Familial Thrombosis Research Articles

AN ENU MUTAGENESIS SCREEN FOR DOMINANT GENETIC MODIFIERS OF THROMBOSIS IN THE FACTOR 5 LEIDEN MOUSE

ISTH07A1_P-W-473: Contact View [P-W-473] AN ENU MUTAGENESIS SCREEN FOR DOMINANT GENETIC MODIFIERS OF THROMBOSIS IN THE FACTOR 5 LEIDEN MOUSE R.J. Westrick, S.L. Manning, M.E. Winn, G.M. Stotz, E. Sanford, D. Ginsburg. Human Genetics; Howard Hughes Medical Institute; Internal Medicine; Life Sciences Institute, University of Michigan, Ann Arbor, United States Introduction: Factor V Leiden, (F5Q) is the most common inherited risk factor for venous thrombosis. However, a relatively small percentage of people carrying F5Q will develop venous thrombosis in their lifetimes. This variability results from complex interactions between the environment and unknown genetic factors (modifier genes). We previously identified a synthetically lethal interaction between mice inheriting two copies of F5Q (F5Q/Q) and partial Tfpi (Tfpi+/-) deficiency (F5Q/Q Tfpi+/-). Complete Tfpi deficiency in mice is embryonic lethal, whereas heterozygosity is compatible with normal survival. However, all mice inheriting F5Q/Q and Tfpi+/die of thrombosis shortly after birth. Methods: The F5Q/Q Tfpi+/lethal interaction was utilized as the basis for a sensitized ENU mutagenesis screen designed to uncover novel dominant suppressor mutations that alter the hemostatic balance. Male F5Q/Q mice were ENU mutagenized and bred to F5Q/+ Tfpi+/double heterozygous females. Surviving offspring were analyzed to identify rescued mice with the F5Q/Q Tfpi+/genotype. Results: Analysis of 5600 G1 offspring to date has identified 64 mice that survived to weaning. Of the 12 F5Q/Q Tfpi+/mutants tested for heritability, five produced additional F5Q/Q Tfpi+/progeny, demonstrating that the associated thrombosis suppressor is heritable. The latter progeny have been genotyped with a panel of markers spanning the genome. For one of these mutant lines, this analysis has mapped the corresponding suppressor mutation to a small region on Chromosome 9, with fine mapping to identify the corresponding gene underway. Conclusions: We have demonstrated the existence of novel dominant mutations that improve hemostatic balance leading to survival of F5Q/Q Tfpi+/mice. Characterization of the genes may provide novel insight into the regulation of hemostasis, as well as identifying potential candidates for thrombosis modifiers in humans. Westrick RJ, Manning SL, Winn ME, Stotz GM, Sanford E, Ginsburg D. AN ENU MUTAGENESIS SCREEN FOR DOMINANT GENETIC MODIFIERS OF THROMBOSIS IN THE FACTOR 5 LEIDEN MOUSE. J Thromb Haemost 2007; 5 Supplement 2: P-W-473 Date: Wednesday, July 11, 2007 Session Info: Poster: Thrombophilia and familial thrombosis Room: Exhibition Area file:///E|/working/RAJAN/Wednesday/P-W-473.htm [1/22/2014 3:39:03 PM]

Thrombose aiguë de la veine mésentérique supérieure. Étude rétrospective de neuf cas

Aim of the study To determine diagnostic modalities and both immediate and long-term treatment of superior mesenteric venous thrombosis. Patients and methods Retrospective study from 1997 to 2004 in two institutions concerning patients with superior mesenteric vein thrombosis. Results Nine patients (all males, mean age = 55 years), were included. Abdominal pain (100%), vomiting (44%), and bowel activity disorders (44%) were the most common symptoms. A personal or familial thrombosis history was present in 67% of patients. A genetic predisposing factor of thrombosis was present in 78% of patients. The diagnosis was established with CT-scan in 8 cases with a mean delay of 8 days. Treatment was exclusively medical in 33% of patients and included surgery in 67%. All operated patients underwent resection for bowel infarction and only one had immediate anastomosis. All enterostomies were subsequently closed. No patient died. Conclusion Diagnosis of superior mesenteric vein thrombosis is frequently delayed and relies on CT-scan with intravenous contrast. Prognosis is globally favourable but depends on early application of anticoagulation therapy. In case of surgery, bowel-sparing resection is indicated and enterostomies are often needed. Genetic disorders predisposing to thrombosis are very frequent, that may indicate prolonged even definitive anticoagulation therapy.

