Unselected women with elevated levels of factor VIII:C or homocysteine are not at increased risk for obstetric complications

Acquired and hereditary thrombophilias are associated with obstetric complications such as (pre-)eclampsia, HELLP syndrome and fetal loss. Our objective was to assess the risk of obstetric complications in women with elevated levels of FVIII:C or hyperhomocysteinemia, as compared with their relatives who had normal FVIII:C or homocysteine levels. From a large family study of patients with venous thromboembolism or premature atherosclerosis and elevated levels of FVIII:C or hyperhomocysteinemia (propositi), the obstetric histories of female first degree relatives, who had been pregnant at least once, were studied. Levels of FVIII:C and homocysteine (both fasting and post-methionine loading) were determined. The number of obstetric complications was calculated and compared in women with normal and elevated levels of FVIII:C, and normal and elevated levels of homocysteine. Women with elevated levels of FVIII:C had a 15.4% risk for toxicosis, preeclampsia, or HELLP syndrome and a 23.9% for fetal loss. This was not statistically different from women with normal levels of FVIII:C. Women with hyperhomocysteinemia tended to have a lower risk for toxicosis, pre-eclampsia, or HELLP syndrome (8.0%, RR 0.6, 95% CI 0.2-1.7) and fetal loss (22.0%, RR 0.8, 95% CI 0.5-1.5) as compared to relatives with normal levels, although these differences did not reach statistical significance. If the analysis was limited to comparing extremes, the results did not materially differ. Unselected women with elevated plasma levels of FVIII:C or hyperhomocysteinemia are not at increased risk for obstetric complications as compared to their relatives with normal levels.     

Thrombin activation of endometrial endothelial cells: a possible role in intrauterine growth restriction

Preeclampsia (PE), intrauterine growth restriction (IUGR) and abruption with or without fetal loss are associated with reduced uteroplacental blood flow, decidual vasculopathy, endothelial cell dysfunction, thrombosis, inflammation and hemorrhage. Our hypothesis is that reduced uteroplacental blood flow causes focal decidual hypoxia that generates vascular endothelial growth factor (VEGF). The latter acts directly on decidual endothelial cells to induce aberrant expression of tissue factor (TF), the primary initiator of coagulation. This in turn generates thrombin that induces: i) further TF expression; and ii) inflammatory cytokines. Both VEGF and TF induce aberrant angiogenesis-vessel maintenance reflected by endothelial cell fenestrations and induction of a prothrombotic surface causing both the decidual hemorrhage (i.e. abruption) and thrombosis (i.e. uteroplacental vascular insufficiency) observed in these adverse pregnancy outcomes. This novel hypothesis is supported by our finding of TF expression in decidual endothelium of pregnancies complicated by IUGR and/or fetal loss. Moreover, treatment of cultured endometrial endothelial cells with VEGF or thrombin induces TF protein and mRNA expression. Quantitative RT-PCR analysis indicates that thrombin enhances (>10-fold) the output of diverse inflammatory cytokines in these cultures. The greatest effect (>2-log) was seen on macrophage inflammatory protein 3alpha (MIP3alpha). In vitro, thrombin results in endometrial endothelial cell aggregations and changes in the apoptotic pathway. Thus, we postulate that reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes.     

Blood group AB and factor V Leiden as risk factors for pre-eclampsia: A population-based nested case-control study

