ABSTRACT
BACKGROUND: Acquired hemophilia A (AHA) is a rare autoimmune disorder due to autoantibodies against Factor VIII, with a high mortality risk. Treatments aim to control bleeding and eradicate antibodies by immunosuppression. International recommendations rely on registers and international expert panels. METHODS: CREHA, an open-label randomized trial, compared the efficacy and safety of cyclophosphamide and rituximab in association with steroids in patients with newly diagnosed AHA. Participants were treated with 1 mg/kg prednisone daily and randomly assigned to receive either 1.5-2 mg/kg/day cyclophosphamide orally for 6 weeks, or 375 mg/m2 rituximab once weekly for 4 weeks. The primary endpoint was complete remission over 18 months. Secondary endpoints included time to achieve complete remission, relapse occurrence, mortality, infections and bleeding, and severe adverse events. RESULTS: Recruitment was interrupted because of new treatment recommendations after 108 patients included (58 cyclophosphamide, 50 rituximab). After 18 months, 39 cyclophosphamide patients (67.2 %) and 31 rituximab patients (62.0 %) were in complete remission (OR 1.26; 95 % CI, 0.57 to 2.78). In the poor prognosis group (FVIII < 1 IU/dL, inhibitor titer > 20 BU mL-1), significantly more remissions were observed with cyclophosphamide (22 patients, 78.6 %) than with rituximab (12 patients, 48.0 %; p = 0.02). Relapse rates, deaths, severe infections, and bleeding were similar in the 2 groups. In patients with severe infection, cumulative doses of steroids were significantly higher than in patients without infection (p = 0.03). CONCLUSION: Cyclophosphamide and rituximab showed similar efficacy and safety. As first line, cyclophosphamide seems preferable, especially in poor prognosis patients, as administered orally and less expensive. FUNDING: French Ministry of Health. CLINICALTRIALS: gov number: NCT01808911.
Subject(s)
Cyclophosphamide , Hemophilia A , Rituximab , Humans , Rituximab/therapeutic use , Hemophilia A/drug therapy , Cyclophosphamide/therapeutic use , Male , Female , Middle Aged , Aged , Immunosuppressive Agents/therapeutic use , Adult , Factor VIII/therapeutic use , Factor VIII/immunology , Aged, 80 and overABSTRACT
Thrombin generation assay (TGA) is a useful tool to evaluate the initiation, propagation and inhibition of coagulation. TGA is a global test that is used to assess hemorrhagic risk in hemophilia patients, but it can also be used to study hypercoagulable states. The interest of TGA is to screen for cardiovascular risk, which is regularly associated with autoimmune disease (AID) such as antiphospholipid syndrome. Indeed, TGA has been used to evaluate hypercoagulability in patients with antiphospholipid syndrome treated with rivaroxaban versus warfarin. In other AIDs without thrombotic events, TGA measurement is elevated, mainly in rheumatoid arthritis (RA), systemic lupus erythematosus and Behçet's disease. These findings in RA are correlated with the inflammatory activity of the disease. In systemic lupus erythematosus and Behçet's disease, TGA appears to reflect disease activity. In conclusion, TGA remains relatively under used in the clinical evaluation of AID, but it could play a greater role in the evaluation of certain potentially thrombogenic treatments in AID. Finally, TGA helps measuring AID activity, due to the clearlink between coagulation and inflammation, despite some limitations of interpretation mainly due to a lack of standardization.
