Thrombophilia Assessment Research Articles

Referral Patterns and Outcomes for Women with for Recurrent Pregnancy Loss Managed At a Multidisciplinary Thrombosis Program,

Abstract 4190 INTRODUCTION:Recurrent pregnancy loss (RPL) can affect up to 5% of couples who are trying to conceive. In addition to the mental anguish, miscarriages are accompanied by the physical component of pain with the potential need for hospitalization and medical or surgical intervention. While, the recommended evaluation of RPL includes an assessment of multiple variables, including disorders of thrombophilia, the definition of RPL remains vague. Because no explicit definitions exist for RPL, we undertook an analysis of patients referred to a large, tertiary care center specifically for the evaluation and treatment of RPL. METHODS:We utilized data from the Duke University site of the Thrombosis and Hemostasis Centers Research and Prevention Network established by the Division of Blood Disorders of the Centers for Disease Control and Prevention (CDC). Patients referred to Duke University with a diagnosis of RPL were followed prospectively and their data regarding the diagnostic evaluation, prescribed treatments, and subsequent maternal-fetal outcomes were recorded. Information from the initial intake included demographic data, reason for referral, number and sequence of pregnancy losses, thrombophilia assessment, as well as the additional recommendations. Results of clinical evaluations performed at Duke, including coagulation assays, autoimmunity testing, examination of uterine anatomy, and parental chromosomal analysis were recorded, as well as any prescribed treatments of the current/subsequent pregnancy. Where follow-up data was available, results of the current and subsequent maternal and fetal outcomes were noted. RESULTS:As of March 2010, 2566 participants were enrolled in the CDC Patient Registry at Duke University, of which 62 were referred specifically for RPL. We found that almost 30% of referred patients (18/62) had undergone no prior testing, whereas at least 25% of referred patients came with a diagnosis that could not be confirmed. The most common misdiagnosis was of a thrombophilic marker, particularly with low-titer anti-phospholipid antibodies. Our evaluation found no discernible cause for RPL in 38% (23/62) of the women referred; our most common identified factor was a thrombophilic disorder (32%, 20/62) (Table 1). We found that analysis of the uterine cavity and assessment of parental chromosomes was infrequently performed prior to referral. The most common treatment recommendation was low molecular weight heparin, followed by observation alone. For patients who subsequently became pregnant, an overwhelming majority of women had no adverse maternal outcomes (86%), and a 72% live birth rate was recorded. Fortunately, no maternal deaths were observed.Table 1Composite assessment of referred patients, n=62Cause of Pregnancy LossesnNo cause identified23Thrombophilia Alone20Autoimmunity Alone7Thrombophilia + Uterine Anomaly3Thrombophilia + Autoimmunity2Uterine Anomaly alone2Autoimmunity + Hemoglobinopathy1Autoimmunity + Uterine Anomaly1Thrombophilia + Genetic Abnormality1Thrombotic history alone1Hemoglobinopathy alone1*Autoimmunity = antiphospholipid syndrome or systemic lupus erythematosus. CONCLUSION:Women with underlying thrombophilia who are interested in having a successful pregnancy can be effectively diagnosed, counseled, and treated. These results show that for women with RPL, a coordinated, multi-disciplinary approach can be beneficial to achieving a safe pregnancy and healthy baby. Furthermore, the CDC Thrombosis and Hemostasis Centers Research and Prevention Network is enrolling a broad and robust patient population with thrombotic disorders and provides a national registry for tracking and evaluating pregnancy outcomes. Disclosures:Metjian:Expert testimony: Consultancy; Quintiles: Speakers Bureau; Avila Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Cerebral Venous Thrombosis in a Mexican Multicenter Registry of Acute Cerebrovascular Disease: The RENAMEVASC Study

Cerebral venous thrombosis (CVT) is a rare form of cerebrovascular disease that is usually not mentioned in multicenter registries on all-type acute stroke. We aimed to describe the experience on hospitalized patients with CVT in a Mexican multicenter registry on acute cerebrovascular disease. CVT patients were selected from the RENAMEVASC registry, which was conducted between 2002 and 2004 in 25 Mexican hospitals. Risk factors, neuroimaging, and 30-day outcome as assessed by the modified Rankin scale (mRS) were analyzed. Among 2000 all-type acute stroke patients, 59 (3%; 95% CI, 2.3-3.8%) had CVT (50 women; female:male ratio, 5:1; median age, 31 years). Puerperium (42%), contraceptive use (18%), and pregnancy (12%) were the main risk factors in women. In 67% of men, CVT was registered as idiopathic, but thrombophilia assessment was suboptimal. Longitudinal superior sinus was the most frequent thrombosis location (78%). Extensive (>5 cm) venous infarction occurred in 36% of patients. Only 81% of patients received anticoagulation since the acute phase, and 3% needed decompressive craniectomy. Mechanical ventilation (13.6%), pneumonia (10.2%) and systemic thromboembolism (8.5%) were the main in-hospital complications. The 30-day case fatality rate was 3% (2 patients; 95% CI, 0.23-12.2%). In a Cox proportional hazards model, only age <40 years was associated with a mRS score of 0 to 2 (functional independence; rate ratio, 3.46; 95% CI, 1.34-8.92). The relative frequency of CVT and the associated in-hospital complications were higher than in other registries. Thrombophilia assessment and acute treatment was suboptimal. Young age is the main determinant of a good short-term outcome.

