Activated protein C resistance and the factor V Leiden mutation in children with thrombosis

To determine the prevalence of activated protein C resistance and the factor V Leiden mutation (position 1691, arginine 506 to glutamine substitution) in children with thrombosis, plasma samples from children with thrombosis were tested for activated protein C resistance. DNA was analyzed for the factor V Leiden mutation. Five of 34 children (15%) had activated protein C resistance; each was heterozygous for the factor V Leiden mutation. All 5 children heterozygous for the factor V Leiden mutation suffered non-CNS venous thromboses comprising 21% of the group of children (5/24) with non-CNS venous thrombotic events. Each of these 5 children had a family history of thrombosis. In conclusion, children with non-CNS venous thrombosis should be evaluated for the factor V Leiden mutation. Children most likely affected are those with a family history of thrombosis. Am. J. Hematol. 57:29–32, 1998. © 1998 Wiley-Liss, Inc.     

Mesenteric and portal vein thrombosis associated with hyperhomocysteinemia and heterozygosity for factor V Leiden mutation

TO THE EDITOR A 79-year-old man was hospitalized because of worsening upper abdominal pain which started two days before admission and was continuously present. His personal and family historywas uneventful, he did not smoke and denied toxic habits or using any medications, including over the-counter medications, herbal remedies or any vitamin supplements.     

Extrahepatic portal vein thrombosis in children and adolescents: Influence of genetic thrombophilic disorders

AIM:To explore the prevalence of local and genetic thrombophilic disorders as risk factors for portal vein thrombosis (PVT) in our series,the largest ever published in pediatric literature. METHODS:We conducted a case-control study enrolling 31 children with PVT and 26 age-matched controls. All were screened for thrombophilia,including genetic disorders,protein C,protein S and homocysteine deficiencies. All coagulation parameters were studied at least 3 mo after the diagnosis of portal vein obstruction.RESULTS:In our study we showed that most pediatric patients with PVT have local prothrombotic risk factors,which are probably the most important factors leading to PVT. However,there is a clear association between the presence of prothrombotic disorders and PVT,suggesting that these increase the risk of thrombosis in patients with local factors such as perinatal umbilical vein catheterization or sepsis. CONCLUSION:Patients with PVT should be screened for inherited prothrombotic disorders regardless of a history of an obvious local risk factor.     

Budd-Chiari syndrome, portal vein and mesenteric vein thrombosis in a patient homozygous for factor V Leiden mutation treated by TIPS and thrombolysis

We present the first case of Budd-Chiari syndrome in association with portal and mesenteric vein thrombosis in a patient homozygous for the factor V Leiden mutation. She was treated by transjugular intrahepatic portosystemic stent (TIPS) placement followed by local thrombolytic therapy. Venous outflow from the liver was established and the thrombi in the portal and mesenteric veins were lysed completely. This therapeutic approach may be used for such patients with this severe thrombotic event, who generally have a poor prognosis.     

The factor V Leiden mutation in children with cancer and thrombosis

Thromboembolic phenomena, frequently observed in children with cancer who are undergoing chemotherapy, can cause significant morbidity and, less frequently, mortality. Many contributory factors have been identified. Whether the recently identified and most common coagulation defect predisposing to thrombosis, factor V Leiden, is associated with thrombosis in this setting, has not been explored. The current study was undertaken to determine the prevalence of the factor V Leiden mutation in children with cancer who developed thromboembolic phenomena as compared to those with cancer who did not. Genomic DNA was amplified using the polymerase chain reaction (PCR), followed by digestion of the amplification product with the restriction enzyme Mnl I. The digested PCR products were then size-fractionated to classify samples as heterozygous, homozygous or normal for the factor V Leiden mutation. 67 children with cancer were evaluated for the factor V Leiden mutation. One of 32 children with cancer and thrombosis, and none of 35 who had not experienced thrombotic problems, was found heterozygous for this mutation. We conclude that the factor V Leiden mutation does not play a significant role in the overall incidence of thromboses that occur in children with cancer.     

