Leiden Heterozygosity Research Articles

Factor V Leiden Homozygosity, Dyspnea, and Reduced Pulmonary Function

Factor V Leiden homozygosity predisposes patients to deep venous thrombosis and major pulmonary thromboembolism. Consequently, factor V Leiden homozygosity could, via unrecognized repeated minor pulmonary thromboemboli, cause chronic pulmonary disease. We tested the hypothesis that factor V Leiden homozygosity is associated with pulmonary symptoms and signs. We studied a general population sample of 9253 individuals from the Copenhagen City Heart Study who were examined in 1991-1994. Of these, 6475 participants were also examined in 1976-1978 and/or 1981-1983. End points were dyspnea and lung function. Among 20 factor V Leiden homozygotes, a mean +/- SD of 32% +/- 11% had severe dyspnea compared with 6% +/- 0.3% of 8534 noncarriers (chi(2) test; P<.001). The corresponding adjusted odds ratio for severe dyspnea was 5.4 (95% confidence interval, 1.9-15.7). During follow-up, forced expiratory volume in 1 second and forced vital capacity were 5% to 10% lower in homozygotes vs noncarriers (analysis of variance; P = .003 and P = .03). The annual mean +/- SD loss of forced expiratory volume in 1 second and forced vital capacity was 39 +/- 8 mL/y and 35 +/- 8 mL/y in homozygotes vs 21 +/- 10 mL/y and 15 +/- 10 mL/y in noncarriers (t test; P = .03 and P = .04), respectively. Factor V Leiden heterozygosity (n = 699) did not influence pulmonary symptoms and signs. We demonstrate a previously unrecognized clinical presentation of factor V Leiden homozygosity with severe dyspnea and decreased pulmonary function.

The Role of the Intrauterine and Perinatal Environment in Cerebral Palsy

Author Disclosure Drs Paneth, Korzeniewski, and Hong did not disclose any relationships relevant to this article. After completing this article, readers should be able to: 1. Discuss the prevalence of cerebral palsy (CP) in school-aged children. 2. Describe the role of neuroimaging in CP. 3. Describe the impact of ventilatory practices in low-birthweight infants on the risk of CP. 4. Delineate the role of infection and fetal inflammation in pregnancy in the development of CP. The special importance of CP to clinicians whose practices encompass pregnancy and the perinatal or neonatal period is that no other neurodevelopmental disorder bears as close a causal relationship to the hazards of intrauterine and perinatal life. Although the strength of that relationship has been exaggerated at times, especially in relation to obstetric trauma and birth asphyxia, there can be no serious doubt that adverse events in pregnancy and the perinatal period do occasionally damage the fetal or neonatal brain. A distinctive feature of brain damage produced between early gestation and infancy is destruction of cerebral white matter or extrapyramidal tracts, thereby producing a clinical syndrome in which disturbance of motor control is a prominent and probably a necessary feature. Depending on the nature and extent of the insult, the motor disorder may be predominantly spastic, dyskinetic, or ataxic and may involve all four limbs (quadriplegia), one side (hemiplegia), or be most prominent in the legs (diplegia). CP severe enough to be recognized as a disability is found in about 1 in 500 school-age children in most developed countries, with little variation between countries or over the past 30 years. (1) Because CP often is accompanied by other neurodevelopmental disabilities, particularly seizure disorders, varying degrees of mental retardation, blindness, or deafness, affected children constitute the single largest group of children in the population who have major disabilities. (2) More …

Estrogen-containing oral contraceptives are allowable in young women with factor V Leiden heterozygosity without a history of thrombosis

AN 18-YEAR-OLD WOMAN without significant past medical and surgical history presents to discuss the safety and efficacy of oral contraceptives. She is sexually active and currently relying on condoms alone for birth control. Her cousin had a deep venous thrombosis (DVT) following a pregnancy. As part of the family screening, this patient was identified as a factor V Leiden heterozygote. The risks and benefits of initiating oral contraceptives are discussed.

