Characterization of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Clusters Based on Integrated Genomic Surveillance, Outbreak Analysis and Contact Tracing in an Urban Setting.

BACKGROUND: Tracing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission chains is still a major challenge for public health authorities, when incidental contacts are not recalled or are not perceived as potential risk contacts. Viral sequencing can address key questions about SARS-CoV-2 evolution and may support reconstruction of viral transmission networks by integration of molecular epidemiology into classical contact tracing. METHODS: In collaboration with local public health authorities, we set up an integrated system of genomic surveillance in an urban setting, combining a) viral surveillance sequencing, b) genetically based identification of infection clusters in the population, c) integration of public health authority contact tracing data, and d) a user-friendly dashboard application as a central data analysis platform. RESULTS: Application of the integrated system from August to December 2020 enabled a characterization of viral population structure, analysis of 4 outbreaks at a maximum care hospital, and genetically based identification of 5 putative population infection clusters, all of which were confirmed by contact tracing. The system contributed to the development of improved hospital infection control and prevention measures and enabled the identification of previously unrecognized transmission chains, involving a martial arts gym and establishing a link between the hospital to the local population. CONCLUSIONS: Integrated systems of genomic surveillance could contribute to the monitoring and, potentially, improved management of SARS-CoV-2 transmission in the population.

Integrated genomic surveillance enables tracing of person-to-person SARS-CoV-2 transmission chains during community transmission and reveals extensive onward transmission of travel-imported infections, Germany, June to July 2021.

BackgroundTracking person-to-person SARS-CoV-2 transmission in the population is important to understand the epidemiology of community transmission and may contribute to the containment of SARS-CoV-2. Neither contact tracing nor genomic surveillance alone, however, are typically sufficient to achieve this objective.AimWe demonstrate the successful application of the integrated genomic surveillance (IGS) system of the German city of Düsseldorf for tracing SARS-CoV-2 transmission chains in the population as well as detecting and investigating travel-associated SARS-CoV-2 infection clusters.MethodsGenomic surveillance, phylogenetic analysis, and structured case interviews were integrated to elucidate two genetically defined clusters of SARS-CoV-2 isolates detected by IGS in Düsseldorf in July 2021.ResultsCluster 1 (n = 67 Düsseldorf cases) and Cluster 2 (n = 36) were detected in a surveillance dataset of 518 high-quality SARS-CoV-2 genomes from Düsseldorf (53% of total cases, sampled mid-June to July 2021). Cluster 1 could be traced back to a complex pattern of transmission in nightlife venues following a putative importation by a SARS-CoV-2-infected return traveller (IP) in late June; 28 SARS-CoV-2 cases could be epidemiologically directly linked to IP. Supported by viral genome data from Spain, Cluster 2 was shown to represent multiple independent introduction events of a viral strain circulating in Catalonia and other European countries, followed by diffuse community transmission in Düsseldorf.ConclusionIGS enabled high-resolution tracing of SARS-CoV-2 transmission in an internationally connected city during community transmission and provided infection chain-level evidence of the downstream propagation of travel-imported SARS-CoV-2 cases.

The von Willebrand factor Tyr2561 allele is a gain-of-function variant and a risk factor for early myocardial infarction.

The frequent von Willebrand factor (VWF) variant p.Phe2561Tyr is located within the C4 domain, which also harbors the platelet GPIIb/IIIa-binding RGD sequence. To investigate its potential effect on hemostasis, we genotyped 865 patients with coronary artery disease (CAD), 915 with myocardial infarction (MI), and 417 control patients (Ludwigshafen Risk and Cardiovascular Health Study) and performed functional studies of this variant. A univariate analysis of male and female carriers of the Tyr2561 allele aged 55 years or younger revealed an elevated risk for repeated MI (odds ratio, 2.53; 95% confidence interval [CI], 1.07-5.98). The odds ratio was even higher in females aged 55 years or younger, at a value of 5.93 (95% CI, 1.12-31.24). Cone and plate aggregometry showed that compared with Phe2561, Tyr2561 was associated with increased platelet aggregate size both in probands' blood and with the recombinant variants. Microfluidic assays revealed that the critical shear rate for inducing aggregate formation was decreased to 50% by Tyr2561 compared with Phe2561. Differences in C-domain circular dichroism spectra resulting from Tyr2561 suggest an increased shear sensitivity of VWF as a result of altered association of the C domains that disrupts the normal dimer interface. In summary, our data emphasize the functional effect of the VWF C4 domain for VWF-mediated platelet aggregation in a shear-dependent manner and provide the first evidence that a functional variant of VWF plays a role in arterial thromboembolism.

Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium.

Venous thromboembolism (VTE) is a leading cause of maternal mortality. Few studies have evaluated the individual risk of gestational VTE associated with heritable thrombophilia, and current recommendations for antenatal thromboprophylaxis in women with severe thrombophilia such as homozygous factor V Leiden mutation (FVL) depend on a positive family history of VTE. To better stratify thromboprophylaxis in pregnancy, we aimed to estimate the individual probability (absolute risk) of gestational VTE associated with thrombophilia and to see whether these risk factors are independent of a family history of VTE in first-degree relatives. We studied 243 women with the first VTE during pregnancy and the puerperium and 243 age-matched normal women. Baseline incidence of VTE of 1:483 pregnancies in women ≥35 years and 1:741 deliveries in women <35 years was assumed, according to a recent population-based study. In women ≥35 years (<35 years), the individual probability of gestational VTE was as follows: 0.7% (0.5%) for heterozygous FVL; 3.4% (2.2%) for homozygous FVL; 0.6% (0.4%) for heterozygous prothrombin G20210A; 8.2% (5.5%) for compound heterozygotes for FVL and prothrombin G20210A; 9.0% (6.1%) for antithrombin deficiency; 1.1% (0.7%) for protein C deficiency; and 1.0% (0.7%) for protein S deficiency. These results were independent of a positive family history of VTE. We provide evidence that unselected women with these thrombophilias have an increased risk of gestational VTE independent of a positive family history of VTE. In contrast to current guidelines, these data suggest that women with high-risk thrombophilia should be considered for antenatal thromboprophylaxis regardless of family history of VTE.

Sex hormones and venous thromboembolism - from contraception to hormone replacement therapy.

The use of sex hormones such as combined oral contraceptives (COC) or hormone replacement therapy (HRT) increases the risk for venous thromboembolism (VTE) considerably, especially in patients with an increased intrinsic risk for thromboembolic complications. Despite public and media attention and increasing scientific evidence, prescription patterns seem to be hard to change. It is well recognized that the patient's baseline risk is the most relevant factor in the absolute risk for developing VTE. The relative risk increase associated with sex hormones, depends on the type and dosage of hormones, the route of application (oral, vaginal, transdermal), and for COC, on the specific combination of oestrogen and gestagen components. Consequently, a careful decision for or against any specific type of hormone treatment needs to be based on an assessment of the patient's risk profile (disposition) as well as on the treatment-associated risks and benefits (exposition). This review discusses the most common sex hormone treatments in contraception and HRT, the relevance for VTE risk patients, and strategies to counsel patients with regard to hormone use according to their risk profiles. Keywords: Oral contraceptives, hormonal contraception, hormone replacement therapy, venous thromboembolism.

Independent adjudicator assessments of platelet refractoriness and rFVIIa efficacy in bleeding episodes and surgeries from the multinational Glanzmann's thrombasthenia registry.

Glanzmann's thrombasthenia (GT) is a rare congenital bleeding disorder associated with decreased platelet aggregation due to qualitative/quantitative deficiencies of the fibrinogen receptor. Severe bleeding episodes and perioperative bleeding are typically managed with platelet transfusions, although patients can develop anti-platelet antibodies or experience clinical refractoriness. The GT Registry (GTR) was established to collect efficacy/safety data on hemostatic treatments for GT, including recombinant factor VIIa (rFVIIa). At the request of the United States Food and Drug Administration, three hematology experts evaluated platelet refractoriness, antibody status, and rFVIIa efficacy data on a case-by-case basis to support a potential indication for rFVIIa in GT. Adjudication included 195 patients with 810 events (619 severe bleeding episodes, 192 surgeries), and a consensus algorithm was developed to describe adjudicators' coding of refractoriness and antibody status based on treatment patterns over time. Most rFVIIa-treated events were in patients without refractoriness or antibodies. Adjudicators rated most rFVIIa-treated bleeding episodes as successful (251/266, 94.4%; rFVIIa only, 101/109, 92.7%; rFVIIa ± platelets ± other agents, 150/157, 95.5%); efficacy was consistent in patients with platelet refractoriness ± antibodies (75/79, 94.9%), antibodies only (10/10, 100.0%), and neither/unknown (166/177, 93.8%). Adjudicators also rated most rFVIIa-treated surgeries as successful (159/160, 99.4%; rFVIIa only, 65/66, 98.5%; rFVIIa ± platelets ± other agents, 94/94, 100.0%); efficacy was consistent in patients with platelet refractoriness ± antibodies (69/70, 98.6%), antibodies only (24/24, 100.0%), and neither/unknown (66/66, 100.0%). Unblinding the adjudicators to investigator efficacy ratings changed few assessments. Doses of rFVIIa were narrowly distributed, regardless of other hemostatic agents used.