Different risk of deep vein thrombosis and pulmonary embolism in carriers with factor V Leiden compared with non-carriers, but not in other thrombophilic defects. Results from a large retrospective family cohort study

The term factor V Leiden (FVL) paradox is used to describe the different risk of deep vein thrombosis and pulmonary embolism that has been found in carriers of FVL. In a thrombophilic family-cohort, we estimated differences in absolute risks of deep vein thrombosis and pulmonary embolism for various thrombophilic defects. Of 2,054 relatives, 1,131 were female, 41 had pulmonary embolism and 126 deep vein thrombosis. Annual incidence for deep vein thrombosis in non-carriers of FVL was 0.19% (95%CI, 0.16–0.23), and 0.41% (95%CI, 0.28–0.58) in carriers; relative risk (RR) 2.1 (95%CI, 1.4–3.2). For pulmonary embolism these incidences were similar in carriers and non-carriers 0.07%, respectively; RR 1.0 (95% CI, 0.4–2.5). When co-inheritance of other thrombophilic defects was excluded the RR for deep vein thrombosis in FVL carriers was 7.0 (95%CI, 2.3–21.7) compared to non-carriers and 2.8 (95%CI, 0.5–14.4) for pulmonary embolism. For other thrombophilic defects no such effect was observed. Thus the FVL paradox was confirmed in our study. However, a similar paradox in carriers of other thrombophilic defects was not observed.     

Factor V Leiden and prothrombin gene G20210A mutations in Italian patients with Behçet's disease and deep vein thrombosis

Objective

To evaluate the frequency and type of vascular lesions and to study the association of factor V gene G1691A (Leiden) and prothrombin gene G20210A polymorphisms with venous thrombosis in Italian patients with Behçet's disease (BD).

Methods

Included were 118 consecutive Italian BD patients followed over a 3‐year period (1997–1999) who satisfied the International Study Group criteria for BD. The control group consisted of 132 healthy Italian blood donors. All BD patients and controls were genotyped by polymerase chain reaction and allele‐specific restriction enzyme techniques for factor V Leiden and prothrombin gene G20210A polymorphisms.

Results

Vascular lesions were observed in 37 (31.4%) patients. The 2 most common lesions were subcutaneous thrombophlebitis (10.2%) and deep vein thrombosis (DVT) of the legs (22.8%). No significant demographic and clinical differences between patients with and without DVT were present. The distribution of allele and genotype frequencies of prothrombin gene G20210A and factor V Leiden polymorphisms did not differ significantly between BD patients and healthy controls. The frequencies of carriage rates of prothrombin gene G20210A and factor V Leiden polymorphisms in BD patients with and without DVT were similar. However, the frequency of 20210A allele was significantly higher in BD patients with ocular disease than in those without, particularly in the patients with posterior uveitis/retinal vasculitis.

Conclusions

The frequency and types of vascular lesions in Italian BD patients were similar to those reported in studies from other countries. No association between factor V Leiden mutation and G20210A mutation in the 3′‐untranslated region of the prothrombin gene with DVT was found. However, a prothrombin gene G20210A mutation may influence the development and severity of ocular involvement in BD.

     

Cerebral infarct associated with factor V Leiden mutation in a boy with hemophilia A

An 11-year-old boy with mild hemophilia A was admitted to our hospital because of focal convulsions. Magnetic resonance imaging showed an old occipital infarct. Protein C, S, antithrombin III, anticardiolipin antibodies and fibrinogen were normal. Heterozygosity for factor V Leiden mutation was detected. We suggest that factor V Leiden mutation should be studied in hemophiliacs with thrombosis. Am. J. Hematol. 56:189–190, 1997. © 1997 Wiley-Liss, Inc.     

Factor V Q 506 mutation in children with thrombosis

The factor V Leiden mutation in 12 children with thrombosis and in 20 controls was investigated. Five heterozygous individuals and 1 homozygous individual among the cases with thrombosis and 1 heterozygous individual among controls were found. Central nervous system thromboses were increased in children with the factor V mutation, associated with protein S deficiency. © 1996 Wiley-Liss, Inc.     