Etiology and Assessment of Hypercoagulability with Lessons from Heparin-Induced Thrombocytopenia

Hypercoagulability, or thrombophilia, is a condition associated with an abnormally increased tendency toward blood clotting. Affected individuals are prone to developing venous or arterial thrombosis and often require thromboprophylaxis. Hypercoagulability can be generally classified as either an inherited or acquired condition. Patients with an inherited thrombophilia have genetic variances that alter the quality or quantity of proteins involved with hemostasis. Hypercoagulability may also be acquired and develop as an exaggeration of normal physiologic responses to major tissue injury, or an abnormal response to various prothrombotic clinical factors. Careful assessment for hypercoagulability is important because effective management strategies, often involving anticoagulation, may be available. Heparin-induced thrombocytopenia is an example of an acquired hypercoagulable state that has been well studied and, when recognized, responds to appropriate therapy. In this article, we review the etiology, risks, and assessment of thrombophilia, with emphasis on the clinical lessons learned from heparin-induced thrombocytopenia.

Risk factors for thrombophilia in young adults presenting with thrombosis

The increased risk for thrombosis is known as hypercoagulability or thrombophilia. Here, we investigated risk factors for thrombophilia which were screened in young adult patients presenting with thrombotic events or with recurrent abortions with unknown etiology. A total of 115 patients aged between 16 and 50 years who were found to harbor thrombophilia were retrospectively evaluated. The laboratory investigations performed for the assessment of thrombophilia included protein C, protein S, antithrombin III deficiencies, activated protein C resistance, factor V Leiden (FVL), prothrombin 20210A (PT 20210) and methylenetetrahydrofolate reductase (MTHFR) gene mutations, factor VIII elevation, lupus anticoagulant and antiphospholipid antibodies (APA). In 66% of the cases a single thrombophilic defect was identified while some of the patients had combined thrombophilic defects. The most common thrombophilic defect was mutation in the MTHFR gene, and was followed by FVL mutation, the presence of APA and PT 20210 gene mutation, respectively. The patients were divided into two different age groups, 16-35 and 36-50 years, and arterial thrombosis was more common in the older age group. Our results indicated that some important thrombophilic defects such as gene mutations may appear in young adult patients presenting with thrombotic events.

Low birthweight in relation to placental abruption and maternal thrombophilia status

The objective of the study was to evaluate whether the association between low birthweight and placental abruption is mediated through preterm birth or restricted fetal growth and whether these associations were influenced by maternal thrombophilia status. Data were derived from the New Jersey-Placental Abruption Study, an ongoing, multicenter, case-control study conducted in New Jersey since August 2002. Abruption cases (n = 156) were identified based on a clinical diagnosis, and controls (n = 170) were matched to cases based on parity and maternal race. Low birthweight (<2500 g) was stratified based on preterm birth (<37 weeks' gestation) and small for gestational age (birthweight < the 10th percentile for gestational age). Maternal thrombophilia assessment was based on serum evaluation (protein C and S deficiency, activated protein C resistance ratio, and anticardiolipin antibodies) as well as genetic polymorphisms (methylenetetrahydrofolate reductase, prothrombin gene, and factor V Leiden). Associations were expressed based on odds ratios (ORs) with 95% confidence interval (CI). Among abruption cases, 60.3% (n = 94) were low birthweight in comparison with 11.2% (n = 19) of controls (OR, 13.7; 95% CI, 7.4-25.2). Furthermore, placental abruption had a significantly increased association with preterm birth in both small for gestational age (OR, 17.4; 95% CI, 4.6-64.9) and appropriately grown fetuses (OR, 15.8; 95% CI, 8.4-29.8). However, the association between abruption and low birthweight were similar between women with and without thrombophilia. The association between placental abruption and low birthweight is chiefly mediated through preterm birth, and this association does not appear to be modified by maternal thrombophilia status.

Spectrum of Thromboses in Patients with Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms: Continuing Controversy.