Treatment of pregnancy-associated venous thromboembolism - position paper from the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH).

Venous thromboembolism (VTE) is a major cause of maternal morbidity during pregnancy and the postpartum period. However, because there is a lack of adequate study data, management strategies for pregnancy-associated VTE must be deduced from observational stu-dies and extrapolated from recommendations for non-pregnant patients. In this review, the members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH) have summarised the evidence that is currently available in the literature to provide a practical approach for treating pregnancy-associated VTE. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low molecular weight heparin (LMWH) is the anticoagulant treatment of choice in cases of acute VTE during pregnancy. No differences between once and twice daily LMWH dosing regimens have been reported, but twice daily dosing seems to be advisable, at least peripartally. It remains unclear whether determining dose adjustments according to factor Xa activities during pregnancy provides any benefit. Management of delivery deserves attention and mainly depends on the time interval between the diagnosis of VTE and the expected delivery date. In particular, if VTE manifests at term, delivery should be attended by an experienced multidisciplinary team. In lactating women, an overlapping switch from LMWH to warfarin is possible. Anticoagulation should be continued for at least 6 weeks postpartum or for a minimum period of 3 months. Although recommendations are provided for the treatment of pregnancy-associated VTE, there is an urgent need for well-designed prospective studies that compare different management strategies and define the optimal duration and intensity of anticoagulant treatment.

Diagnosis of pregnancy-associated venous thromboembolism - position paper of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH).

Pregnancy and the postpartum period are associated with an increased risk of venous thromboembolism (VTE). Over the past decade, new diagnostic algorithms have been established, combining clinical probability, laboratory testing and imaging studies for the diagnosis of deep vein thrombosis (DVT) and pulmonary embolism (PE) in the non-pregnant population. However, there is no such generally accepted algorithm for the diagnosis of pregnancy-associated VTE. Studies establishing clinical prediction rules have excluded pregnant women, and prediction scores currently in use have not been prospectively validated in pregnancy or during the postpartum period. D-dimers physiologically increase throughout pregnancy and peak at delivery, so a negative D-dimer test result, based on the reference values of non-pregnant subjects, becomes unlikely in the second and third trimesters. Imaging studies therefore play a major role in confirming suspected DVT or PE in pregnant women. Major concerns have been raised against radiologic imaging because of foetal radiation exposure, and doubts about the diagnostic value of ultrasound techniques in attempting to exclude isolated iliac vein thrombosis grow stronger as pregnancy progresses. As members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH), we summarise evidence from the available literature and aim to establish a more uniform strategy for diagnosing pregnancy-associated VTE.

The international, prospective Glanzmann Thrombasthenia Registry: treatment modalities and outcomes of non-surgical bleeding episodes in patients with Glanzmann thrombasthenia.