Subject(s)
Antiphospholipid Syndrome , Autoimmune Diseases , Antiphospholipid Syndrome/diagnosis , Autoimmune Diseases/diagnosis , Autoimmune Diseases/epidemiology , Blood Coagulation , Humans , Rivaroxaban , ThrombinABSTRACT
INTRODUCTION: Hemolacria is a rare hemorrhagic syndrome characterized by bloody tears. The most common etiologies are inflammation, infection or laceration. However, other rarer diseases may also cause this clinical manifestation. CASE REPORT: We describe the case of a 14-year-old male patient hospitalized for hemolacria. A history of von Willebrand disease was present in his family, diagnosed in his mother and sister, but absent in our patient. A vitamin C dosage was obtained in our patient and revealed scurvy consecutive to malnutrition. After having excluded other bleeding symptoms like bruises we retained vitamin C deficiency as the etiology of the hemorrhagic syndrome. CONCLUSION: Bloody tears are a rare clinical manifestation and the etiology may be difficult to determine. Bloody tears are a rare clinical manifestation of hemorrhagic syndrome. To determine the underlying etiology, screening should consider all possible causes including the rarest.
Subject(s)
Eye Hemorrhage/diagnosis , Scurvy/diagnosis , Tears , Adolescent , Diagnosis, Differential , Eye Hemorrhage/etiology , Humans , Male , Malnutrition/complications , Malnutrition/diagnosis , Scurvy/etiology , SyndromeABSTRACT
A 31-year-old man with mild hemophilia B developed a herniated disc treated with prednisolone for back pain. Surprisingly, hemostasis result tests performed before epidural infiltration were a normal activated partial thrombin time at 36.1â¯s. (normal range 27.9-37.7â¯s.) and factor IX (FIX) level 76% (normal range>70%), 13 days after prednisolone introduction. After a second control with a normal FIX level and a second genetic confirmation of hemophilia, no FIX concentrates was administered to perform the infiltration, which occurred without hemorrhagic complication. This new case of FIX normalization showed the necessity to have a perfect knowledge of patient's treatment to avoid misdiagnosis and a temporary normal hemostasis permit to perform epidural infiltration without replacement therapy.
Subject(s)
Factor IX/metabolism , Hemophilia B/blood , Intervertebral Disc Displacement/blood , Intervertebral Disc Displacement/therapy , Prednisolone/administration & dosage , Adult , Humans , Male , Partial Thromboplastin TimeABSTRACT
PURPOSE: Antiphospholipid syndrome (APS) is a clinico-biological syndrome, which associates vascular injury and persisting antiphospholipid antibodies (aPL). Patients with clinical symptoms of APS but without aPL are defined as "seronegative APS" (SNAPS). The aim of this study was to evaluate antiphosphatidylethanolamine antibody (aPE) investigation in patients with SNAPS suspicion. METHODS: This retrospective study was conducted in patients with SNAPS suspicion. A homemade enzyme-linked immunosorbent assay (ELISA) was used to search for aPE. The results of this homemade method were compared with those from a global screening ELISA. RESULTS: Two hundred twenty-eight patients with SNAPS suspicion were included. Among them, 58.3% had a thrombotic event. The homemade ELISA found positive persisting aPE in 23 patients (10%): 15 with a thrombotic event, 6 with obstetrical morbidity and 2 with a combined event. The global screening ELISA was positive in only 11 of these 23 patients (47.8%). CONCLUSION: These results suggest the implication of aPE in SNAPS.
Subject(s)
Antibodies, Antiphospholipid/blood , Antiphospholipid Syndrome/blood , Antiphospholipid Syndrome/immunology , Phosphatidylethanolamines/immunology , Adult , Aged , Antiphospholipid Syndrome/diagnosis , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Retrospective StudiesABSTRACT
INTRODUCTION: Factor XIII (FXIII) deficiency is a rare hemorrhagic disorder whose early diagnosis is crucial for appropriate treatment and prophylactic supplementation in cases of severe deficiency. International guidelines recommend a quantitative FXIII activity assay as first-line screening test. FXIII antigen measurement may be performed to establish the subtype of FXIII deficiency (FXIIID) when activity is decreased. METHODS: The aim of this multicenter study was to evaluate the analytical and diagnostic levels of performance of a new latex immunoassay, K-Assay® FXIII reagent from Stago, for first-line measurement of FXIII antigen. Results were compared to those obtained with the Berichrom® FXIII chromogenic assay for measurement of FXIII activity. Of the 147 patient plasma samples, 138 were selected for analysis. RESULTS: The accuracy was very good, with intercenter reproducibility close to 7%. Five groups were defined on FXIII activity level (<5% (n = 5), 5%-30% (n = 23), 30%-60% (n = 17), 60%-120% (n = 69), above 120% (n = 24)), without statistical differences between activity and antigen levels (P value >0.05). Correlation of the K-Assay® with the Berichrom® FXIII activity results was excellent (r = 0.919). Good agreement was established by the Bland and Altman method, with a bias of +9.4% on all samples, and of -1.4% for FXIII levels lower than 30%. One patient with afibrinogenemia showed low levels of Berichrom® FXIII activity but normal antigen level and clot solubility as expected. CONCLUSIONS: The measurement of FXIII antigen using the K-Assay® is a reliable first-line tool for detection of FXIII deficiency when an activity assay is not available.