Thromboembolic disease is common with an annual incidence of 1–3/1000 individuals. Both acquired and genetic risk factors are responsible. A risk factor for thrombosis can now be identified in over 80 percent of patients. Fifty percent of thrombotic events in patients with inherited thrombophilia are associated with an acquired risk factor. Patients with multiple inherited risk factors are at a greater risk. Two common variations of the MTHFR gene (677CàT and 1298AàC) result in amino acid substitutions and enhanced thermolability of the enzyme. The latter, in the presence of folic acid deficiency, results in elevated homocysteine levels. Thrombosis has been observed in these patients, but there is still controversy whether there is a direct association (Bezemer I, et al. Arch Int Med 167, 497–501, 2007; den Heijer M et al. J Thromb Haemost 3:292–299, 2005). In the present study, we describe the spectrum of thromboembolic disease observed in 39 patients with a variety of MTHFR polymorphisms referred to a specialty center with a personal or family history of thromboses or obstetrical loss, 18 of these patients having no other risk factor other than MTHFR polymorphisms. These polymorphisms include 18 heterozygotes (11 with 677CàT; 7 with 1298AàC), 9 homozygotes (5 with 677CàT; 4 with 1298AàC) and 12 compound heterozygotes (677CàT and 1298AàC). Concomitant risk factors were found in twenty-one patients (factor V Leiden - 6; prothrombin G20210A - 3; protein C deficiency - 1; protein S deficiency - 1; PAI-1 polymorphism - 2; activated protein C resistance - 2; antiphospholipid antibody syndrome - 5; malignancy - 3; coronary artery disease - 1; hemolytic anemia - 1; factor VIII deficiency - 1). Types of thromboembolic manifestations observed in the 39 patients include venous thromboembolism (22), obstetrical loss (7), arterial thrombosis (3), myocardial infarction (3), ischemic CNS lesions (2), and palpable purpura (1), for a total of 38 manifestations. Seven of the patients had a family history of thromboembolic disease. Patients with only MTHFR polymorphisms suffered 16 types of thromboembolic events (16/38=42%). Our observations suggest that MTHFR polymorphisms alone do play a role in clinically relevant thrombotic disease and probably increase the incidence of these diseases in patients harboring other causes of thrombophilia. Therefore, continuing surveillance for this polymorphism as part of a clinical thrombophilia assessment is recommended, particularly if homocysteine levels are elevated.

Favorable influence of local injury to the endometrium in intracytoplasmic sperm injection patients with high-order implantation failure

Local injury to the endometrium prior to controlled ovarian stimulation may considerably improve implantation rates and pregnancy outcomes in intracytoplasmic sperm injection patients with high-order implantation failure (> or =4 IVF trials and > or =12 transferred embryos).

Very Low Prevalence of Hyperhomocysteinemia among US Children with Personal/Family History of Thrombosis. Towards Reconsideration of the Recommendation for Routine Testing.

Background: Comprehensive thrombophilia laboratory testing is recommended for the evaluation of children with thrombosis by the Perinatal and Pediatric Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH). The C677T thermolabile variant of the methylene tetrahydrofolate reductase (MTHFR) gene is highly prevalent in Caucasians, carried in heterozygous form in 45% and homozygously in 10%. The thrombogenicity of the MTHFR C667T mutation is mediated via elevation in plasma homocysteine concentration. However, in the U.S., folate fortification of food products may circumvent the impact of this mutation upon plasma homocysteine.Objective: To determine the prevalence of hyperhomocysteinemia among U.S. children with a personal history of thrombosis (thrombosis group) or a first-degree family history of thrombosis or thrombophilia (familial risk group).Methods: All children comprising the two study groups had been referred to the Thrombosis/Thrombophilia Program at The Children's Hospital, Denver, and were consecutively recruited for participation in collection of laboratory and clinical data for this research. Plasma homocysteine, performed clinically as part of the ISTH recommended thrombophilia laboratory assessment, was determined by gas chromatograph mass spectroscopy.Results: Homocysteine concentration was normally distributed within the study population, and did not vary with age or differ significantly between the two study groups. Table 1 displays the results relative to age and study group. In 100% of subjects, homocysteine level was either low or normal with respect to the previously-established reference range for healthy individuals.Conclusions: Despite a high historical prevalence of the MTHFR C677T mutation in Caucasians, the prevalence of hyperhomocysteinemia among U.S. children with thrombosis or a familial risk of thrombosis is extremely low, being absent among nearly 200 children studied. Because other mutations that do result in hyperhomocysteinemia and thrombosis occur rarely, homocysteine testing as part of a comprehensive thrombophilia assessment in U.S. children should be targeted to those patients in whom metabolic disease is suspected clinically.Plasma Homocysteine Levels (UMl/L) in Children.CategoryTotal< 1 year1 - < 7 years7 - < 13 years13 - < 24 years+ Thrombosis− ThrombosisN1932548447612865Mean5.64.45.05.36.65.65.6Median5.64.85.05.36.25.85.4Std. Dev.2.42.22.32.62.12.61.9