Standard treatment for Glanzmann thrombasthenia is platelet transfusion. Recombinant activated factor VII has been shown to be successful in patients with Glanzmann thrombasthenia with platelet antibodies or who are refractory to platelet transfusions. The Glanzmann Thrombasthenia Registry prospectively collected worldwide information on the effectiveness and safety of platelet transfusion, recombinant activated factor VII and/or antifibrinolytics for the treatment of bleeds in patients with Glanzmann thrombasthenia. Data relating to 829 non-surgical bleeding episodes were entered into the Glanzmann Thrombasthenia Registry (severe/moderate: 216/613; spontaneous/post-traumatic: 630/199). Recombinant activated factor VII alone was used in 124/829 bleeds, recombinant activated factor VII+antifibrinolytics in 107/829, platelets±antifibrinolytics in 312/829, antifibrinolytics alone in 219/829, and recombinant activated factor VII+platelets±antifibrinolytics in 67/829. The proportion of successful treatments to stop bleeding was 91.0% in cases treated with recombinant activated factor VII only, 82.7% for recombinant activated factor VII+antifibrinolytics, 72.7% for treatment with recombinant activated factor VII+platelets±antifibrinolytics, 78.8% for platelets±antifibrinolytics and 84.7% for antifibrinolytics alone. Treatment failure was documented in 18 bleeding events (2% of the total treatments), the majority of which were in patients receiving treatment with antifibrinolytics; bleeding re-started in 6% of bleeds after initial effective treatment. Thirty-five adverse events were reported, none of which was a thromboembolic event. Among treatments that included recombinant activated factor VII, only one patient reported three possibly drug-related non-serious adverse events (nausea, dyspnea and headache). To conclude, non-surgical bleeds were common and often severe in Glanzmann thrombasthenia; both platelets and recombinant activated factor VII appeared to be effective, and with good safety profiles, for the treatment of non-surgical bleeds. This trial was registered at clinicaltrials.gov identifier: NCT01476423.

The international, prospective Glanzmann Thrombasthenia Registry: treatment and outcomes in surgical intervention.

Standard treatment for Glanzmann thrombasthenia, a severe inherited bleeding disorder, is platelet transfusion. Recombinant factor VIIa is reported to be effective in Glanzmann thrombasthenia with platelet antibodies and/or refractoriness to platelet transfusions. We aimed to evaluate recombinant factor VIIa effectiveness and safety for the treatment and prevention of surgical bleeding in patients, with or without platelet antibodies and/or refractoriness, using data from the Glanzmann Thrombasthenia Registry, an international, multicenter, observational, post-marketing study of rFVIIa. Between 2007 and 2011, 96 patients were treated for 206 surgical procedures (minor 169, major 37). History of platelet antibodies was present in 43 patients, refractoriness in 23, antibodies+refractoriness in 17, while 47 had no confirmed antibodies/refractoriness. Treatments analyzed included antifibrinolytics, recombinant factor VIIa, recombinant factor VIIa+antifibrinolytics, platelets±antifibrinolytics and recombinant factor VIIa+platelets±antifibrinolytics. The most frequent treatment for minor procedures was recombinant factor VIIa+antifibrinolytics (n=65), and for major procedures, recombinant factor VIIa+platelets±antifibrinolytics (n=13). In patients without antibodies/refractoriness, recombinant factor VIIa, either alone or with antifibrinolytics, and platelets±antifibrinolytics were rated 100% effective for minor and major procedures. The effectiveness of treatment for minor procedures in patients with antibodies and refractoriness was 88.9% for recombinant factor VIIa, 100% for recombinant factor VIIa+antifibrinolytics, 66.7% for platelets±antifibrinolytics and 100% for recombinant factor VIIa+platelets±antifibrinolytics. One of four adverse events reported for surgery was considered recombinant factor VIIa-treatment-related (non-fatal thromboembolic event in an adult female receiving recombinant factor VIIa+platelets+antifibrinolytics). For all patients, regardless of platelet antibody or refractoriness status, recombinant factor VIIa, administered with or without platelets (±antifibrinolytics), provided effective hemostasis with a low frequency of adverse events in surgical procedures in Glanzmann thrombasthenia patients. This trial was registered at clinicaltrials.gov identifier: 01476423.

Elevated lipoprotein(a) levels and homozygous human platelet antigen 1b (HPA-1b) genotype are risk factors for intrauterine growth restriction (IUGR).

The risk of premature manifestation of cardiovascular disease is higher in women after a maternal placental syndrome, especially with a history of fetal IUGR. Aim of the study was to assess hereditary risk factors for arterial thrombosis as risk factors for IUGR. 183 women with fetal IUGR birth weight below the 10th percentile for gestational age and 300 control women were evaluated using a case-control design. In 121 of the 183 women, the newborns' birth weight was below the 5th percentile for gestational age. A risk association could be shown for homozygous human platelet antigen 1b genotype (OR 3.2, P = 0.038) in women with a history for a newborn's birth weight below the 5th percentile. Elevated levels of lipoprotein(a) (>0.7 g/l [95 % percentile], OR 2.9, P = 0.048) also represent a risk association in the same group of subjects. So did elevated levels of lipoprotein(a) (>0.7 g/l [95 % percentile], OR 3.4, P = 0.015) in women with a history for a newborn's birth weight below the 10th percentile. Risk factors of arterial thrombosis such as platelet receptor genotypes associated with platelet thrombogenicity and elevated levels of lipoprotein(a) might be of importance in the pathogenesis of IUGR.