IntroductionPre-eclampsia is an important cause of maternal morbidity and mortality. Its etiology is still unknown. Clinical symptoms correlate with activation of coagulation and inherited thrombophilia has been associated with pre-eclampsia. ABO blood group has been associated with thrombotic disorders and pre-eclampsia.We assessed ABO blood group, seven thrombophilia associated polymorphisms, and anti-beta2-glycoprotein I antibodies as risk factors for pre-eclampsia.Materials and methodsWe performed a population-based nested case-control study of 100,000 consecutive pregnancies in Finland. Cases and controls were identified by combining national registers and medical records were reviewed. We studied 248 cases fulfilling strict criteria for pre-eclampsia and 679 controls. Severe pre-eclampsia, early pre-eclampsia, and pre-eclampsia with intra-uterine growth restriction (IUGR) were analyzed separately.ResultsBlood group AB increased the risk for pre-eclampsia as a whole (OR 2.1, 95% CI 1.3-3.5), and in the three subgroups (OR 2.3, 3.8, 3.4; 95% CI 1.3-3.9, 2.0-7.1, 1.6-7.1). FV Leiden increased the risk as a whole (OR 1.7, 95% CI 0.8-3.9), and in the three subgroups, although not statistically significantly. Anti-beta2-glycoprotein I antibodies were not associated with pre-eclampsia. High body mass index, diabetes, first pregnancy, and twin pregnancy increased the risk from 1.5-fold to 8.2-fold.ConclusionsOur results confirm and extend the prior observation of blood group AB being a risk factor for pre-eclampsia. ABO blood group is known from all pregnant women. The value of blood group as risk factor for pre-eclampsia should be further assessed in prospective studies. In this study, FV Leiden was not statistically significant risk factor.     

Placental pathology and neurodevelopment of the infant with intrauterine growth restriction

The placentas of 68 infants with intrauterine growth restriction (IUGR) were examined for evidence of impaired uteroplacental circulation and compared with those of 65 appropriately grown infants. Infarcts and/or accelerated villous maturation were present in the placentas in 27 (40%) of the infants with IUGR compared with seven (11%) of the infants without IUGR (P<0.001). The infants were followed-up at 4 and 12 months of age and growth parameters recorded. Medical and developmental assessments and neuromotor developmental examinations were also performed. The 23 infants in the IUGR group with placentas with evidence of impaired uteroplacental circulation were compared with the 31 infants with IUGR with normal placentas. There was no difference between the groups in growth, cognitive development, or neuromotor abnormality. It was concluded that IUGR is strongly associated with placental markers of impaired uteroplacental blood flow while it would appear that there is no association between placental pathology and growth or neurodevelopment in the first year.     

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.     

Thrombophilia: implications for pregnancy outcome

There is growing evidence implicating congenital and acquired thrombophilias in the pathophysiological processes underlying miscarriage, intrauterine growth restriction (IUGR) and pre-eclampsia. Pregnancy itself is notably a hypercoagulable state, at least in part, due to the physiological changes in the coagulation and fibrinolytic systems; this has the potential for interaction with an acquired or heritable thrombophilia to cause adverse experiences. Recurrent fetal loss is associated with antiphospholipid antibody syndrome, procoagulant platelet microparticles and some inherited thrombophilias such as Factor V Leiden. There have been reports of both heritable and acquired thrombophilias being associated with pre-eclampsia, IUGR and abruption. However, these associations are not consistently reported with hereditary thrombophilias. The presence of thrombophilia might influence the severity of a condition such as pre-eclampsia, rather than cause it. The risk of fetal loss related to antiphospholipid syndrome can be reduced with antithrombotic therapy with heparin and low dose aspirin. Whether this extends to other thrombophilic conditions associated with adverse pregnancy outcome is not clear and further investigation is required. Screening for, and finding a, thrombophilic disease in patients with problems such as recurrent miscarriage, intrauterine death, intrauterine growth restriction and pre-eclampsia, may reflect an increased risk of venous thromboembolism (VTE).     

