[Anti-Xa activity in LMWH treatment: when to assess and what to do with the result]. / Anti-Xa-activiteit bij laagmoleculairgewicht heparine.

The anti-factor Xa assay is designed to measure plasma low-molecular-weight heparin (LMWH) levels and to monitor heparin therapy. Notably, the results of anti-factor Xa testing cannot be used in the same way as the International Normalized Ratio (INR) is used to guide cumarin treatment: dose adjustments to remain in the therapeutic range have not been shown to be associated with better outcomes of care and lower rates of thrombotic and/or bleeding complications. The anti-factor Xa activity should therefore only be assessed in cases of considerable concern regarding an LWMH under- or overdosis. It is reasonable to lower the LMWH dose in case of a supratherapeutic anti-factor Xa activity. Increasing the LMWH dose in case of a subtherapeutic anti-factor Xa activity should however only be considered in case of morbid obesity or in the setting of breakthrough thrombosis in patients receiving therapeutic dosed LMWH, as long as the anti-factor Xa activity remains below the upper-level of the recommend range.

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders.

BACKGROUND: In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). METHODS: We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. FINDINGS: We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years (p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. INTERPRETATION: Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. FUNDING: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

An evidence-based approach to pre-pregnancy counselling for patients with systemic lupus erythematosus.

Patients with SLE are often young females of childbearing age and a pregnancy wish in this patient group is common. However, SLE patients are at high risk for adverse pregnancy outcomes that require adequate guidance. It is widely acknowledged that pre-pregnancy counselling is the pivotal first step in the management of SLE patients with a wish to become pregnant. Next, management of these patients is usually multidisciplinary and often requires specific expertise from the different physicians involved. Very recently a EULAR recommendation was published emphasizing the need for adequate preconception counselling and risk stratification. Therefore the present review specifically addresses the issue of pre-pregnancy counselling for SLE patients with an evidence-based approach. The review summarizes data retrieved from recently published, high-quality cohort studies that have contributed to a better understanding and estimation of pregnancy-related risks for SLE patients. The present review categorizes risks from a patient-oriented point of view, that is, the influence of pregnancy on SLE, of SLE on pregnancy, of SLE on the foetus/neonate and of SLE-related medication. Lastly, pre-pregnancy counselling of SLE patients with additional secondary APS is reviewed. Collectively these data can guide clinicians to formulate appropriate preventive strategies and patient-tailored monitoring plans during pre-pregnancy counselling of SLE patients.

Effect of fibrinolysis on bleeding phenotype in moderate and severe von Willebrand disease.

Patients with von Willebrand disease (VWD), the most common inherited bleeding disorder, display large variation in bleeding tendency, which is not completely related to VWF levels. The cause of variability in clinical expression is largely unknown. The effect of plasma fibrinolytic capacity on bleeding tendency in VWD patients has not been investigated. We hypothesized that enhanced fibrinolysis may result in a more severe bleeding phenotype. Therefore, we measured the fibrinolytic potential in patients with moderate or severe VWD to investigate the contribution of fibrinolysis to the bleeding tendency. Fibrinolytic potential was measured as plasma clot lysis time (CLT) with and without addition of potato carboxypeptidase inhibitor (PCI) in 638 patients with moderate or severe VWD who participated in a nationwide multicentre cross-sectional study. Bleeding severity was measured using the Bleeding Score (BS).The CLTs were significantly longer, indicative of hypofibrinolysis, in men compared to women with VWD [106.2 (IQR 95.7-118.1) vs. 101.9 (IQR 92.8-114.0) min]. The CLTs prolonged with increasing age. No association was found between VWF or FVIII levels and CLT, or between VWF or FVIII levels and CLT(+PCI) . No association was observed for BS in a model with 10log-transformed CLT, adjusted for age, gender, VWF:Act and FVIII [b = 6.5 (95%CI -0.3 to 13.4)]. Our study showed that the plasma fibrinolytic potential does not influence bleeding tendency in VWD patients and therefore does not explain the variability in bleeding phenotype in VWD.

Plasma levels of microparticle-associated tissue factor activity in patients with clinically suspected pulmonary embolism.