Family History for Venous Thromboembolism and the Risk for Recurrence

Purpose The relevance of a family history for venous thromboembolism with regard to the likelihood for recurrence is unknown. Subjects and methods We studied 826 patients for an average of 36 months after a first unprovoked venous thromboembolism and withdrawal of oral anticoagulation. Patients with cancer, lupus anticoagulant, or deficiency of antithrombin, protein C, or protein S were excluded. The study endpoint was objective evidence of recurrent symptomatic venous thromboembolism. Results Recurrence for venous thromboembolism was recorded in 23 of 190 patients (12.1%) with a family history (at least one affected first-degree family member) and in 79 of 636 patients (12.4%) without familial thrombosis (relative risk for recurrence 1.0; 95% confidence interval, 0.7-1.6; P = .9). At 5 years, the likelihood for recurrence was 20% among patients with a family history for venous thromboembolism and 18% among those without a family history for venous thromboembolism ( P = .9). Risk determinants for venous thromboembolism including factor V Leiden, factor II G20210A, and high factor VIII were not statistically different between the 2 groups. Conclusion A family history for venous thromboembolism does not segregate patients into high- or low-risk categories and is not suitable to identify patients at increased risk for recurrent venous thromboembolism.

Role of gene polymorphism in development of thromboses

The development of thromboses is one of the most common causes of morbidity and mortality in the Western world. The perturbation of haemostasis is the central event in the pathogenesis of all thromboses. Most patients with thromboses have no recognisable associated haemostatic disorders. However, some patients do manifest hereditary hypercoagulable states, which contribute to the development of thromboses as well as other clinical manifestations, such as miscarriages and foetal complications. The major determinants of thrombosis include both environmental influences and genetic factors. Transient or long-lasting environmental influences may play important roles in arterial and venous thromboses. Haemostatic perturbance may also be genetically determined and exert a life-long influence. Specific mutations of genes predisposed to thrombosis, such as deficiency of antithrombin, protein C, or protein S, are found in relatively small number of families. In the absence of genetic deficiencies, thrombosis occurs in the older population, largely within the context of marked environmental influences (such as surgery, obesity, and malignancy). In contrast, familial thrombosis, associated with gene mutation, is associated with a younger age. The general importance of gene polymorphism was established after the recognition of activated protein C resistance (APCR) due to gene polymorphism G1691A in factor V (Factor V Leiden). This single gene defect increases the risk of venous thrombosis, without interaction with other genetic or environmental risk factors. The development of APCR led to many other investigations of gene polymorphism, such as prothrombin 20210, thrombomodulin, factors in the coagulation and fibrinolytic system, glycoproteins of platelet membranes, as well as polymorphism C677T of methylene tetrahydrofolate reductase. The number of potential genetic risk factors for occlusive thrombotic disease has increased significantly. Most of these gene polymorphisms increase the risk of venous thrombosis but there is no strong evidence of their influence as far as arterial thrombosis is concerned.

Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT)

Reliable risk estimates for venous thrombosis in families with inherited thrombophilia are scarce but necessary for determining optimal screening and treatment policies. In the present analysis, we determined the risk of a first venous thrombotic event in carriers of a thrombophilic defect (i.e. antithrombin-, protein C- or protein S deficiency, or factor V Leiden). The asymptomatic carriers had been tested prior to this study in nine European thrombosis centers because of a symptomatic carrier in the family, and were followed prospectively for 5.7 years on average between March 1994 and January 2001. Annually, data were recorded on the occurrence of risk situations for venous thrombosis and events (e.g. venous thrombosis, death). Twenty-six of the 575 asymptomatic carriers (4.5%) and seven of the 1118 controls (0.6%) experienced a first deep venous thrombosis or pulmonary embolism during follow-up. Of these events, 58% occurred spontaneously in the carriers compared with 43% in the controls. The incidence of first events was 0.8% per year (95% CI 0.5-1.2) in the carriers compared with 0.1% per year (95% CI 0.0-0.2) in the controls. The highest incidence was associated with antithrombin deficiency or combined defects, and the lowest incidence with factor V Leiden. The incidence of venous events in asymptomatic individuals from thrombophilic families does not exceed the risk of bleeding associated with long-term anticoagulant treatment in the literature (1-3%).