The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism

Factor VIII (FVIII), von Willebrand factor (vWF) and the ABO blood groups have been associated with thrombosis. The ABO locus has functional effects on vWF and FVIII levels and is genetically correlated with FVIII, vWF and thrombosis. We carried out a case-control study to assess the role of FVIII, vWF and ABO types on thrombotic risk. We analyzed 250 patients with venous thrombosis and 250 unrelated controls. FVIII, vWF and other factors related to thrombophilia were measured, ABO groups were analyzed by genotyping. FVIII and vWF were higher in non-O individuals. Group O was more frequent in the controls (44.3% v 23.3%; difference 21.1%; 95% CI: 13.0-29.3%) and Group A in patients (59.2% v. 41.5%; difference 17.7%, 95% CI: 9.1-26.4%). Individuals carrying the A1 allele had a higher risk of thrombosis (OR 2.6; 95% CI, 1.8-3.8). The risk attributed to vWF disappeared after adjusting for the ABO group. Patients with FVIII above the 90th percentile had a high thrombotic risk (adjusted OR 3.7; 95% CI, 2.1-6.5), and a high risk of recurrence (OR 2.3; 95% CI: 1.3-4.1). In conclusion, high FVIII levels and non-O blood groups, likely those with the A1 allele, are independent risk factors for venous thromboembolism and should be considered in evaluating of thrombophilia.     

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.     

von Willebrand因子和凝血因子Ⅷ 水平与急性脑梗死的临床转归

目的探索急性脑梗死患者血浆FVIII(factor VIII,FVIII)和VWF(von Willebrand factor,VWF)水平的升高与疾病的严重性、预后、住院期间发生感染或神经功能损伤加重等事件的关系。方法在2014年12月至2015年3月期间就诊于中国医科大学附属盛京医院神经内科的住院患者中,筛选出急性脑梗死病例组90例,无急性脑梗死的对照组50例,测定血浆FVIII和VWF水平。按两因子水平是否升高将病例组分成4组:FVIII和VWF均不升高组(FVIII-/VWF-)、FVIII升高且VWF不升高组(FVIII↑/VWF-)、FVIII不升高且VWF升高组(FVIII-/VWF↑)和FVIII和VWF均升高组(FVIII↑/VWF↑)。比较各病例组和对照组的临床特点。结果病例组的VWF水平的中位数1521.88 U/L,明显高于对照组的中位数1281.77 U/L(P=0.023)。与FVIII-/VWF-组相比,FVIII↑/VWF↑组急性脑梗死的发病症状较重(入院NIHSS评分5分)(OR=3.643,95%CI:1.258~10.549,P=0.017),疾病预后较差(3个月m RS评分2分)(OR=7,95%CI:2.304~21.266,P=0.001),出院时m RS评分2分者所占比例高(OR=3.797,95%CI:1.346~10.713,P=0.012),住院期间更易发生神经功能损伤加重(OR=5.538,95%CI:1.099~27.908,P=0.038),且更易并发感染(OR=3.913,95%CI:1.115~13.729,P=0.033)。对各种混杂因素进行校正后,发现FVIII和VWF水平同时升高是急性脑梗死患者预后不良的独立预测因素(OR=4.495,95%CI:1.012~19.957,P=0.048)。结论急性脑梗死患者很可能存在FVIII或VWF水平升高,二者水平同时升高可能对疾病的严重性及临床转归有影响,并且很可能是预后不良的独立预测因素。     

Intrauterine growth and neuropsychological performance in very low birth weight preschoolers

In this study we examined the association between intrauterine growth, indexed either as a categorical variable or continuous dimension, and neuropsychological outcome, in a very low birth weight (VLBW) sample of 143 preschoolers. When the commonly used split at the 10th percentile rank was applied to classify intrauterine growth restriction (IUGR), we found that the growth restricted group (n = 25) exhibited significantly poorer performance in the global motor domain, but not on any other neuropsychological measure. In contrast, when adequacy of intrauterine growth was indexed by standardized birth weight, a continuous dimension, this early risk factor explained a unique portion of the variance in global cognitive abilities and visuospatial skills, as well as in global, fine, and gross motor skills. These findings are consistent with recent magnetic resonance imaging data disclosing global neurodevelopmental changes in the brains of preterm infants with IUGR. When cases classified with IUGR (<10th percentile) were excluded, the relationship between adequacy of intrauterine growth and global cognitive abilities remained significant despite range restriction. Hence, an association between appropriateness of intrauterine growth and global intellectual outcome may be observed even within the population of VLBW preschoolers with adequate standardized birth weight.     