Prevalence of Factor V Leiden, prothrombin G20210A, and MTHFR G677A among 594 thrombotic Jordanian patients

Venous thromboembolism develops as the result of multiple interactions between non-genetic and genetic risk factors. In order to estimate the frequency of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in Jordanian thrombotic patients, we studied 594 patients admitted to the King Hussein Medical Center for thrombophilia assessment. Polymerase chain reaction detected 25.7% (20.7% heterozygous, 5% homozygous), 6% (5.8% heterozygous, 0.2% homozygous) and 31.7% (25% heterozygous, 6.7% homozygous) for factor V Leiden, prothrombin G20210A and MTHFR C677T mutations, respectively. A one-stage clotting assay was used to measure prothrombin activity. None of the prothrombin G20210A mutant patients had high prothrombin activity. The high prevalence found among our study group of factor V Leiden and prothrombin G20210A confirms the importance of thrombophilia screening for patients with venous thrombosis with family history and those with additional risk factors. On the contrary, the high prevalence of the MTHFR C677T mutation among arterial thrombosis patients shows its importance in screening in arterial thrombosis patients. These results, which are close to the prevalence found by other studies in the region, suggests that the Eastern Mediterranean region is probably the area of origin of these mutations, especially factor V Leiden. The knowledge of these frequencies in the Middle East region through population-based studies will contribute to a better understanding of the interaction between genetic and environmental risk factors underlying the mentioned mutations.

Common C677T Polymorphism of the Methylenetetrahydrofolate Reductase Gene and the Risk of Venous Thromboembolism: Meta-Analysis of 31 Studies

Background: Although the common 677 C → T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene is implicated in the development of hyperhomocysteinemia, its correlation with venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis of previously published studies to clarify the role of the MTHFR 677 TT homozygous genotype in association with VTE. Methods and Results: Relevant articles were retrieved from a systematic search of Medline and Embase from 1990 to September 2001. Two independent reviewers abstracted data on the characteristics of the cases with VTE and controls without VTE. We pooled the rates of the MTHFR 677 TT genotype in both groups, as well as the odds ratio (OR) of VTE in the presence of the TT versus CC or CT genotypes. In 31 published studies, comprising 4,901 cases and 7,886 controls, the pooled prevalence of the MTHFR 677 TT genotype was slightly higher among cases (14.3%) than controls (11.7%), conferring a borderline degree of heightened risk [pooled OR (OR_p) 1.2, 95% confidence interval (CI) 1.1–1.4]. After excluding cases with a classic thrombophilia factor, the pooled prevalence rates of the MTHFR 677 TT genotype among 11 studies were 17.7 and 12.3%, respectively (OR_p 1.5, 95% CI 1.2–1.9). Conclusions: The classic MTHFR C677T gene polymorphism is weakly associated with an increased risk of VTE. It is unlikely that the purported relationship between hyperhomocysteinemia and VTE is mediated by this gene defect to a substantial degree, although other undiscovered gene polymorphisms may explain this association. Until more compelling data are made available, we do not recommend that testing for the MTHFR C677T polymorphism be routinely included as part of any clinical thrombophilia assessment.

Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage

Objective: To describe the characteristics of thrombophilia in women with idiopathic pregnancy loss. Design: Prospective observational study. Setting: Tertiary referral center in a teaching academic hospital. Patient(s): One hundred forty-five patients with repeated pregnancy loss and 145 matched controls. Intervention(s): Prospective assessment of thrombophilia in patients and controls. Main Outcome Measure(s): Prevalence of activated protein C (APC) resistance, protein C, protein S, and antithrombin III deficiencies, antiphospholipid antibodies, factor V Leiden, factor II G20210A, and MTHFR C677T mutations. Result(s): At least one thrombophilic defect was found in 66% of study group patients compared with 28% in control group patients. Combined thrombophilic defects were documented in 21% of women with pregnancy loss compared with 5.5% of control patients. Late pregnancy wastage occurred more frequently in women with thrombophilia compared with women without thrombophilia (160/429 [37%] vs. 39/162 [24%], respectively). APC resistance was documented in 39% of women with pregnancy loss compared with 3% of the control patients. APC resistance without factor V Leiden mutation was documented in 18% of women with pregnancy loss compared with none of the controls. While factor V Leiden mutation was more common in women with pregnancy loss (25% vs. 7.6%), factor II G20210A and homozygosity for MTHFR C677T contributed to pregnancy loss only in the presence of other thrombophilia. Conclusion(s): Thrombophilia was found in the majority (66%) of women with idiopathic pregnancy loss. APC resistance with or without factor V Leiden mutation is the most common thrombophilic defect, and combined thrombophilia is a frequent finding in women with pregnancy loss. Thrombophilia is associated with increased frequency of late pregnancy wastage.