Subject(s)
Factor XIII Deficiency/blood , Factor XIII/analysis , Factor XIII/metabolism , Female , France , Humans , MaleABSTRACT
Acquired A haemophilia is a rare but severe autoimmune disease. It is caused by autoantibodies against the coagulation factor VIII. These autoantibodies could have different consequences: no effect, inhibition of factor VIII or factor VIII activity hydrolyzing. In about half of the cases, no cause is associated with the disorder [idiopathic acquired A haemophilia]. But in remaining 50% of the patients, some circumstances could be associated with acquired hemophilia: post-partum, autoimmune disorders, cancer and sometimes malignant blood disorders. The objective of this article was to review the literature about acquired A hemophilia associated with lymphoproliferative diseases.
Subject(s)
Hemophilia A/complications , Lymphoproliferative Disorders/complications , HumansABSTRACT
Although extremely rare, acquired haemophilia A (AHA) can cause severe bleeding, which may be fatal. The underlying causes of autoantibody development are not fully understood. Treatment goals are bleeding control and autoantibody eradication. At the time of our study, there was no consensus on a standard treatment strategy for AHA. Previous data were mainly retrospective or from single-centre cohorts. We conducted a prospective, controlled, registry-based study of patients with AHA in France. The prospective French registry (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise [SACHA]) collected data on prevalence, clinical course, disease associations and outcomes for haemostatic treatment and autoantibody eradication in 82 patients with a 1-year follow-up. Similar to earlier studies, the prevalence of AHA was higher in the elderly, with two thirds of patients aged >70 years. Around half of AHA cases were associated with underlying disease, most commonly autoimmune disease and cancer in younger and older patients respectively. Haemostatic treatment was initially administered to 46% of patients. Complete resolution or improvement of initial bleeding occurred in 22/27 (81%) rFVIIa-treated patients and in all six cases receiving pd-aPCC. The majority of patients (94%) received immunosuppressive therapy, with complete remission at 3 months in 61% (36/59) and in 98% (50/51) at 1 year. Overall mortality was 33%: secondary to bleeding in only three patients but to sepsis in 10. Bypassing agents were effective at controlling bleeding in patients with AHA. Immunosuppressive therapy should be used early but with caution, particularly in elderly patients.
Subject(s)
Hemophilia A/drug therapy , Hemophilia A/epidemiology , Registries , Adult , Age Distribution , Aged , Aged, 80 and over , Autoantibodies/immunology , Cause of Death , Factor VIII/immunology , Female , France/epidemiology , Hemophilia A/complications , Hemophilia A/mortality , Hemorrhage/complications , Hemorrhage/drug therapy , Hemostatics/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Prospective Studies , Recurrence , Treatment OutcomeABSTRACT
Protein Z (PZ) is a vitamin K dependent protein acting as the cofactor of the protein Z dependent inhibitor (ZPI), in the inhibition of activated factor X bound on the phospholipids. Normal plasma protein Z concentrations have wide variations among individuals, partly explained by a genetic control. Several protein Z gene polymorphisms influence plasma concentration, separately and in combination. The role of PZ in blood coagulation regulation has been demonstrated in vitro. The responsibility of low PZ level in the occurrence of thrombosis has been questioned. However, the roles of PZ plasma level and PZ gene polymorphisms remain debated with conflicting results in arterial, venous, or placental thrombosis. These discrepancies can be explained by the heterogeneity of populations chosen as control, by the PZ interindividual variability, by the small size of the cohorts in mainly retrospective studies and perhaps by the lack of real important influence of this protein on coagulation. PZ measurement is not actually considered as a biological marker of thrombophilia. Large prospective studies remain to be done to investigate its possible role in thrombosis.