Platelet function and coagulation in normal and preeclamptic pregnancy

Platelet function and coagulation activity were followed prospectively throughout normal pregnancy and in puerperium in 17 healthy women. Plasma beta-thromboglobulin reflecting platelet activation increased progressively during pregnancy. This was not accompanied by any changes in platelet count or lifespan nor in serum or plasma thromboxane B2 levels. The levels of both factor VIII:C and factor VIIIR:Ag increased, the former less than the latter resulting in a rise of the FVIIIR:Ag/FVIII:C ratio. Antithrombin III (AT III), however remained unaltered. FVIIIR:Ag/FVIII:C ratio was increased both in mild (n = 7) and severe (n = 9) preeclampsia, whereas beta-thromboglobulin was increased and AT III was decreased only in severe preeclampsia. Platelet count and lifespan, plasma and serum thromboxane B2 as well as FVIII:C were normal in severe preeclampsia.     

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.     

Studies on the pathophysiology and treatment of von Willebrand's disease. VI. Variant von Willebrand's disease complicating placenta previa

The clinical course of a pregnant patient with a variant form of von Willebrand's disease (type IIA) who was complicated with placenta previa totalis, breech presentation and premature delivery is described. Following whole blood transfusion, she underwent a cesarean section without postoperative hemorrhagic complications. Factor VIII/von Willebrand factor (FVIII/vWF)-related activities (factor VIII procoagulant activity [VIII:C], factor VIII-related antigen [VIIIR:Ag] and ristocetin cofactor [VIIIR:RCo]), Duke bleeding time and platelet retention to glass beads were monitored during pregnancy, labor and puerperium. Gradual increase in FVIII/vWF-related activities and shortening of bleeding time were found during her gestation. Platelet retention, however, remained low. Qualitative analysis of plasma FVIII/vWF with crossed immunoelectrophoresis and gel filtration on Sepharose 2B demonstrated that the large forms of FVIII/vWF, which is important for primary hemostasis, did not appear in the blood during gestation. Therefore, patients with type IIA von Willebrand's disease seem to be more susceptible to bleeding complications at delivery.     

The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis

Background

The association between antiphospholipid antibodies (APLA) and placenta mediated pregnancy complications (pre-eclampsia, intrauterine growth restriction (IUGR), late fetal loss and placental abruption) remains controversial.

Methods

We performed a systematic review of published case-control, cohort and cross sectional studies (MEDLINE (1975 to 2009), EMBASE 16 (1980 to 2009) and all EBM Reviews (2009)) to evaluate the association between APLA and placenta mediated complications in untreated women without autoimmune diseases.

Results

Our search strategy identified 1207 potentially relevant studies. Twenty eight were included in the final analysis. LA was associated with pre-eclampsia (OR 2.34; 95%CI 1.18-4.64), IUGR (OR 4.65 95% CI 1.29-16.71) and late fetal loss (OR 4.73; 95%CI 1.08-20.81) amongst case-control studies and only with late fetal loss (OR 10.59 95% CI 1.87-59.88) amongst cohort studies. ACA were associated with pre-eclampsia (OR 1.52; 95%CI 1.05-2.20) and late fetal loss (OR 4.29; 95% CI 1.34-13.68) amongst case-control studies and only late fetal loss (OR 8.85 95% CI 1.84-42.50) amongst cohort studies. Finally, anti-B2 GP1 antibodies showed associations with pre-eclampsia (OR 19.14, 95% CI 6.34-57.77), IUGR (OR 20.03; 95%CI 4.59-87.43) and late fetal loss (OR 23.46, 95% CI 1.21-455.01) in two cohort studies.

Conclusion

APLAs appear to be associated with late fetal losses. However, the association between APLAs and other placenta mediated complications is inconsistent. LA is most strongly and consistently associated with placenta mediated complications. There are currently insufficient data to support a significant link between anti-B2 GP1 antibodies and pregnancy morbidity.     