Venous thromboembolism associated with the management of acute thrombotic thrombocytopenic purpura

Venous thromboembolism (VTE) is not a feature of thrombotic thrombocytopenic purpura (TTP), but there has been a recent report of VTE in association with plasma exchange (PEX) treatment for TTP using the solvent detergent (SD) plasma, PLAS+SD. We reviewed the occurrence of VTE in 68 consecutive patients with TTP (25 men, 43 women). Eight documented VTE events [six deep venous thromboses (DVTs), three pulmonary emboli] were identified in seven patients (all female) during PEX therapy. All six DVTs were associated with central lines at the site of thrombosis. Other known precipitating factors included pregnancy, immobility, obesity and factor V Leiden heterozygosity. VTE occurred at a mean of 53 d following the first PEX. The European SD plasma, Octaplas was the last plasma to be used in PEX prior to the VTE in 7/8 events. This is the first report of VTE following Octaplas infusion. VTE is a multifactorial disease and, although several known precipitating factors were present in all patients in this study, the use of large volumes of SD plasma in PEX may be an additional risk factor. We recommend prevention of VTE with graduated elastic compression stockings (class I) at diagnosis and prophylactic low-molecular-weight heparin once the platelet count rises above 50 x 10(9)/l.

Frequency of factor V Leiden and prothrombin G20210A in placentas and their relationship with placental lesions

The most common hereditary hypercoaguable states are factor V Leiden (FVL) and prothrombin mutations (PRO). FVL and PRO present with an incidence of approximately 5% in a heterogeneous population, and 45% to 63% of the thrombophilic population. The frequency of these mutations in the fetal population and their clinical importance is unknown. Fetal side thromboembolic events (FST) include congenital stroke and renal vein thromboses. In some cases, FST can be diagnosed by placental histopathology when avascular (infarcted) villi are present in a patent maternal vascular space. FST can present as placenta-fetal-vascular or fetal-visceral-vascular lesions. Causes include vascular damage from cord compression or inflammation, but most remain unclear. Potential causes of FST include FVL and PRO. We describe the incidence of FVL and PRO from a prospective group of 169 consecutive placentas and in a retrospective group of archived placentas diagnosed with placental FST. One each of FVL and PRO heterozygosity was found in the prospective set (<1% incidence for each). Five prospective placentas were diagnosed with placental FST, for an incidence of 3%; all were wild-type for FLV and PRO. Twenty-seven of 65 archived FST cases had analyzable DNA to find 5 FVL heterozygotes (18.5%); all were wild-type for PRO. Twenty-one of 65 retrospective archived controls analyzable found 1 case of FVL heterozygosity (<5%). We find that the frequency of FVL and PRO may be decreased in the pregnant population but increased in cases of placental FST. Because factor V Leiden heterozygosity carries an increased risk for thrombotic complications, we suggest placental diagnosis of fetal side thromboemboli warrants clinical evaluation for FVL in infant and potentially the parents. H UM P ATHOL 31:1036-1043.

Perinatal cortical infarction within middle cerebral artery trunks

AIMTo define neonatal pial middle cerebral artery infarction.METHODSA retrospective study was made of neonates in whom focal arterial infarction had been detected ultrasonographically. A detailed study was made of cortical...

Pseudohomozygosity for activated protein C resistance is a risk factor for venous thrombosis.