Subject(s)
Blood Proteins/genetics , Polymorphism, Genetic , Thrombosis/genetics , Cerebral Infarction/genetics , Coronary Disease/genetics , HumansABSTRACT
INTRODUCTION: Anticoagulation clinics and computerized management of chronic oral anticoagulation increase the time spent in the therapeutic range with both mortality and morbidity reduction. Usually, anticoagulation clinics are hospital-based medical care centers. We report the five-year results from a general medicine center (CSCTA) using a computer-assisted management. METHODS: A prospective cohort observational study of 530 primary care patients that were receiving long term oral anticoagulation. RESULTS: Cardiac arrhythmia (55%), heart valve disease and venous thrombo-embolic disease (30%) represented the most common indications of oral anticoagulation. Patients received fluindione, warfarin and acenocoumarol in 80%, 13% and 7%, respectively. The duration of treatment was at least one year in 54% of the cases, and was at least three years in 25% of the cases. The rate of patients that were in average within the therapeutic range (INR 2-3) was 72%, while 12% were under and 16% over the therapeutic range. Corresponding rates were 82, 17 and 1% respectively for all anticoagulation targets (INR 1.5-4.5). Twenty-six bleeding events (4.9 per 100 patient-years) and four thrombotic complications (0.75 per 100 patient-years) occurred. Life-threatening hemorrhage occurred in 1.3 per 100 patient-years. After the equilibration of the anticoagulation, the average delay of control between two consecutive INR was 19 days. CONCLUSION: The results obtained with CSCTA were similar to those reported by other anticoagulation clinics regarding hemorrhagic complications and time spent in the therapeutic range. In contrast, thrombotic events were less frequent. Because of the absence of a control group, a medico-economic analysis could not be performed.
Subject(s)
Anticoagulants/therapeutic use , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , France , Humans , International Normalized Ratio , Male , Middle Aged , Outpatient Clinics, Hospital , Prospective Studies , Young AdultABSTRACT
BACKGROUND AND PURPOSE: Protein Z (PZ), a vitamin Kdependent protein, plays a role in inhibiting coagulation. Its plasma level or PZ gene polymorphisms have been discussed as risk factors for stroke with conflicting results reported between various studies. Only one of these polymorphisms was studied in a cohort of patients suffering from cerebral venous thrombosis (CVT). METHODS: We performed a retrospective genetic study comparing 100 healthy controls to 54 patients referred to our hemostasis unit after CVT occurrence. We compared the distribution of three PZ gene polymorphisms that may influence PZ plasma levels: A-13G in the promoter and G79A in intron F were tested using previously described techniques, and we developed a technique to evaluate the G-103A in intron A. RESULTS: The G79A polymorphism was significantly more frequent in patients than in controls (p = 0.012): the presence of at least one A allele led to an odds ratio of 2.57 with a 95 % confidence interval of 1.23-5.34. The A-13G polymorphism also showed a nonsignificant trend towards a higher prevalence in patients. CONCLUSION: The G79A polymorphism of the PZ gene was shown to be a new independent risk factor for cerebral venous thrombosis. Nevertheless, these results have to be confirmed by a prospective study including plasma PZ evaluation.
