Factor VIII levels and the risk of pre-eclampsia, HELLP syndrome, pregnancy related hypertension and severe intrauterine growth retardation

OBJECTIVE: Recently, acquired as well as genetic prothrombotic factors are associated with thrombotic events. These factors have also been related to conditions of uteroplacental insufficiency such as pre-eclampsia, HELLP syndrome and severe intrauterine growth restriction (IUGR). The aim of this study was to determine whether elevated factor VIII levels are associated with uteroplacental insufficiency, in particular pre-eclampsia, HELLP syndrome or pregnancy-induced hypertension and intrauterine growth retardation. METHODS: Plasma samples of 75 women with a history of pregnancy complicated by pre-eclampsia, HELLP syndrome, pregnancy induced hypertension or intrauterine growth restriction were tested for factor VIII:C (FVIII:C) levels at a minimum of 10 weeks post-partum. Laboratory results were compared to factor VIII:C levels found in a healthy control group of 272 women. RESULTS: Mean factor VIII:C levels were similar at 123 IU/dl in both the patient group and the controls. In a logistic regression model, after adjusting for age and blood group, no effect of factor VIII:C levels on the risk of pregnancy complications was observed, with the exception of IUGR with (OR 2.9, CI 1.0-8.7) or without hypertension (OR 2.0, CI 0.7-6.4). CONCLUSION: If the elevated level of factor VIII would be the sole factor responsible for the increased risk observed, one would expect to find an effect of blood group on risk as well (blood group being an important determinant of FVIII:C). While no such effect could be shown a causal relationship between elevated levels of factor VIII and conditions of uteroplacental insufficiency such as pre-eclampsia, HELLP syndrome, pregnancy-induced hypertension and IUGR is not very likely.     

Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study

Elevated levels of factor VIII:c (elevated FVIII:c) are associated with an increased risk for venous thromboembolism (VTE) and arterial vascular events, and are at least in part determined genetically. We prospectively followed 192 asymptomatic individuals with elevated FVIII:c (>150%) and 340 with normal levels for an average duration of 31 months (range 7 to 56 months) to investigate the risk of VTE and arterial vascular events. Participants were first degree relatives of consecutive patients with elevated FVIII:c and VTE or arterial vascular events before the age of 50 years. The incidences of VTE were 1.25% (0.46-2.73) per year in the subjects with elevated FVIII:c, versus 0.23% (0.03-0.82) in those with normal levels (OR 5.5 [1.1-27.3]). The annual incidences of arterial vascular events were 1.04% (0.34-2.42) and 0.23% (0.03-0.82) in relatives with and without elevated levels of FVIII:c, respectively (OR: 4.5 [0.9-23.5]). After adjustment for age, smoking, known diabetes mellitus, hyperlipidemia, and hypertension, the odds ratio for any event was 3.7 (1.1-13.1). In conclusion, asymptomatic individuals with elevated FVIII:c levels and a positive family history of VTE or arterial vascular events before the age of 50 appear to have a high annual incidence of first VTE and arterial vascular events. Elevated FVIII:c may be a common risk factor for both clinical entities.     

Absolute risk of venous and arterial thromboembolism in thrombophilic families is not increased by high thrombin-activatable fibrinolysis inhibitor (TAFI) levels

High levels of thrombin-activatable fibrinolysis inhibitor (TAFI) are a supposed risk factor for thrombosis. However, results from previous studies are conflicting. We assessed the absolute risk of venous and arterial thromboembolism in subjects with high TAFI levels (>126 U/dl) versus subjects with normal levels, and the contribution of other concomitant thrombophilic defects. Relatives from four identical cohort studies in families with either deficiencies of antithrombin, protein C or protein S, prothrombin 20210A, high factor VIII levels, or hyperhomocysteinemia were pooled. Probands were excluded. Of 1,940 relatives, 187 had high TAFI levels. Annual incidences of venous thromboembolism were 0.23% in relatives with high TAFI levels versus 0.26% in relatives with normal TAFI levels (adjusted relative risk [RR] 0.8; 95% confidence interval [CI], 0.5-1.3). For arterial thrombosis these were 0.31% versus 0.23% (adjusted RR 1.4; 95% CI, 0.9-2.2). High levels of factor VIII, IX and XI were observed more frequently in relatives with high TAFI levels. Only high factor VIII levels were associated with an increased risk of venous and arterial thrombosis, independently of TAFI levels. None of these concomitant defects showed interaction with high TAFI levels. High TAFI levels were not associated with an increased risk of venous and arterial thromboembolism in thrombophilic families.     