Pregnancy-associated venous thromboembolism (VTE) in combined heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone

The risk of venous thromboembolism (VTE) in the absence of prophylaxis was evaluated in a retrospective study of 47 women (84 pregnancies) with combined thrombophilia [heterozygous factor V Leiden (FVL) plus prothrombin (FII) 20210A mutation (group I)] and in 82 women (193 pregnancies) with the FII alone (group II). VTE was more frequent in group I than in group II [17.8% versus 6.2%, P = 0.003, relative risk (RR) 2.9, 95% confidence interval (CI) 1.4-5.9], ante partum (7.1% and 2.1%) and post partum (11.5% and 4.2%). The risk was higher in index cases than in family members (RR 2.5, 95% CI 1.2-5.2 and RR 2.1, 95% CI 0.2-22.3 respectively) Even women who had no history of VTE before pregnancy had an increased risk (RR 2.2, 95% CI 1.0-4.8). Our results suggest that, during ante partum, prophylaxis is indicated in women with combined thrombophilia and with a VTE before pregnancy. In those without VTE before pregnancy, prophylaxis might be decided for each individual case, taking into consideration all risk factors. In women with the FII mutation alone, the low risk may not justify prophylaxis in the absence of previous VTE. In post partum, prophylaxis is indicated in all cases.     

R255h amino acid substitution of protein Z identified in patients with factor V Leiden mutation

The clinical significance of diminished protein Z in plasma is controversial. Studies in mice demonstrated that deficiency of protein Z dramatically increases the prothrombotic tendency of factor V Leiden mutation. This finding was confirmed by initial results in humans, indicating that thromboembolism in factor V Leiden patients with lowered protein Z level occurs earlier than in patients with normal protein Z levels. Consequently, the aim of our present study was to find out whether genetic alterations of protein Z were demonstrated in patients with factor V Leiden mutation and early onset of thromboembolic disease. DNA-sequencing of the protein Z gene was performed in two patients with factor V Leiden mutation, early onset of thromboembolism, and lowered protein Z levels. In both patients, R255H substitution of the protein Z gene was identified. Subsequently, the R255H substitution was also found in 12 of 132 additional patients. Patients presenting with the R255H substitution in addition to factor V Leiden mutation showed thromboembolic events more frequently than factor V Leiden patients without R255H substitution of the protein Z gene. In conclusion, R255H substitution of the protein Z gene seems to influence clinical symptoms of thromboembolism in factor V Leiden patients.     

MTHFR C677TT, PAI1 4G-4G, V Leiden Q506, and prothrombin G20210A in hepatocellular carcinoma with and without portal vein thrombosis

We studied thrombophilic genetic factors (TGFs) MTHFR C677TT, PAI1 4G-4G, V Leiden Q506, prothrombin G20210A as risk factors in 94 patients with HCC with and without portal vein thrombosis (PVT), compared with 214 patients with liver cirrhosis (LC) with and without PVT and 94 healthy controls (HC). The OR (95% CI) for MTHFR C677TT with HCC was 3.85 (1.55–7.39) vs. HC. The OR for PAI1 4G-4G in HCC, was 2.87 (1.27–6.55) vs. HC. Also prothrombin G20210A was significantly more frequent among HCC, mainly in patients with PVT, while V Leiden factor was equally distributed among HCC and HC. Differences were more significant in patients with associated PVT. These findings suggest that frequently TGFs are needed for patients to be at risk of HCC and PVT. We conclude that in all patients with chronic liver disease TGF screening should be performed to individuate patients at risk of HCC and PVT.     