Subject(s)
Blood Proteins/genetics , Cerebral Veins , Intracranial Thrombosis/genetics , Polymorphism, Genetic , Venous Thrombosis/genetics , Adult , Blood Proteins/analysis , Cohort Studies , DNA Mutational Analysis , Female , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Risk FactorsABSTRACT
Erythropoietin is a glycoprotein hormone mainly released by the kidney, which stimulates red blood cell production. However, in sepsis, the mechanisms responsible for the final increase in circulating erythropoietin remain unclear Seventeen critically ill patients with Simplified Acute Physiologic Score average 66 (range 43 to 103) were included in this study. Ten patients survived and seven died within 28 days. Blood samples obtained at different times were assayed for erythropoietin, cytokine levels and lactate measurements. PCO2 gap was assessed to detect the presence of gastric mucosal acidosis. Erythropoietin decreased in the patients who survived while it remained high or increased in non-survivors (37+/-6.5 vs 147+/-6. 7 UI/l respectively, P<0.05). Erythropoietin plasma levels were correlated with IL-6 levels (r=0.84, P<0.05) and TNFalpha levels (r=0.84, P<0.05). We observed a significant positive relationship between erythropoietin plasma levels and lactate concentrations (r= 0.89, P< 0. 05) and with PCO2 gap (r=0.9, P < 0.05). No correlation was found between erythropoietin concentration and the other parameters. High serum erythropoietin levels in non-survivors were observed with septic shock despite an increase in the levels of proinflammatory cytokines. We found a relationship between erythropoietin concentration and biological markers of tissue hypoperfusion i.e. lactate levels or PCO2 gap. This relationship could suggest tissue hypoperfusion as the stimulating factor for erythropoietin production in septic shock.
Subject(s)
Erythropoietin/blood , Shock, Septic/blood , Adult , Aged , Humans , Interleukin-6/blood , Middle Aged , Prognosis , Severity of Illness Index , Shock, Septic/mortality , Survival Analysis , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND AND OBJECTIVES: Inherited factor VII (FVII) deficiency is a rare bleeding disorder characterized by a poor relationship between reported FVII clotting activity (FVII:C) and bleeding tendency. Our study was aimed at defining biological parameters that are possibly predictive for bleeding risk in this condition. DESIGN AND METHODS: Forty-two FVII-deficient patients (FVII:C <30%) were classified into two opposite clinical groups defined as severe and non-or-mild bleeders. For each patient, plasma samples were collected and then investigated for FVII:C (using a sensitive method and human recombinant thromboplastin as the reagent), FVII antigen, activated FVII coagulant activity (FVIIa:C) and the free-form of tissue factor pathway inhibitor. RESULTS: None of these tests could be used as highly accurate predictors of bleeding. Nevertheless, both FVII:C and FVIIa:C differed significantly between the two clinical groups. Using ROC-curve analysis, two critical values of 8% and 3mIU/mL for FVII:C and FVIIa:C, respectively, could be proposed to discriminate between severe bleeders and non-or-mild bleeders. INTERPRETATION AND CONCLUSIONS: A highly accurate diagnostic test for predicting bleeding tendency in inherited FVII deficiency still eludes definition, highlighting the fact that factors other than FVII itself interfere with the expression of bleeding phenotypes in this condition. Nevertheless, potential critical values using sensitive FVII:C and FVIIa:C methods may be useful in clinical laboratories for FVII-deficient patients. Those patients with FVII:C levels higher than 8% FVII:C or FVIIa:C higher than 3 mIU/mL, with no other hemostatic defect, seem to have a minimal risk of severe bleeding. Extended clinical studies are needed to support these findings.