The Incidence of Chronic Lymphocytic Leukemia in the General Population.

Background. Chronic Lymphocytic Leukemia is the most frequent leukemia in the Western countries (Rozman, 1995) but its incidence is not well established. Epidemiological data are based on reports from tumour registries, with an estimated incidence lower than 3-cases/100000 pts-year. Tumour registries can however underestimate the incidence of CLL as highlighted by the 37% higher incidence reported in a selected population of Veterans (Zent, 2000). We aimed to assessing the incidence of CLL in a population-based cohort from an epidemiological survey on familial thrombosis, (Tosetto, 2003) which was followed for at least 8 years.Material and Methods. 15109 healthy people from 18 to 65 years of age in the Vicenza township were enrolled in the VITA Project (8017 females and 7092 males, with a median age of 43 years). A clinical history was collected and blood and DNA samples were withdrawn and stored at the time of enrolment. The study begun in 1993 and ended in 1996. Patients with a diagnosis of CLL (ICD-9 code 204) were traced using data from the Veneto Region Health Service database, which records all hospital admission for residents in the enrolment area. Moreover, the database encompasses data of all the subjects visited in the Vicenza Hematology Department, the unique hematological facility of the area, even if not subsequently admitted to the hospital. Diagnosis of CLL was validated if based on morphological and immunophenotypic data according to currently accepted criteria (Cheson, 1988; IWCC, 1989; Rozman, 1995).Results. Six out 15109 people were diagnosed with a CLL (4 males). The median follow-up for the entire cohort was 8.2 years and the total time of exposure was 121000 pts-year. Incidence of CLL is estimated to be 4.9 cases/100000 pts-year (CI: 1.8–10.7). Diagnosis of CLL was done from 36 to 97 months after the enrolment. Mean age at diagnosis was 66 years (61 – 70). At the time of enrolment in the study, all of the patients had a normal WBC. Three persons presented an immunoglobulin VH gene rearrangement, 32, 54 and 57 months before diagnosis. All of the patients were asymptomatic at diagnosis. The median follow-up of all the subjects was 28 months (7 – 57 months). Only one of them became symptomatic and needed a treatment, 40 months after the diagnosis.Conclusions. According to our data, the incidence of CLL appears to be higher than assessed so far. In our opinion it's noteworthy that the estimation is based on data of subjects evaluated in a clinical setting and not from tumour or disease registries. In fact it could be still underestimated comparing the young median age of our cohort with that usually reported at diagnosis (Rozman, 1995). Moreover, the comparison of our data with those available could suggest that only a quote of the cases might be usually diagnosed. Finally, the presence of the Ig VH gene rearrangement at the time of the enrolment suggests that the disease may be present a very long time before any clinical evidence.

Familial thrombophilia and lifetime risk of venous thrombosis

We started a large multicenter prospective follow-up study to provide reliable risk estimates of venous thrombosis in families with various thrombophilic defects. This paper describes data collected at study entry on venous events experienced before study inclusion, i.e. the baseline data. All individuals (probands, relatives) registered in nine European thrombosis centers with the factor (F)V Leiden mutation, a deficiency of antithrombin, protein C or protein S, or a combination of these defects, were enrolled between March 1994 and September 1997. As control individuals, partners, friends or acquaintances of the thrombophilic participants were included. Incidence and relative risk of objectively confirmed venous thrombotic events (VTEs) prior to entry were calculated for the relatives with thrombophilia and the controls. Of the 846 relatives with thrombophilia (excluding probands), 139 (16%) had experienced a VTE with an incidence of 4.4 per 1000 person years. Of the controls, 15 of the 1212 (1%) controls had experienced a VTE with an incidence of 0.3 per 1000 person years. The risk of venous thrombosis associated with familial thrombophilia was 15.7 (95% CI 9.2-26.8) and remained similar after adjustment for regional and sex-effects (16.4; 95% CI 9.6-28.0). The highest incidence per 1000 person years was found in relatives with combined defects (8.4; 95% CI 5.6-12.2), and the lowest incidence was found in those with the FV Leiden mutation (1.5; 95% CI 0.8-2.6). Considerable differences in the lifetime risk of VTE were observed among individuals with different thrombophilia defects.