Endothelial function markers in parkinsonian patients with hyperhomocysteinemia.

Hyperhomocysteinemia is considered a risk factor for vascular disease causing endothelial damage and consequently atherogenesis. The purpose of this study was to investigate the effect of elevated homocysteine on certain biochemical markers of endothelial function in patients with idiopathic Parkinson's disease (PD). Blood homocysteine levels were assessed in 57 PD patients and 40 matched normal controls. Investigation of the C677T 5,10 methylenetetrahydrofolate reductase (MTHFR) genotype was also performed in 43 PD patients. The following markers of endothelial function were assessed: superoxide dismutase (SOD), nitric oxide (NO), sICAM-1 and sE-selectin. Homocysteine levels were found mildly elevated in PD patients particularly in those treated with L-Dopa. MTHFR genotype did not influence significantly this finding. SOD activity was found reduced but it was not correlated to homocysteine levels. All other parameters measured were normal and were not related to hyperhomocysteinemia. Our findings indicate that mild hyperhomocysteinemia in PD patients was not associated with endothelial dysfunction.     

Hypoxic-ischemia-related fetal/neonatal complications and risk of schizophrenia and other nonaffective psychoses: a 19-year longitudinal study

OBJECTIVE: Epidemiologic evidence linking obstetric complications to schizophrenia has been positive but inconclusive. One reason for the lack of conclusive evidence may be the inconsistency in measuring disturbances of fetal/neonatal brain development based on general obstetric markers of maternal health. The authors used data from the National Collaborative Perinatal Project to examine the relationship between schizophrenia and other nonaffective psychoses and a theoretically derived measure of hypoxic-ischemia-related fetal/neonatal complications. METHOD: Six hundred ninety-three men and women (average age 23) born to a community sample of women between 1959 and 1966 were followed up an average of 19 years after early childhood assessments. Subjects with DSM-IV schizophrenia and other nonaffective psychoses were identified using the Diagnostic Interview Schedule and best-estimate consensus diagnoses. RESULTS: Hypoxic-ischemia-related fetal/neonatal complications were associated with a doubling of the risk of developing a psychotic disorder, compared with no relevant complications (6.9% versus 1.4%). When mood disorders were excluded from the group of psychotic diagnoses, the risk of schizophrenia and other nonaffective psychoses associated with hypoxic-ischemia-related fetal/neonatal complications was strikingly elevated, compared with no relevant complications (5.75% versus 0.39%). Nonpsychotic mood disorders were unrelated to these fetal/neonatal complications. Schizophrenia and other nonaffective psychoses were most strongly associated with hypoxic-ischemia-related fetal/neonatal complications of disordered growth and development. CONCLUSIONS: The data show a strikingly elevated, graded, independent risk of schizophrenia and other nonaffective psychoses associated with this classification of antecedent hypoxic-ischemia-related fetal/neonatal complications.     

Associations between high factor VIII and low free protein S levels with traditional arterial thrombotic risk factors and their risk on arterial thrombosis: Results from a retrospective family cohort study

Introduction

Whether high factor (F)VIII and low free protein S levels are risk factors for arterial thrombosis is unclarified.

Material and Methods

In a post-hoc analysis of a single-centre retrospective family cohort, we determined if these two proteins could increase the risk of arterial thrombosis. In total, 1399 relatives were analysed.

Results

Annual incidence in relatives with high FVIII levels was 0.29% (95%CI, 0.22-0.38) compared to 0.13% (95%CI, 0.09-0.19) in relatives with normal FVIII levels. In relatives with low free protein S levels, this risk was 0.26% (95%CI, 0.16-0.40), compared to 0.14% (95%CI, 0.10-0.20) in relatives with normal free protein S levels. Mean FVIII levels adjusted for age and sex were 11 IU/dL, 18 IU/dL, and 21 IU/dL higher in relatives with hypertension, diabetes mellitus, and obesity as compared to relatives without these arterial thrombotic risk factors. Moreover, a dose response relation between increasing FVIII and body mass index was found. None of these associations were shown for free protein S.

Conclusions

High FVIII and low free protein S levels seemed to be mild risk factors for arterial thrombosis. High FVIII levels were particularly observed in relatives with traditional arterial thrombotic risk factors. Free protein S levels were not influenced by these thrombotic risk factors. This assumes that low free protein S levels were genetically determined.     