Subject(s)
Factor VII Deficiency/diagnosis , Factor VII/analysis , Adolescent , Adult , Blood Coagulation Disorders, Inherited , Child , Child, Preschool , Factor VII Deficiency/blood , Female , Hemorrhage/blood , Humans , Male , Middle Aged , Predictive Value of Tests , Risk , Severity of Illness IndexABSTRACT
OBJECTIVE: Genetic thrombophilia may represent a new risk factor for obstetrical complications. The aim of the study was to determine which subgroups may be associated with genetic thrombophilia for small for gestational age infants (SGA). METHODS: A case-control study was performed in three different maternity wards in Normandy. Cases (n=203) were women who had pregnancies complicated by unexplained SGA infants defined as a birth weight below the 3rd centile and control subjects (n=203) were women who had infants with birth weight > or =10th centile. Patients were tested in the immediate postpartum period and 2 months later for factor V Leiden mutation, and prothrombin 20210A mutation. Frequencies of these mutations were observed in different subgroups of SGA infants depending on pregnancy or neonatal outcomes usually associated with intrauterine growth restriction (IUGR), and were then compared with the overall prevalence for these mutations detected in the control group. RESULTS: Prevalences for factor V Leiden mutation (or=2.58; 95% confidence interval: 0.83-8.04), prothrombin 20210A mutation (or=2.03; 95% confidence interval: 0.51-8.01), were comparable between cases and controls (4.9% versus 1.9% and 2.9% versus 1.4%, respectively). Frequencies for these two polymorphisms significantly increased in subgroups of SGA infants with a normal Pourcelot index (13/133 versus 7/203; P=0.04), a gestational age > or =37 weeks of gestation (15/143 versus 7/203; P=0.01), a vaginal delivery (11/117 versus 7/203; P=0.04), a birth weight > or =2000 g (12/121 versus 7/203; P=0.03), no admission to paediatric ward (11/116 versus 7/203; P=0.01), a low Ponderal index <2.5(e) centile (6/45 versus 7/203; P=0.04), and normal head circumference >10th centile (7/53 versus 7/203; P=0.01) in comparison with the control group. CONCLUSIONS: An association was found between polymorphisms for factor V Leiden and prothrombin, and asymmetrical intrauterine growth restriction with immediate favourable neonatal outcomes.
Subject(s)
Fetal Diseases/epidemiology , Fetal Growth Retardation/epidemiology , Thrombophilia/epidemiology , Adult , Case-Control Studies , Factor V/genetics , Female , Fetal Diseases/genetics , Fetal Growth Retardation/genetics , France/epidemiology , Humans , Infant, Low Birth Weight , Infant, Newborn , Pregnancy , Pregnancy Outcome , Prevalence , Thrombophilia/geneticsABSTRACT
OBJECTIVES: Because the incidence of thromboembolism is increased in patients with inflammatory bowel disease, we attempted to assess the role of prothrombotic inherited coagulation abnormalities in the development of thrombosis. METHODS: Four populations were compared: 15 patients with inflammatory bowel disease and a previous venous thrombosis, 58 control patients with inflammatory bowel disease but without thrombosis, 110 patients without inflammatory bowel disease but with previous deep venous thrombosis, and 84 healthy subjects. Inherited and acquired risk factors of venous thrombosis, e.g., factor V Leiden and prothrombin 20210A mutations, C677T methylenetetrahydrofolate reductase polymorphism, a polymorphism located in exon 13 of factor V gene, inflammatory and hypercoagulability markers were studied in each population. RESULTS: In the study, 14.3% of thrombotic patients with inflammatory bowel disease had factor V Leiden mutation versus 0% of control patients with inflammatory bowel disease (p = 0.04), 15.5% of thrombotic patients without inflammatory bowel disease (NS) and 3.6% of the healthy controls. A total of 14% of thrombotic patients with inflammatory bowel disease and 11.8% of thrombotic patients without inflammatory bowel disease carried prothrombin 20210A mutation, compared to 1.7% of control patients with inflammatory bowel disease; however, the difference was just below significance. Other inherited coagulation abnormalities were not statistically significantly different among the four populations. CONCLUSIONS: Our study confirms that factor V Leiden mutation increases the risk for thrombotic events but is not more frequent in patients with inflammatory bowel disease. Our results do not support the role of other thrombotic risk factors.
