recurs.     

Factor V Leiden mutation in Turkish patients with homozygous cystathionine beta-synthase deficiency

Venous and arterial thromboembolism can occur in patients with homocystinuria. Resistance to activated protein C, which is caused by a single point mutation in the gene for factor V, renders an individual at risk for thrombosis. It has been suggested that coexistence of hereditary homocystinuria and factor V Leiden mutation might jointly play a role in the development of thrombosis. We analysed six patients with homocystinuria due to cystathionine -synthase deficiency for factor V Leiden and prothrombin G20210A mutations. Only one patient was found to have the factor V Leiden mutation in homozygous form and this patient had suffered from severe thrombosis. One patient was found to be heterozygous with no documented thrombosis. None of the patients had prothrombin G20210A mutation. We stress the necessity for screening for known thrombophilic risk factors in patients with cystathonine -synthase deficiency. The coexistence of the factor V Leiden mutation can cause severe thrombotic events in patients with homocystinuria.