Genetic determinants of fasting and post-methionine hyperhomocysteinemia in patients with retinal vein occlusion

INTRODUCTION: Moderate hyperhomocysteinemia is considered a risk factor for both venous and arterial thrombosis. A prevalence of up to 30% of fasting hyperhomocysteinemia has been recently reported in patients with retinal vein occlusion (RVO) whereas conflicting data exist on the role of C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene as a risk factor for RVO. No report has been published on cystathionine beta-synthase (CBS) 844ins68 polymorphism (another genetic determinant of blood Hcy levels) in RVO patients. Moreover, scarce information is available on the usefulness of measuring homocysteine also after methionine loading to increase the diagnostic efficacy of hyperhomocysteinemia in RVO patients. MATERIALS AND METHODS: In 55 consecutive patients with diagnosis of RVO and 65 matched controls, plasma fasting total homocysteine (Hcy) levels and CBS and MTHFR polymorphisms were evaluated. In patients with normal fasting Hcy levels, post-methionine Hcy levels were determined. RESULTS: Moderate fasting hyperhomocysteinemia was detected in 18/55 patients (32.7%). In the remaining 37 patients, Hcy was measured again post-methionine loading (PML). Only 3/37 (8.1%) patients had PML hyperhomocysteinemia. Thus, the total prevalence of moderate hyperhomocysteinemia in this cohort of RVO patients was 21/55 (38.2%). The prevalence of homozygosity for C677T MTHFR genotype, but not that of heterozygosity for CBS844ins68, was significantly higher in RVO patients than in controls. CONCLUSIONS: Differently from what has been reported for arterial and/or venous thrombosis, a single fasting Hcy measurement is able to detect most of RVO patients (85.7%) with moderate hyperhomocysteinemia. C677T MTHFR, but not CBS 844ins68, genotype may play a role as risk factor for RVO.     

Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease

BACKGROUND: Hyperhomocysteinemia is a risk factor for vascular disease and potentially for dementia and depression. The most common cause of elevated homocysteine levels is deficiency of folate or vitamin B(12). However, patients with Parkinson disease (PD) may have elevated homocysteine levels resulting from methylation of levodopa and dopamine by catechol O-methyltransferase, an enzyme that uses S-adenosylmethionine as a methyl donor and yields S-adenosylhomocysteine. Since S-adenosylhomocysteine is rapidly converted to homocysteine, levodopa therapy may put patients at increased risk for vascular disease by raising homocysteine levels. OBJECTIVES: To determine whether elevations in plasma homocysteine levels caused by levodopa use are associated with increased prevalence of coronary artery disease (CAD), and to determine what role folate and vitamin B(12) have in levodopa-induced hyperhomocysteinemia. DESIGN/METHODS: Subjects included 235 patients with PD followed up in a movement disorders clinic. Of these, 201 had been treated with levodopa, and 34 had not. Blood samples were collected for the measurement of homocysteine, folate, cobalamin, and methylmalonic acid levels. A history of CAD (prior myocardial infarctions, coronary artery bypass grafting, or coronary angioplasty procedures) was prospectively elicited. We analyzed parametric data by means of 1-way analysis of variance or the t test, and categorical data by means of the Fisher exact test or chi(2) test. RESULTS: Mean +/- SD plasma homocysteine levels were significantly higher in patients treated with levodopa (16.1 +/- 6.2 micro mol/L), compared with levodopa-na?ve patients (12.2 +/- 4.2 micro mol/L; P<.001). We found no difference in the plasma concentration of folate, cobalamin, or methylmalonic acid between the 2 groups. Patients whose homocysteine levels were in the higher quartile (>or=17.7 micro mol/L) had increased prevalence of CAD (relative risk, 1.75; 95% confidence interval, 1.08-2.70;P=.04). CONCLUSIONS: Levodopa therapy, rather than PD, is a cause of hyperhomocysteinemia in patients with PD. Deficiency of folate or vitamin B(12) levels does not explain the elevated homocysteine levels in these patients. To our knowledge, this is the first report that levodopa-related hyperhomocysteinemia is associated with increased risk for CAD. These findings have implications for the treatment of PD in patients at risk for vascular disease, and potentially for those at risk for dementia and depression.     