Subject(s)
Factor V , Inflammatory Bowel Diseases/genetics , Venous Thrombosis/genetics , Adult , Aged , Female , Fibrin Fibrinogen Degradation Products/analysis , Gene Frequency , Humans , Inflammatory Bowel Diseases/blood , Male , Methylenetetrahydrofolate Reductase (NADPH2) , Middle Aged , Mutation/physiology , Oxidoreductases Acting on CH-NH Group Donors/genetics , Protein S/analysis , Prothrombin/genetics , Reference ValuesABSTRACT
Inherited thrombophilia include deficiences of antithrombin III, protein C and protein S, and the factor V Leiden mutation, the prothrombin gene variant, and homozygosity for the thermolabile variant of methylenetetrahydrofolate reductase (MTHFR). The incidence of thromboembolism events during pregnancy and postpartum period among women with thrombophilia is not well known and depends on the prethrombotic state resulting from the interaction of the underlying thrombophilic defect(s), history of congenital thrombophilia, and additional risk factors. In that way, many patients with congenital thrombophilia will require antenatal thromboprophylaxis, the timing of which will depend on the patient's history and thrombophilic disorders. Low molecular weight heparin appeared to be a safe alternative to unfractionated heparin for both the fetus and the mother during the pregnancy. Case-control studies have recently demonstrated that serious obstetrical complications i. e severe preeclampsia, abruptio placentae, intrauterine growth restriction, and stillbirth were frequently associated with inherited thrombophilia. Controlled trials are now urgently needed to determine the possible potential benefits of anticoagulant therapy in pregnancy outcome. Finally, there is no evidence to support routine screening for congenital thrombophilia during pregnancy.
Subject(s)
Pregnancy Complications, Hematologic , Thrombophilia/genetics , Antithrombin III Deficiency/genetics , Drug Resistance/genetics , Female , Humans , Mutation , Pregnancy , Protein C , Prothrombin/genetics , Thrombophilia/complications , Thrombosis/etiologyABSTRACT
The factor V (FV) Arg 506 to Gln mutation is the most common abnormality observed in familial thrombophilia. Many studies have shown that its clinical expression differs among families and among carriers. Some thrombotic patients carry an additional genetic risk factor such as protein C, protein S or antithrombin deficiency. We sought to identify other genetic risk factors potentially favouring expression of the thrombotic phenotype in 370 members of 43 families with the FV Arg 506 to Gln mutation. We analysed three candidate polymorphisms in genes involved in the PC anticoagulant pathway, consisting of two polymorphic sites in the 5' non-transcribed region of the PC gene, -1654 C/T and -1641 A/G, with three known combinations (TA, CA and CG) that influence the protein C plasma level; one polymorphic site (4070 A/G) in exon 13 of the FV gene, which influences the plasma factor V concentration, and one polymorphic site (677 C/T) in the methylenetetrahydrofolate reductase gene, which is often associated with moderate hyperhomocysteinaemia. The distribution of these different polymorphisms was similar in patients with a history of thrombosis and those who remained asymptomatic, ruling out the possibility that each of these polymorphisms alone can play a role in the onset of thrombosis in carriers of the FV Arg 506 to Gln mutation.
Subject(s)
Factor V/genetics , Mutation/genetics , Thrombosis/genetics , Adolescent , Adult , Aged , Alleles , Female , Heterozygote , Homozygote , Humans , Male , Middle Aged , Polymorphism, Genetic , Risk FactorsABSTRACT
Most of disproportionate infants born small for gestational age (SGA) have an history of placental dysfunction with no explained cause. We report a case of an unexplained SGA infant with placental infarctions and thrombosis. Maternal thrombophilic disorder tests revealed that the patient was heterozygous for the A20210 prothrombin gene variant a newly identified thrombotic risk factor. It may be suggest that prothrombin gene variant, as factor V Leiden, could be a genetic risk factor for placental insufficiency.