Elevated factor VIII is a risk factor for idiopathic venous thromboembolism in Canada - is it necessary to define a new upper reference range for factor VIII?

Previous studies suggest elevated factor VIII is a common, independent risk factor for venous thromboembolism (VTE); however, these studies included secondary and idiopathic VTE. We sought to explore the association between elevated factor VIII and VTE in Canadian patients with idiopathic thrombosis, and confirm the current upper factor VIII reference range was appropriate. We enrolled 300 consecutive patients with idiopathic VTE who were matched to friend controls by age, sex and ethnicity. Factor VIII levels were measured and compared between cases and controls. The optimal cut-off value to designate factor VIII levels as elevated was determined using a variety of methods. The optimal upper cut-off value for factor VIII levels was 270 IU/dl. In the logistic regression analysis, cases were more likely to have elevated factor VIII levels (OR:8.76), as were females (OR:1.93) and older subjects (OR: 1.05). Factor VIII cutoffs for a 95% specificity by age were 238 IU/dl for subjects <40 years, 248 IU/dl age 40-55 years, 261 IU/dl age 56-70 years, and 313 IU/dl age >70. Our findings confirm that elevated factor VIII is associated with an increased risk of idiopathic VTE. In our patients and matched controls, the current upper limit of normal (150 IU/dl) for factor VIII is not of clinical use. We propose that the upper limit be increased to 270 IU/dl or individual labs should establish their upper limit if they wish their assays to be discriminatory in patients with VTE. Age specific cut-offs may be clinically relevant.     

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.     

Plasma fibrinopeptide A and beta-thromboglobulin in pre-eclampsia and pregnancy hypertension

Increased plasma levels of beta-thromboglobulin (beta TG) and fibrinopeptide A (FPA), markers of platelet release and thrombin generation respectively, were measured in normal women, women taking oral contraceptives, normal pregnancy and pregnant women with hypertension or pre-eclampsia. No significant increases in beta TG or FPA were found in women taking oral contraceptives. Significantly increased concentrations of beta TG, but not FPA, were found in normal pregnant women in the second and third trimester of pregnancy when compared with non-pregnant age-matched controls. In eleven women with pregnancy hypertension and thirteen women with pre-eclampsia significantly elevated levels of both beta TG and FPA were found when compared with age, parity and gestation-matched pregnant controls. Although the mean value for both beta TG and FPA in the group with pre-eclampsia was higher than the group with pregnancy hypertension, the difference was not statistically significant. These findings provide additional evidence that pre-eclampsia and pregnancy hypertension are associated with activation of the coagulation system and the platelet release reaction.     

Procoagulant stress reactivity and recovery in apparently healthy men with systolic and diastolic hypertension

OBJECTIVE: The aim of this study was to investigate whether systemic systolic hypertension (SHT) and diastolic hypertension (DHT) are associated with an exaggerated response of factor VII clotting activity (FVII:C), factor VIII clotting activity (FVIII:C), fibrinogen, and d-dimer to acute psychosocial stress. METHODS: We performed the 15-min Trier Social Stress Test (i.e., combination of task preparation, job interview and mental arithmetic) in a sample of 42 middle-aged apparently healthy and unmedicated men with normal and elevated blood pressure (BP) (i.e. screening systolic and/or diastolic BP>or=130/85 mmHg). Blood samples for coagulation measures were obtained immediately pre and post stress and 20 min and 60 min thereafter. Repeated measures analyses of covariance controlled for age, body mass index, screening mean arterial BP, and resting level of coagulation factors. RESULTS: There was a stress-by-DHT interaction for changes across all time points in FVII:C (P=.027), FVIII:C (P=.018), and d-dimer (P=.011) explaining between 14% and 17% of the variance. Compared to subjects without DHT, diastolic hypertensives had higher FVII:C immediately post stress (P=.085, Cohen's d=.60) and at 20-min recovery (P=.19, d=.46), higher FVIII:C at 20- (P=.028, d=.78) and at 60-min (P=.035, d=.75) recovery, and higher D-dimer at 20-min recovery (P=.10, d=.58). A significant stress-by-SHT interaction for fibrinogen (P=.050) became nonsignificant when controlling for covariates. CONCLUSION: Diastolic hypertension exaggerated the acute procoagulant response to stress in middle-aged men. This effect was particularly observed during recovery of hypercoagulability from stress. The findings suggest a psychobiological mechanism linking stress with an increased atherothrombotic risk in hypertensive individuals.     