Higher homocysteine concentrations in women undergoing caesarean section under general anesthesia

To determine whether homocysteine, a risk factor for possible endothelial cell dysfunction, procoagulant effects and premature vascular disease but with a potential nutritional role for fetal and neonatal metabolism and development, is elevated in women at time of elective caesarean section with nitrous oxide general anesthesia. Plasma homocysteine levels were measured in 50 consecutive women, 25 of whom undergoing vaginal delivery and 25 elective caesarean section under nitrous oxide general anesthesia, and in the cord plasma of the respective offspring. Mean (+/-standard deviation) plasma homocysteine levels in the women of the caesarean section group were significantly higher than in the women of the vaginal delivery group (9.77+/-2.3 vs. 6.60+/-2.6 micromol/l, respectively; p<0.02). Cord plasma homocysteine levels in the neonates of the caesarean section group were also significantly higher than in the group of neonates vaginally delivered (9.47+/-3.94 and 7.36+/-2.35 micromol/l; p<0.01). Maternal homocysteine levels significantly correlated with cord levels of caesarean and vaginally delivered neonates (r=0.57; p<0.01 and r=0.66; p<0.001, respectively). Homocysteine levels were elevated at time of delivery in women undergoing elective caesarean section in nitrous oxide general anesthesia, and cord levels of corresponding neonates were affected by mode of delivery. Future studies are necessary to identify factors involved in the hyperhomocysteinemia observed in pregnant women at time of delivery by elective caesarean section in general anesthesia.     

Risk factors for venous thrombosis in the black population

Risk factors for venous thrombo-embolism (VTE) in the black population are poorly characterized. Of 142 black cases tested a genetic cause was identified in only 9.1%: 4.2% had protein C deficiency, 2.8% protein S deficiency, 0.7% antithrombin deficiency and 1.4% were heterozygous for FV Leiden. We hypothesised that elevated factor VIII levels constitute a candidate risk factor for venous thrombosis in the black population. Factor VIII (FVIII:C) levels were determined in 100 black patients with VTE and 100 black controls in a case-control study. Of the patients 34% had a FVIII:C above 228 IU/dL (the 90th centile value in normal blacks) compared to 10% controls. Relative to those with FVIII:C below this value, odds ratio (OR) for risk of VTE was 4.64 (95% CI 2.02-10.85). When FVIII:C below 150 IU/dL was used as a comparator, OR was 11.1 (95% CI 4.29-29.43). There was evidence for a dose-response relationship. We propose that raised FVIII:C is a major risk factor for VTE in black subjects with prevalence and odds ratio exceeding those reported for white subjects.     

Lethal pontine hemorrhage in postpartum syndrome of hemolysis, elevated liver enzyme levels, and low platelet count

BACKGROUND: HELLP syndrome (a combination of hemolysis, elevated liver enzyme levels, and low platelet count) is a severe variant of preeclampsia that generally occurs before delivery but can occur post partum. This syndrome is more common than eclampsia and frequently leads to devastating neurological consequences such as intracerebral hemorrhage. OBJECTIVE: Although mentioned in the obstetric literature, there has been sparse reporting in the neurology literature specifically regarding intracerebral hemorrhage in HELLP syndrome. We illustrate such a case and review the existing literature regarding this severe complication. SETTING: Obstetric unit at an academic medical center. PATIENT: A 34-year-old primigravida experienced a pontine hemorrhage and subsequent respiratory arrest 22 hours after a normal delivery. This hemorrhage occurred 7 hours after the sudden onset of hypertension, severe headache, and intermittent abdominal pain. RESULTS: Laboratory and postmortem evidence suggested HELLP syndrome with disseminated intravascular coagulation as the cause of her intracerebral hemorrhage. CONCLUSIONS: Our case suggests the importance of the neurology consultant's familiarity with HELLP syndrome and the need for thorough laboratory testing and close monitoring in the puerperal patient with headache and hypertension.     