Thrombophilic polymorphisms – factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations – and preterm birth

To evaluate the influence of three common thrombophilic polymorphisms, factor V Leiden (FV), prothrombin G20210A (PT), and methylenetetrahydrofolate reductase (MTHFR) C677T mutations, on preterm birth of unknown cause. A single-centre case-control study of women with preterm infants < or =35 weeks of gestation, in whom obvious maternal, uterine, and fetal causes responsible for preterm birth were excluded (n = 35). The controls were 54 women with term infants hospitalised in the same ward. There were no significant differences between the groups of mothers in history of fetal loss, venous or familial thrombosis, or previous preterm birth. FV was found in 8.6% of the cases, PT in 5.7%, and MTHFR mutation (homozygous) in 4.8% compared with 5.4% (p=0.292, OR 1.594, CI95% 0.303-8.384), 7.4% (p=0.379, OR 0.758, CI95% 0.131-4.374), and 4.5% (p = 0.485, OR 1.050, CI95% 0.090-12.276), respectively, in the controls. Differences in the three thrombophilic polymorphisms in the two groups of infants were also not significant. We could not demonstrate a distinct association between these thrombophilic polymorphisms and preterm birth.

Two electrophoretic fibrinogen variants found in patients with normal coagulation and familial thrombosis

Two electrophoretic fibrinogen variants found in patients with normal coagulation and familial thrombosis

Evidence Tor Inherited Risk of Thrombosis in Families with Premature Myocardial Infarction

Evidence Tor Inherited Risk of Thrombosis in Families with Premature Myocardial Infarction

Characterization of the human prostaglandin H synthase 1 gene (PTGS1): exclusion by genetic linkage analysis as a second modifier gene in familial thrombosis.

Genetic evidence from a large Vermont kindred indicates that an unknown gene promotes thrombosis when inherited in conjunction with type I protein C deficiency. Cyclooxygenase-1 [prostaglandin H synthase 1 gene (PTGS1)] was tested as a plausible candidate for the unknown gene because of its role in primary hemostasis. The complete sequence of PTGS1 (25 638 nucleotides) was determined from a 37 kb human genomic cosmid clone to characterize intronic regions and subsequently to allow the search for mutations by direct sequencing of genomic DNA. Northern blot analysis confirms usage of a newly described distal poly-adenylation signal. Short tandem repeat (STR) sequences found in intron 2 and the 3' flanking region were developed as new genetic markers for PTGS1. The position of PTGS1 was refined on the CHLC chromosome 9 linkage map using the new markers scored in four Centre d'Etude du Polymorphisme Humain families and multipoint linkage analysis. Direct sequencing of DNA from members of the Vermont kindred led to the discovery of two new single nucleotide polymorphisms (SNPs) that give rise to non-conservative amino acid changes in the signal peptide (Arg(8) to Trp and Pro(17) to Leu) of cyclooxygenase-1. Linkage analysis of the SNP and STR markers indicated that PTGS1 is not the interacting gene associated with an increased incidence of thrombosis in the Vermont kindred.

Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family

The study of the molecular bases of thrombophilia in a large family with 4 symptomatic members is reported. Three thrombophilic genetic components (FV R506Q, FV H1299R, and PT 20210G/A), all affecting the activity of the prothrombinase complex, were detected alone and in combination in various family members. In addition, a newly identified missense mutation (factor V [FV] Y1702C), causing FV deficiency, was also present in the family and appeared to enhance activated protein C (APC) resistance in carriers of FV R506Q or FV H1299R by abolishing the expression of the counterpart FV allele. The relationships between complex genotypes, coagulation laboratory findings, and clinical phenotypes were analyzed in the family. All symptomatic family members were carriers of combined defects and showed APC resistance and elevated F1 + 2 values. Evidence for the causative role of the FV Y1702C mutation, which affects a residue absolutely conserved in all 3 A domains of FV, factor VIII, and ceruloplasmin, relies on (1) the absolute cosegregation between the mutation and FV deficiency, both in the family and in the general population; (2) FV antigen and immunoblot studies indicating the absence of Y1702C FV molecules in plasma of carriers of the mutation, despite normal levels of the FV Y1702C messenger RNA; and (3) molecular modeling data that support a crucial role of the mutated residue in the A domain structure. These findings help to interpret the variable penetrance of thrombosis in thrombophilic families and to define the molecular bases of FV deficiency. (Blood. 2000;96:1443-1448)

Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family

AbstractThe study of the molecular bases of thrombophilia in a large family with 4 symptomatic members is reported. Three thrombophilic genetic components (FV R506Q, FV H1299R, and PT 20210G/A), all affecting the activity of the prothrombinase complex, were detected alone and in combination in various family members. In addition, a newly identified missense mutation (factor V [FV] Y1702C), causing FV deficiency, was also present in the family and appeared to enhance activated protein C (APC) resistance in carriers of FV R506Q or FV H1299R by abolishing the expression of the counterpart FV allele. The relationships between complex genotypes, coagulation laboratory findings, and clinical phenotypes were analyzed in the family. All symptomatic family members were carriers of combined defects and showed APC resistance and elevated F1 + 2 values. Evidence for the causative role of the FV Y1702C mutation, which affects a residue absolutely conserved in all 3 A domains of FV, factor VIII, and ceruloplasmin, relies on (1) the absolute cosegregation between the mutation and FV deficiency, both in the family and in the general population; (2) FV antigen and immunoblot studies indicating the absence of Y1702C FV molecules in plasma of carriers of the mutation, despite normal levels of the FV Y1702C messenger RNA; and (3) molecular modeling data that support a crucial role of the mutated residue in the A domain structure. These findings help to interpret the variable penetrance of thrombosis in thrombophilic families and to define the molecular bases of FV deficiency.

Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

AbstractProtein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1.5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons withPROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency.

Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease

Venous thromboembolic disorders form a spectrum of conditions characterized by in situ thrombus formation and the variable presence of embolic manifestations. The clinical presentation depends to a large extent on the site and extent of thrombus formation and on the underlying cause. In the absence of genetic deficiencies, thrombosis occurs in the older population, largely in the context of marked environmental influences such as surgery, obesity, and underlying malignancy. In contrast, at the other extreme, familial thrombosis associated with mutations in genes for protein S, protein C, or antithrombin is associated with younger age of onset, lesser environmental stimulus, and thrombus formation often in unusual sites. There is an increasing awareness of the importance of hemostatic mechanisms in the pathogenesis of venous thrombosis. The hemostatic process comprises coagulation and fibrinolytic systems with activators, zymogens, cofactors, surfaces (such as platelets), and inhibitors. The function and regulation of these composite systems and factors have been extensively studied. Understanding their functional integration in vivo, however, still presents a major challenge. A starting point for a simplified model of integration envisages a balance between procoagulant (clot-promoting) and anticoagulant (clot-preventing) mechanisms. This balance serves to prevent an explosive generation of thrombin when coagulation is triggered. The balance is determined by the (functional) levels of all coagulation and fibrinolytic factors, with increases in the levels of coagulation factors and decreases in the levels of both fibrinolytic factors and natural inhibitors being procoagulant. The role of inhibitory mechanisms in preventing venous occlusion was established after the identification of the link between inherited deficiencies of antithrombin, protein C, protein S, and venous thrombosis during the 1960s and the 1970s. The general importance of the anticoagulant pathway involving protein C and protein S was established by the widespread prevalence among white populations and the clinical consequences of the phenotype of activated protein C resistance (APCR) and its main causative gene mutation, factor V G1691A (factor V Arg506Gln, factor V Leiden). There has been slower appreciation of the procoagulant effect of increased levels of coagulation factors in venous disease, but recent work has highlighted the likely importance of prothrombin and factor VIII levels in this regard.