Low density lipoprotein receptor-related protein polymorphisms are not risk factors for venous thromboembolism

Low-density lipoprotein receptor-related protein is a receptor involved in factor VIII catabolism. In spite of elevated factor VIII coagulant activity levels being a well-established independent risk factor for venous thrombosis, the origin of this abnormality is unknown. In this study, we investigated the role of polymorphisms C220T (exon 22), A775P (exon 14) and D2080N (exon 39) in the gene coding for this receptor in 249 patients (100 males/149 female, mean age 36.5 SD:11 years) with venous thromboembolism and 366 controls (155 male/211 females, mean age 38 SD:11 years ) matched by age and gender. The polymorphisms C220T (CT OR: 0.9, 95%CI: 0.6-1.2; TT OR: 1.0, 95%CI: 0.6-1.5) and D2080N (OR: 0.8, 95%CI: 0.3-2.4) were not associated to thrombosis susceptibility while the polymorphism A775P was identified in neither patients or controls. D2080N polymorphism was associated with factor VIII and von Willebrand factor levels, in the control group. Heterozygous individuals (DN), compared with homozygotes individuals (DD), presented lower levels of factor VIII (mean difference: 42.3 IU/dL, 95%CI: 5.7-78.9) and von Willebrand factor (mean difference: 34.8 IU/dL, 95%CI: 4.9-64.6). In conclusion, we demonstrated an association between D2080N polymorphism with factor VIII and von Willebrand factor levels in Brazilian normal individuals. However, none of the three polymorphisms in low-density lipoprotein receptor related protein gene were related to venous thrombosis risk in these patients.     

Endogenous or exogenous coagulation factor level and the response to activated protein C

BACKGROUND: The abnormal response to activated protein C could be the mechanism to explain the prothrombotic role of elevated coagulation factor levels. OBJECTIVE: We evaluated the effect of factor VIII, II, or X (FVIII, FII, or FX) levels on activated protein C resistance technique and its association with the resistant phenotype. MATERIALS AND METHODS: The correlation between APCR and FVIII was assessed in 36 samples, after Desmopressin infusion and the correlation between FII or FX and APCR in 15 patients with plasma levels between 100-125 U/dl. Also, the effect of the addition of purified human factors (FII, FX) to a normal plasma pool (final concentration: 100, 120, 140, 180, 220 U/dl) was estimated on the APCR technique. RESULTS: APCR values correlated with FVIII increase (r(Spearman) = 0.839; p < 0.001); APCR was abnormal (<2.4) in 9/36 samples, showing higher FVIII values in the abnormal group (VIII(abnormalAPCR) = 176.7 +/- 14.2; VIII(normalAPCR) = 103.5 +/- 8.0). APCR did not correlate with endogenous FII (r(Spearman) = 0.423) or FX (r(Spearman) = -0.169). However, the addition of human FII or FX to the normal plasma pool caused a decrease in APCR (r(SpearmanFII) = -0.843; r(SpearmanFX) = -0.958) without reaching abnormal (<2.4) results. FVIII levels may be associated with a resistant phenotype at values >153.0 U/dl, according to the linear regression analysis. Exogenous FII or FX levels greater than 120 U/dl would affect the APCR, without obtaining abnormal results. CONCLUSIONS: The data do not allow the direct association of the FII or FX increase with a defect in the protein C system in the current conditions.