Effects of maternal hyperhomocysteinemia induced by methionine intake on oxidative stress and apoptosis in pup rat brain

Maternal hyperhomocysteinemia is associated with a number of complications such as preeclampsia syndrome, thromboembolic events, repeated miscarriages, abruptio placentae, in utero fetal death, intrauterine fetal growth restriction and fetal neural tube defects. However, little is known about the mechanism of homocysteine on the degeneration of fetal brain. Thus, our study is aimed to investigate the effects of maternal hyperhomocysteinemia on oxidative stress and apoptosis in pup brain. Hyperhomocysteinemia was induced in female rats by way of administrating methionine dissolved in water at a dose of 1 g/kg body weight throughout the pregnancy. After delivery, level of lipid peroxidation (LPO; as malondialdehyde + 4-hydroxyalkenals) was determined in various fractions of pub brains. Furthermore, DNA fragmentation, levels of Bcl-2 protein and p53 mRNA expression were determined to evaluate apoptosis. Significant elevation was found in the levels of LPO in subcellular fractions of pup brains delivered from hyperhomocysteinemic mothers. DNA fragmentation, a hallmark of apoptosis was observed in the brain of pups of homocysteine group while significant reduction was seen in the levels of anti-apoptotic Bcl-2 levels. In addition, maternal hyperhomocysteinemia increased cerebral p53 mRNA expression above the control value. As a conclusion, we demonstrate and suggest that the pups of hyperhomocysteinemic mothers have an increased oxidative stress in brain tissues. The increased oxidative stress appears to cause apoptosis and cell death. These results may be significant to understand chronic pathology of the complications of hyperhomocysteinemia and congenital malformations of fetuses.     

Homocysteine in neuropsychiatric disorders of the elderly

OBJECTIVE: There is increasing interest in homocysteine as a risk factor for neuropsychiatric disorders such as stroke, dementia, depression and Parkinson's disease. This article reviews the current literature on the relationship between homocysteine and these disorders to ascertain if any clinical recommendations can be made. METHOD: A MEDLINE and EMBASE search was made for English language publications between 1966 and 2002 using the search terms 'Homocysteine' and 'Stroke', 'Dementia', 'Vascular Dementia', 'Alzheimer's dementia', 'Cognition disorders or cognitive decline or memory disorders', 'Depression or depressive disorders' or 'Parkinson's disease'. In addition, individual articles were hand searched for relevant references. RESULTS: Cross-sectional studies consistently suggest that elevated homocysteine increases the risk of stroke, and may also increase the risk of leukoariosis, vascular dementia (VaD), cognitive impairment and Alzheimer's disease (AD). Longitudinal studies of homocysteine as a risk factor are few and inconsistently supportive of these associations. No intervention trials to determine the effect of lowering homocysteine levels have yet been published. The pathological mechanisms for homocysteine-mediated disease await complete elucidation. Mild hyperhomocysteinemia is common in the elderly population, and folate supplementation can decrease homocysteine levels. CONCLUSION: The epidemiological evidence for homocysteine as a risk factor for neuropsychiatric disease is an emerging area of great interest. Screening the population for hyperhomocysteinemia cannot be recommended at this stage, but individuals at increased risk of cerebrovascular disease or cognitive impairment should be investigated and treated for elevated homocysteine levels.     

Increased risk of gestational vascular complications in women with low free tissue factor pathway inhibitor plasma levels out of pregnancy

Tissue factor pathway inhibitor (TFPI) plays a crucial role in haemostasis by regulating TF-induced initiation of coagulation. Since it is expressed by endothelial and trophoblastic cells, TFPI is of particular importance at the placental level and might be involved in the occurrence of gestational vascular complications (GVC). In the present study, we investigated plasma free TFPI antigen in four groups of women: healthy non-pregnant women without history of pregnancy complications; women at the beginning (<12 weeks) and women during the third trimester of a normal pregnancy; women with late pregnancy complications (pre-eclampsia / HELLP syndrome, intra-uterine fetal death, fetal growth retardation) at the time of obstetrical event and/or at distance from pregnancy. In normal pregnancy, TFPI increased between first trimester and delivery (median 5.0 ng/ml vs. 7.1 ng/ml; p<0.0001) but remained lower than in non-pregnant controls (median 8.2 ng/ml; p<0.0001). In patients, when measured concomitantly to the obstetrical event, TFPI showed no difference with normal late pregnancy levels. In contrast, at distance from pregnancy, in the absence of any hormonal influence, TFPI was significantly lower than in non-pregnant controls (median 5.9 vs. 8.2ng/ml, p < 0.0001). After categorisation into quartiles, an inverse dose-effect relationship was demonstrated between TFPI categories recorded apart from pregnancy and GVC risk, with a crude odds ratio of 43.5 (95% confidence interval 8.2-230) for patients with TFPI values in the lowest quartile (< 5.7 ng/ml). In conclusion, low free TFPI at distance from pregnancy appears to be a strong indicator of GVC risk.     