Prevalence of the JAK2V617F mutation in Chinese patients with Budd-Chiari syndrome and portal vein thrombosis: a prospective study

Background and Aim: Whether routine screening for the JAK2V617F mutation should be performed in Chinese patients with Budd‐Chiari syndrome (BCS) and portal vein thrombosis (PVT) is unclear. Therefore, we aimed to evaluate the prevalence of the JAK2V617F mutation in such patients and to explore the risk factors associated with the mutation. Methods: All consecutive patients with BCS and PVT diagnosed between September 2009 and May 2011 were prospectively enrolled in the observational study and underwent the JAK2V617F mutation detection. Results: Prevalence of the JAK2V617F mutation was 4.3% (4/92) in patients with primary BCS, 26.6% (17/64) in non‐malignant and non‐cirrhotic patients with PVT, and 1.4% (1/71) in cirrhotic patients with PVT. All BCS patients with the JAK2V617F mutation had both platelet count (PLT) of above 100 × 10⁹/L (range, 107–188 × 10⁹/L) and splenomegaly. In non‐malignant and non‐cirrhotic patients with PVT, higher PLT and older ages were the independent predictors of the JAK2V617F mutation. Further, the difference in PLT between the patients with and without the mutation displayed greater significance in the subgroup of patients with splenomegaly (P < 0.0001), but the statistical significance disappeared in the subgroup of patients with splenectomy (P = 0.1312). Conclusions: The low prevalence of the JAK2V617F mutation in patients with BCS suggests that myeloproliferative neoplasm should be an uncommon etiological factor of BCS in China. Routine screening for the JAK2V617F mutation might be recommended in non‐malignant and non‐cirrhotic patients with PVT, but not in cirrhotic patients with PVT. The coexistence of higher PLT and splenomegaly might be closely associated with the JAK2V617F mutation.     

Activated protein C resistance: a comparison between two clotting assays and their relationship to the presence of the factor V Leiden mutation

Resistance to the anticoagulant effect of activated protein C (APC resistance), a frequent abnormality in patients with a history of venous thrombosis, is known to be due, in the large majority of cases, to the presence of an abnormal factor V: the factor V Leiden. It is reasonable to surmise that screening for this abnormality should be performed with a clotting method for APC resistance, before submitting the patients with abnormal results to DNA analysis. The present study was performed on 216 individuals enrolled at the Bologna centre, of which 189 were unrelated patients with a history of juvenile venous thromboembolism and 27 were relatives with or without thrombosis. APC resistance was first measured in Bologna by a standard commercial method and then, in Leiden, by an in-house method; DNA analysis was performed in those cases in which at least one of the clotting methods was abnormal. The data obtained confirm the good performance and the optimal positive predictive value for the Leiden mutation (100%) of the Leiden in-house clotting method. Performance of the commercial method was less satisfactory but markedly improved by expressing the data in relation to the values simultaneously obtained with a normal plasma pool. Even with optimal data expression, however, the positive predictive value of the commercial method, versus DNA analysis, did not exceed 88%.
It is concluded that further standardization of the commercial method here evaluated is necessary before it can be widely adopted for the screening of APC resistance and prediction of the presence of factor V Leiden.     

Prevalence of factor V Leiden and prothrombin G20210A in patients with gastric cancer

AIM: To analyze the prevalence of the two commonest thrombophilic mutations, factor V Leiden and prothrom-bin G20210A, in patients with gastric cancer. METHODS: One hundred and twenty-one patients with primary gastric carcinoma and 130 healthy subjects, comparable for age and sex, were investigated. Factor V Leiden was detected by using polymerase chain reaction and restriction enzyme digestion, and prothrombin G20210A gene mutation by allele-specific PCR. RESULTS: Among the 121 cancer patients, factor V Leiden was found in 4 cases (GA genotype: 3.3%) and prothrombin G20210A in 10 cases (GA genotype: 8.3%). Of the 130 control subjects, factor V Leiden was detected in 6 cases (GA genotype: 4.6%) and prothrombin G20210A in 8 cases (GA genotype: 6.1%). No double heterozygous carriers of both mutations were found in either group. The prevalence of both factor V Leiden and prothrombin G20210A variant was not statistically different between the cancer patients and the healthy subjects. CONCLUSION: Our study suggests that, in gastric cancer, the risk factors of thrombophilic cancer state are on acquired rather than on a genetic basis and that prothrombin G20210A does not seem to be a cofactor in gastric cancer pathogenesis.     