INTRODUCTION: Microparticles (MPs) carrying active tissue factor (TF) have been detected in the plasma of cancer patients in particular in those presenting with acute deep vein thrombosis (DVT) or pulmonary embolism (PE). Experimental studies in mice have revealed that circulating MPs carrying TF contribute to thrombus formation. AIM: To study whether unselected patients with an acute confirmed PE have elevated TF activity in the MP fraction (MP-TF activity). MATERIALS AND METHODS: Plasma MP-TF activity was measured in 159 non-selected patients with clinically suspected PE and in 48 healthy controls as previously described. Blood was collected at time of inclusion. The diagnosis of acute PE was confirmed in 54 patients and excluded in 105 patients. RESULTS: Median MP-TF activity in 159 patients with clinically suspected PE was 72 fM Xa/min [range 32-6657] fM Xa/min and higher than in healthy controls (66 [range 28-183] fM Xa/min; P<0.05). There was no significant difference (P=0.169) in MP-TF activity between patients with confirmed PE (median 84.5 fM Xa/min [range 36-2149]) and patients without PE (72 fM Xa/min [range 32-6657]) fM Xa/min). In the 159 patients with clinically suspected PE we observed in an exploratory analysis higher MP-TF activity levels in patients with active cancer (median 137 fM Xa/min [range 36-6657]) and cardiovascular disease (median 131.5 fM Xa/min [range 45-2149]) than in patients without these disorders (P=0.0004 and P=0.014, respectively). CONCLUSION: In patients presenting with clinically suspected PE plasma MP-TF activity was not associated with confirmed PE.

Health-related quality of life among adult patients with moderate and severe von Willebrand disease.

SUMMARY BACKGROUND: von Willebrand Disease (VWD) is the most frequent inherited bleeding disorder. It is unknown how this disorder affects quality of life. OBJECTIVES: This nationwide multicenter cross-sectional study determined health-related quality of life (HR-QoL) in adult patients with moderate or severe VWD, and assessed whether bleeding severity and type of VWD are associated with HR-QoL. METHODS: HR-QoL was assessed using the Short Form (SF)-36, and bleeding severity was measured using the Bleeding Score (BS). RESULTS: Five hundred and nine patients participated; 192 males and 317 females, median age and range 45 (16-87) and 47 (16-84) years, respectively. Compared with the general population, HR-QoL in VWD patients was lower in the vitality domain (61 vs. 66 P < 0.001 for females, 67 vs. 72 P < 0.001 for males). Patients with the most severe bleeding phenotype (highest quartile BS, BS > 17) had a lower HR-QoL in eight domains than patients with a less severe bleeding type (lowest quartile BS, BS < 7) in the univariate analysis. After adjustment for age, gender, co-morbidity and employment/educational status, a more severe bleeding phenotype was associated with lower scores on the domains of physical functioning, role limitations due to physical functioning, bodily pain, general health, social functioning and physical component summary. CONCLUSIONS: HR-QoL is lower in VWD patients compared with the general population. HR-QoL is strongly associated with bleeding phenotype.

High D-dimer level is associated with increased 15-d and 3 months mortality through a more central localization of pulmonary emboli and serious comorbidity.

High D-dimer levels are predictors of death in patients with pulmonary embolism (PE), as are more proximally located, larger emboli. The direct link between these three has not yet been described. A cohort of 674 consecutive patients with confirmed PE was studied. Patients were followed up for 3 months. D-dimer levels were measured only in patients with an unlikely clinical probability (n = 262). The odds ratio (OR) for death of all variables was calculated. Multivariate analysis was performed to identify independent risk factors for mortality. The best predictive D-dimer cut-off point for mortality was a concentration >3000 ng/ml FEU (OR 7.29). High D-dimer levels were correlated with active malignancy and age over 65 years, both being indicators of 3-month mortality. High D-dimer levels were also correlated with centrally located pulmonary emboli and 15-d mortality. The combination of high D-dimer levels and central emboli increased early mortality risk by 2.2. High D-dimer levels in patients with an unlikely clinical probability were associated with fatal outcome after PE. Centrally located pulmonary emboli were associated with higher D-dimer levels and worse 15-d mortality. Active malignancy, being an inpatient at time of diagnosis and age over 65 years were associated with higher D-dimer levels and worse 3-month survival.

von Willebrand factor and its propeptide: the influence of secretion and clearance on protein levels and the risk of venous thrombosis.