Pseudohomozygosity for activated protein C resistance (APC-r) is a rare condition due to the association of heterozygous FV Leiden mutation and partial type I FV deficiency. To assess the risk of venous thromboembolism in these subjects, seven families including 11 pseudohomozygotes and 45 relatives were examined. Among the relatives, 16 were heterozygous FV Leiden carriers, nine showed partial FV deficiency and 20 no abnormalities. Deep vein thrombosis occurred in 4/11 (36.3%) pseudohomozygous patients versus 6/16 (37. 4%) FV Leiden carriers and 1/20 (5%) normal relatives. Pseudohomozygotes and FV Leiden carriers had a significantly increased risk of venous thrombosis in comparison to normal relatives (RR 8.8 and 5.7, respectively). There was no difference between the thrombotic risk of pseudohomozygous subjects and of FV Leiden carriers (RR 1.6, 95% CI 0.43-5.7). Furthermore, there was no difference in thrombosis-free survival between pseudohomozygotes and 45 consecutive FV Leiden heterozygous outpatients, suggesting that a referral bias may explain the apparent younger age of thrombosis in the pseudohomozygotes in comparison to relatives with FV Leiden heterozygosity (27 years v 54 years; P = 0.01). Pseudohomozygosity for APC resistance carries a significantly higher risk for venous thromboembolism in comparison to normal subjects, but probably not in comparison to heterozygous FV Leiden carriers.

Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss

Objective: Antiphospholipid antibodies (APA) and other coagulation abnormalities have been associated with an increased risk of venous, arterial, and placental thrombosis and recurrent pregnancy loss (RPL). Factor V Leiden (a point mutation [1691G→A] in the factor V gene), the prothrombin 20210G→A mutation, and homozygosity for a common polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene (677C→T) have been associated with arterial and venous thrombosis and arterial occlusive disease. We explored an association between these markers of thrombophilic states and RPL. Design: Prospective case-control evaluation. Setting: University-associated private practice. Patient(s): Fifty nonpregnant women with three or more pregnancy losses and 50 healthy, nonpregnant controls. Intervention(s): None. Main Outcome Measure(s): Anticardiolipin and antiphosphatidylserine antibodies were detected in serum by ELISA. Polymerase chain reaction was performed to identify the factor V Leiden (1691G→A) mutation, the thermobile MTHFR (677C→T) mutation, and the prothrombin 20210G→A mutation. Result(s): The following were identified by restriction fragment-linked polymorphism analyses: 1 (2%) factor V Leiden heterozygosity; 1 (2%) prothrombin 20210G→A heterozygosity; and 4 (8%) thermolabile MTHFR homozygosity. None of these mutation frequencies in women with RPL were statistically significantly different from controls. Conclusion(s): These data suggest that factor V Leiden, thermolabile MTHFR (677C→T), and prothrombin 20210G→A are not found at an increased frequency in women with a history of early RPL.

Vascular surgical society of great britain and ireland: prevalence and significance of thrombophilia in patients with intermittent claudication

BACKGROUND: Thrombophilia may be associated with premature atherosclerosis, an increased susceptibility to primary arterial thrombosis and an increased failure rate for peripheral vascular or endovascular interventions. The aim of this study was to determine the prevalence of thrombophilia in patients with intermittent claudication (IC). METHODS: This was a prospective study of 116 consecutive new patients (70 men; median age 65 (range 43-84) years) referred to this regional vascular surgery unit with IC. Patients on warfarin, or who had previously undergone lower limb reconstruction and/or angioplasty, were excluded. RESULTS: Thrombophilia was demonstrated in 24 patients (21 per cent). The commonest abnormality (15 patients, 13 per cent) was a raised level of anticardiolipin antibody (ACLA) (11 immunoglobulin (Ig) M, four IgG). Other abnormalities comprised: lupus anticoagulant (one), protein C deficiency (two), protein S deficiency (two), activated protein C resistance (one) and factor V Leiden heterozygosity (three). All abnormalities were confirmed on repeat testing. No patient had a history of venous thrombosis. There was no statistically significant relationship between ACLA status and age, sex, ankle : brachial pressure index, previous myocardial infarction or stroke, previous carotid endarterectomy or coronary artery surgery, serum cholesterol, current use of antiplatelet agents or current smoking status. CONCLUSION: Almost one-quarter of new patients referred to this regional vascular unit with IC have thrombophilia; over half of those affected have a raised ACLA level compatible with the antiphospholipid syndrome. At present, the clinical significance and management implications of these abnormalities remain unknown.