Prevalence of factor V Leiden and prothrombin G20210A mutations in unselected patients with venous thromboembolism

We determined the prevalence of factor V Leiden and of prothrombin G20210A mutations in a cohort of unselected outpatients (n = 748) referred for suspected deep vein thrombosis (DVT) and/or pulmonary embolism (PE) and a pooled analysis of similar studies was also performed. Based on the clinical presentation, the prevalence of factor V Leiden was 15.7% in the 83 patients with DVT and 14.1% in the 99 patients with PE compared with 5.3% in patients without DVT and/or PE (control group). The prevalence of the prothrombin G20210A mutation did not differ among the three groups (3.9% for controls, 4. 8% for DVT and 3.9% for PE patients). We then divided the 99 patients with PE by separately analysing those with PE but without DVT (n = 57) and those with PE and DVT (n = 42). Compared with the control group, the prevalence of factor V Leiden was 10.5%, odds ratio (OR) 2.10 [95% confidence interval (95% CI) 0.68-5.45] in patients with primary PE and 19.1%, OR 4.20 (95% CI 1.54-10.30) in patients with DVT and PE. For the prothrombin G20210A mutation, no statistically significant differences were found between the control group and the three other groups. In conclusion, our data and the pooled analysis indicate that patients with primary PE are less often affected by the factor V Leiden mutation. No statistically significant differences were observed between patients and controls for the prothrombin G20210A mutation.     

Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease

Mild hyperhomocysteinaemia is an established risk factor for deep vein thrombosis (DVT); few data concerning its potential interaction with thrombophilic genotypes are available at the present time. We investigated 121 thrombosis-free individuals and 111 patients with at least one objectively confirmed episode of DVT. A thrombophilic condition (deficiency in antithrombin, protein C and S, factor V Leiden, prothrombin G20210A) was detected in 25.2% of the patients; mutant factor V or prothrombin genotypes were present in 6.6% of the controls. Hyperhomocysteinaemia was found in 14.4% of patients and 3. 3% of the controls, with a 3.7-fold increase in risk for DVT (95% CI 1.1-12.3). Adoption of different cut-off levels for definition of hyperhomocysteinaemia did not substantially change the magnitude of the risk. Carriership of both hyperhomocysteinaemia and factor V Leiden or prothrombin G20210A was detected in 2.7% of patients for each combination and in none of the controls. An approximate estimate of 30-fold increased risk in carriers of both hyperhomocysteinaemia and factor V Leiden and 50-fold increased risk in carriers of both hyperhomocysteinaemia and prothrombin G20210A was calculated, suggesting a synergistic interaction between hyperhomocysteinaemia and such thrombophilic genotypes. Yet statistical analysis is highly unstable due to the small number of individuals with combined defects. Further investigations on large series of patients are needed.     

Epidemiological aspects of Budd-Chiari in Egyptian patients: a single-center study

AIM:To describe the socio-demographic features,etiology,and risk factors for Budd-Chiari syndrome(BCS) in Egyptian patients.METHODS:Ninety-four Egyptian patients with confirmed primary Budd-Chiari syndrome were presented to the Budd-Chiari Study Group(BCSG) and admitted tothe Tropical Medicine Department of Ain Shams University Hospital(Cairo,Egypt) . Complete clinical evaluation and laboratory investigations,including a throm bophiliaworkup and full radiological assessment,were performed to determine under...     

Case report: portal vein thrombosis associated with hereditary protein C deficiency: a report of two cases

Protein C deficiency is one of the causes of curable or preventable portal vein thrombosis. We report two patients of portal vein thrombosis associated with hereditary protein C deficiency. The first patient presented with continuous right upper quadrant pain and high fever. The abdominal sonography revealed normal liver parenchyma but portal vein and superior mesenteric vein thrombosis. Based on a 55% (normal 70-140%) plasma protein C level, he was diagnosed as having protein C deficiency. A trace of his family history showed that his elder brother also had protein C deficiency with a 50% plasma C level. Both patients received anticoagulant therapy. The younger brother showed good response. Unfortunately, the elder one suffered from recurrent episodes of variceal bleeding and received a life-saving splenectomy and devascularization. We herein remind clinicians that early screening and therapy are helpful in preventing late complications of protein C deficiency with portal vein thrombosis.