BACKGROUND AND OBJECTIVES: Elevated levels of factor (F)VIII are associated with an increased risk of thrombosis. FVIII levels are determined mainly by von Willebrand factor (VWF). We have investigated the contribution of secretion and clearance rates to the elevated VWF antigen (VWF:Ag) and to the risk of thrombosis. VWF is secreted in equimolar amounts with its propeptide, which has a shorter half-life. VWF propeptide can be used as a measure of VWF secretion and allows estimation of the VWF half-life. METHODS AND RESULTS: We have measured VWF propeptide, VWF:Ag, FVIII:Ag and FVIII activity (FVIII:C) in the Leiden Thrombophilia Study. In controls, high VWF propeptide was associated with high VWF:Ag, FVIII:Ag and FVIII:C. In contrast to mature VWF:Ag, VWF propeptide was not influenced by blood groups. Using an ELISA-based assay we have shown that VWF propeptide lacks ABO antigens. Levels were higher in men and increased with age. A long VWF half-life was also associated with high VWF:Ag, FVIII:Ag and FVIII:C. The VWF half-life was influenced by blood group (10 h in O vs. 12 h in non-O individuals), but not by sex, and only slightly by age. VWF propeptide was higher in thrombosis patients than in controls. The VWF half-life was similar in patients and controls (11.4 and 11.1 h, respectively). CONCLUSIONS: Both secretion and clearance rates are important determinants of VWF and FVIII levels. However, mainly high VWF and FVIII levels caused by increased secretion seem to be associated with thrombosis. ABO blood group influences the clearance rates of VWF rather than VWF secretion rates.

Efficacy, safety and user-friendliness of two devices for postoperative autologous shed red blood cell re-infusion in elective orthopaedic surgery patients: A randomized pilot study.

To determine the safety, efficacy and user-friendliness of two different postoperative autologous blood re-infusion systems, an open, randomized, controlled study was performed. Eligible consecutive primary and revision total hip and knee replacement patients were randomized for one of the two systems or for a control group in which shed blood was not re-infused. The nursing staff scored user-friendliness. Patients were monitored after re-infusion. In all three patient groups, a restrictive transfusion trigger was used. Sixty-nine of 70 randomized patients were evaluated. Ease of use, efficacy and safety of both re-infusion systems were comparable. There was no difference in allogeneic blood use between the groups. Thirty per cent of the patients re-infused with autologous blood developed a mainly mild, febrile transfusion reaction. No other adverse reactions were seen. Signs of coagulopathy after re-infusion were not found. In multivariate analysis, autologous re-infusion was an independent factor associated with a shorter hospital stay. Both postoperative autologous blood re-infusion systems were of equal efficacy and safety. The contribution of autologous wound blood re-infusion to reduce allogeneic transfusions must be investigated in a larger study.

[High concentration of coagulation factor VIII as a risk factor for thrombosis]. / Hoge concentratie van stollingsfactor VIII als risicofactor voor trombose.

Several case-control studies have shown that factor VIII levels > or = 150 IU/100 ml lead to a greatly increased risk of venous thrombosis. High levels of factor VIII are also associated with an increased risk of recurrences of thrombosis. The prevalence of high factor VIII levels is 25% in patients with a first episode of venous thrombosis and 11% among healthy controls. The contribution of high factor VIII levels to the onset of venous thrombosis in the population is 16%. The mechanism causing high factor VIII levels is largely unknown and probably consists of both genetic and acquired factors. At present, the routine screening of thrombosis patients for high factor VIII levels is not recommended.

[Hypothermia during use of pipamperone]. / Hypothermie bij gebruik van pipamperon.

Two women aged 84 and 86 years developed hypothermia after use of pipamperone. In one of the patients repeated administration of pipamperone again induced a decrease of body temperature. Although other clinical and environmental factors may have contributed to the development of hypothermia, a causal relationship between the use of pipamperone and the fall in body temperature appears likely considering the close temporal relationship. Hypothermia has been documented as a side effect of neuroleptics, especially phenothiazines, but it has not been reported in relation to pipamperone. Hypothermia is a potentially lethal condition; the cases described confirm the necessity of being careful with use of neuroleptics in elderly people.