High Levels of Factor VIII and Venous Thrombosis

The first families with a tendency to venous thrombosis were reported in the early 1900s. In 1965, Egeberg reported a family with thrombophilia and an identified hereditary defect (antithrombin deficiency). In the early 1980s, deficiencies of other natural anticoagulants – protein C and protein S – were shown to be associated with venous thrombosis in families with familial thrombophilia. Recently, several other blood abnormalities have been described that increase the risk of thrombosis: resistance to activated protein C, usually the result of a mutation in factor V (factor V 1691A or factor V Leiden), a mutation in the prothrombin gene (PT20210A), and high levels of clotting factor VIII (5–8).

Gene-Gene and Gene-Environment Interactions Determine Risk of Thrombosis in Families With Inherited Antithrombin Deficiency

To analyze inherited antithrombin deficiency as a risk factor for venous thromboembolism in various conditions with regard to the presence or absence of additional genetic or acquired risk factors, we compared 48 antithrombin-deficient individuals with 44 nondeficient individuals of 14 selected families with inherited antithrombin deficiency. The incidence of venous thromboembolism for antithrombin deficient individuals was 20 times higher than among nondeficient individuals (1.1% v 0.05% per year). At the age of 50 years, greater than 50% of antithrombin-deficient individuals had experienced thrombosis compared with 5% of nondeficient individuals. Additional genetic risk factors, Factor V Leiden and PT20210A, were found in more than half of these selected families. The effect of exposure to 2 genetic defects was a 5-fold increased incidence (4.6% per year; 95% confidence interval [CI], 1.9% to 11.1%). Acquired risk factors were often present, determining the onset of thrombosis. The incidence among those with exposure to antithrombin deficiency and an acquired risk factor was increased 20-fold (20.3% per year; 95% CI, 12.0% to 34.3%). In conclusion, in these thrombophilia families, the genetic and environmental factors interact to bring about venous thrombosis. Inherited antithrombin deficiency proves to be a prominent risk factor for venous thromboembolism. The increased risks among those with exposure to acquired risk factors should be considered and adequate prophylactic anticoagulant therapy in high-risk situations seems indicated in selected families with inherited antithrombin deficiency.

The molecular genetics of familial venous thrombosis

In the past few years, important advances have been made in the identification of factors predisposing to familial thrombophilia. Particular attention has been paid to the characterization of known inherited defects and their genotype–phenotype relationship, and to studying the interaction between single or multiple inherited conditions and acquired risk factors for venous thrombosis. The recent discovery of ‘new’ and very common genetic lesions predisposing to thrombosis has greatly expanded the interest in this field. Hereditary predisposition to venous thrombosis may be related to lesions in one or more of 10–15 genes encoding antithrombin, Protein C, Protein S, Factor V, prothrombin, enzymes of the homocysteine metabolic pathway, fibrinogen, heparin cofactor II, plasminogen and thrombomodulin. About 500 different gene lesions (substitutions, deletions, insertions) have so far been reported to affect these genes in patients with thrombotic disease. Because there are potentially multiple interactions between genetic and environmental factors, familial thrombophilia is now considered to be a multifactorial disease. The aim of this chapter is to review aspects of the molecular genetics of familial thrombophilia. In particular, those gene/protein defects for which there is convincing evidence of an association with familial thrombosis will be examined in detail.

Résistance à la protéine C activée et thrombose portale: deux nouveaux cas et revue de la littérature

Resistance to activated protein C is the most common inherited factor at the origin of deep venous thrombosis. As portal vein thrombosis is rare, causes such as cirrhosis, intra-abdominal infection, primary hepatocellular carcinoma, myeloproliferative disorders or coagulation abnormalities must be investigated. We report two cases of portal vein thrombosis associated with resistance to activated protein C. This association is not frequent, as only 12 cases have been reported in the literature. These studies show that resistance to activated protein C was rarely the only factor, as other prothrombotic abnormalities were present in more than 70% of cases. Resistance to activated protein C is rarely associated with portal vein thrombosis. When present, other causes should not be overlooked. The potential existence of resistance to activated protein C should be systematically investigated in case of either portal vein thrombosis in patients with personal or familial thrombosis history, association with multiple thrombosis, or when the disease etiology remains unknown.

Can Low Level of von Willebrand Factor Decrease the Risk of Thrombosis in Families with Antithrombin or Protein C Deficiency?

Can Low Level of von Willebrand Factor Decrease the Risk of Thrombosis in Families with Antithrombin or Protein C Deficiency? -