Haplotypes encoding the factor VIII 1241 Glu variation, factor VIII levels and the risk of venous thrombosis

Levels of factor VIII (FVIII) are associated with the risk of venous thrombosis. The FVIII variation D1241E has been reported to be associated with decreased levels of FVIII. Our objective was to study whether D1241E is associated with levels of FVIII and the risk of venous thrombosis and whether this association is caused by D1241E or another linked variation. We analyzed the association of three FVIII gene haplotypes encoding 1241E (further denoted as HT1, HT3, and HT5) with FVIII levels and thrombosis risk. This analysis was performed in the Leiden Thrombophilia Study (LETS). The control populations of two case-controls studies on arterial thrombosis in men and women, respectively, were used to confirm the effects observed on FVIII:C in the LETS. In men, HT1 was associated with a 6% reduction in FVIII:C and with a reduced risk of venous thrombosis [odds ratio 0.4 (CI95 0.2-0.8)]. Logistic regression showed that the risk reduction was only partially dependent of the reduction in FVIII levels. HT1 showed no effects in women on either FVIII:C or risk of thrombosis. The number of carriers of HT3 and HT5 was too low to make an accurate estimate of the risk of venous thrombosis. Neither HT3 nor HT5 showed effects on levels of FVIII:C. When we consider that all three haplotypes encoding 1241E show different effects on FVIII:C and thrombosis risk, it is possible that D1241E is not the functional variation. However, FVIII gene variations do contribute to both levels of FVIII and the risk of thrombosis.     

Increased fasting total homocysteine plasma levels as a risk factor for thromboembolism in children

Elevated total homocysteine (tHcy) concentrations are an independent risk factor for thromboembolic events in adults. In children with moderate hyperhomocysteinemia data are sparse. Therefore, between 1995 and 2002 we consecutively recruited 163 white pediatric patients with a first symptomatic thromboembolic event and 255 healthy controls (mean age: 6.4 years in patients vs. 6.6 years in controls, range: 3 months to 18 years) and measured fasting tHcy levels. Median tHcy levels in patients were significantly higher (6.6 micromol/l, range 2.9-20.4 micromol/l) than in controls (5.7 micromol/l, 2.0-14.0 micromol/l, p<0.0001). 48 of the 163 patients with thromboembolism (29.5%) versus 26 of the 255 controls (10.2%) had tHcy levels above the age-specific normal 90th percentile (OR 2.9, 95%CI: 1.7-4.8). The odds ratio for children in the highest quintile compared to children with levels in the lowest quintile was 4.3 (1.6-8.1; highest quintile: median tHcy level 9.6 micromol, range 8.0-20.4), showing a significantly increased risk for thromboembolic disease with even mild hyperhomocysteinemia. We conclude that hyperhomocysteinemia above the age-specific cut-off values is a risk factor for thromboembolic events in children. Therefore, screening for elevated fasting tHcy levels of patients with thromboembolism is recommended to stratify the risk of thromboembolism.     

Familial aggregation of Alzheimer disease among whites, African Americans, and Caribbean Hispanics in northern Manhattan

BACKGROUND: Alzheimer disease (AD) aggregates in families. OBJECTIVE: To compare the familial aggregation and lifetime risk of AD to the age of 90 years in the first-degree relatives of patients with AD and unrelated controls among Caribbean Hispanics, African Americans, and whites in Washington Heights, Manhattan, New York, NY. METHODS: Family history of AD and demographic information were obtained from informants of 435 patients with probable or possible AD concerning 1577 siblings and parents and from 1094 controls without dementia concerning 3952 siblings and parents. RESULTS: Lifetime risk of AD to the age of 90 years was 25.9% in relatives of patients and 19.1% in relatives of controls. Rate ratio (RR) for AD in relatives of patients compared with relatives of controls was 1.5 overall (95% confidence interval [CI], 1.2-1.9), and was greater for siblings (RR, 1.8; 95% CI, 1.2-2.5) than for parents (RR, 1.2; 95% CI, 0.9-1.8). Within ethnic groups, RR for AD among relatives was significantly elevated in whites (RR, 2.0; 95% CI, 1.2-3.3) and Hispanics (RR, 1.5; 95% CI, 1.1-2.1), but the difference did not reach statistical significance in African Americans (RR, 1.4; 95% CI, 0.7-2.7). Risk of AD was greater among relatives who were women compared with men (RR, 1.5; 95% CI, 1.2-1.9). CONCLUSIONS: Familial aggregation of AD was increased among families of patients compared with those of controls in all 3 ethnic groups. Risk of AD was highest among siblings and women relatives.     

Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort

OBJECTIVE: Although case-control investigations have shown an association between obstetric complications and schizophrenia, particularly among patients with early onsets, cohort studies have mostly failed to confirm this effect. The authors examined whether a history of fetal hypoxia and other obstetric complications elevated risk for early-onset schizophrenia in a 1955 Helsinki birth cohort. METHOD: The subjects were 80 randomly selected patients with schizophrenia (36 with early and 44 with later onsets) representative of all available probands in the cohort, 61 of their nonschizophrenic siblings, and 56 demographically matched nonpsychiatric comparison subjects. Psychiatric diagnoses were obtained from structured clinical interviews, and obstetric data were taken from standardized, prospectively ascertained obstetric records. A score for hypoxia-associated obstetric complications was entered into logistic regression models, along with measures of prenatal infection and fetal growth retardation. RESULTS: Hypoxia-associated obstetric complications significantly increased the odds of early-onset schizophrenia but not of later-onset schizophrenia or unaffected sibling status, after prenatal infection and fetal growth retardation were taken into account. CONCLUSIONS: These findings support an association between obstetric complications and increased risk for early-onset schizophrenia. The authors advance a model whereby the neurotoxic effects of fetal hypoxia may lead to an early onset of schizophrenia due to premature cortical synaptic pruning.     

Increasing homocysteine levels and diabetic autonomic neuropathy

OBJECTIVE: To determine if hyperhomocysteinemia is a risk factor for the development of diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic autonomic neuropathy (DAN). BACKGROUND: Hyperhomocysteinemia and non-insulin-dependent diabetes mellitus (NIDDM) are both associated with premature vascular disease. Microvascular ischemia may be a risk factor for DSPN and DAN; therefore, the relationship of hyperhomocysteinemia to DSPN and DAN was investigated. METHODS: Baseline neurological tests and homocysteine levels were determined in patients from a large prospective study of diabetic complications, the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. RESULTS: Total homocysteine (tHcy) was independently associated with DAN; for each 1 micromol/l increase in tHcy, there was a 7.1% increased risk of developing DAN (P<0.05). There was no association between tHcy and DSPN. CONCLUSIONS: Hyperhomocysteinemia may be a risk factor for DAN but not for DSPN. This relationship may be related to differential small fiber injury. Further studies are needed to investigate this relationship between tHcy and DAN. specifically whether treatment of hyperhomocysteinemia may modify DAN.     

Risk factors for failure of heparin thromboprophylaxis in patients with acute traumatic spinal cord injury

Venous thromboembolism (VTE) is a well-recognized complication of Acute Traumatic Spinal Cord Injury (ATSCI). Despite prophylaxis by heparins, VTE occurs in a substantial number of ATSCI patients without an obvious explanation. In this matched case-control study we examined whether thrombophilia and other risk factors are associated with failure of thromboprophylaxis.Cases and controls receiving heparin thromboprophylaxis were selected from consecutively admitted ATSCI patients. Patients who developed a new, objectively confirmed, symptomatic VTE despite prophylaxis at hospital were matched by gender, age, level and mechanism of ATSCI with 2-3 controls without VTE. Patients were interviewed about VTE risk factors and tested for factor V Leiden (FVL), prothrombin G20210A (PT), methylenetetrahydrofolate reductase C677T homozygosity (MTHFR), lupus anticoagulant, homocysteine (Hcy) and plasma factor VIII (FVIII) levels.Twenty-two patients with new VTE episodes and 64 controls were ascertained. The total number of gene alterations for MTHFR, FVL and PT or elevated levels of Hcy or FVIII was significantly more common in patients compared to controls (82% vs. 48%, p = 0.006). Multiple logistic regression proved the PT mutation, a positive family history of thrombosis and elevated levels of either FVIII or Hcy to be predictors of thrombosis.

Conclusion

A positive family history of VTE, carriership of the prothrombin mutation and elevated FVIII or Hcy levels were significantly associated with failure to prevent VTE by heparin therapy following ATSCI. Testing for thrombophilia in patients with ATSCI and possibly a more intense thromboprophylactic regimen seem desirable but need to be verified by a prospective study.