Epidemiological study about the mental state of patients after a pulmonary embolism or deep venous thrombosis event.

Venous thromboembolism (VTE) occurs frequently and represents a serious threat to patient health. However, its effects on mental health have not been studied sufficiently. The objective of this study was to investigate whether VTE alters the patients' mental state. We gathered questionnaire data on 100 patients (59 men, 41 women; age ranging from 24 to 85 years) concerning psychological symptoms and body image. Our results show that after a VTE, patients develop psychological symptoms, some of which persist for more than 2 years. Examples of those symptoms include depression, intrusion, and increased scrutiny of the body. Intrusion (flashbacks, nightmares, and other traumatic sensations of reliving the thrombotic event) affected 69% of patients and may lead to social isolation, occasionally including loss of employment. Depression affected more than 50% of patients. Productivity typically decreases, and body functionality and feeling of health changed in 34-76% of patients. However, anxiety, disordered impulse control, and maladjustment were less frequent (40% or less), and patients' emotional attitude to their bodies (liking their bodies or being angry with their bodies, feelings of shame and attractiveness) tended not to change over time. Nevertheless, we feel it may be advisable to identify patients with relevant psychological changes after VTE by means of a short evidence-based questionnaire and to offer them psychological treatment in order to improve management and quality of life of these patients. The goal is, therefore, to develop diagnostic and therapeutic recommendations.

Venous Thromboembolism Issues in Women.

The lifetime risk of venous thromboembolism (VTE) is slightly higher in women than in men. There are several issues related to VTE that are unique to women. Combined hormonal contraceptives and pregnancy increase the risk of VTE in women of childbearing age, whereas hormone replacement therapy increases the VTE risk of postmenopausal women. Hereditary thrombophilia and risk factors such as older age, obesity, or smoking contribute to the risk increase. In women diagnosed with acute hormone-related VTE who are treated with oral anticoagulants, adequate contraception is mandatory to avoid unwanted pregnancies. According to current knowledge, hormonal contraception may be continued during anticoagulant therapy but must be switched to an estrogen-free contraception method at least 6 weeks before the termination of anticoagulation. VTE is also a major cause of maternal morbidity and mortality during pregnancy and the postpartum period. Currently, assisted reproduction technologies such as in vitro fertilization are widely used to treat couples affected by infertility. Complications of fertility treatment comprise VTE cases, especially in women with ovarian hyperstimulation syndrome. With this review, we intended to focus on VTE issues in women and summarize current evidence and guideline recommendations.

Effective high-throughput RT-qPCR screening for SARS-CoV-2 infections in children.

Systematic SARS-CoV-2 testing is a valuable tool for infection control and surveillance. However, broad application of high sensitive RT-qPCR testing in children is often hampered due to unpleasant sample collection, limited RT-qPCR capacities and high costs. Here, we developed a high-throughput approach ('Lolli-Method') for SARS-CoV-2 detection in children, combining non-invasive sample collection with an RT-qPCR-pool testing strategy. SARS-CoV-2 infections were diagnosed with sensitivities of 100% and 93.9% when viral loads were >106 copies/ml and >103 copies/ml in corresponding Naso-/Oropharyngeal-swabs, respectively. For effective application of the Lolli-Method in schools and daycare facilities, SEIR-modeling indicated a preferred frequency of two tests per week. The developed test strategy was implemented in 3,700 schools and 698 daycare facilities in Germany, screening over 800,000 individuals twice per week. In a period of 3 months, 6,364 pool-RT-qPCRs tested positive (0.64%), ranging from 0.05% to 2.61% per week. Notably, infections correlated with local SARS-CoV-2 incidences and with a school social deprivation index. Moreover, in comparison with the alpha variant, statistical modeling revealed a 36.8% increase for multiple (≥2 children) infections per class following infections with the delta variant. We conclude that the Lolli-Method is a powerful tool for SARS-CoV-2 surveillance and can support infection control in schools and daycare facilities.

A single nucleotide polymorphism determines protein isoform production of the human c-FLIP protein.

The cellular FLICE-inhibitory protein (c-FLIP) is a modulator of death receptor-mediated apoptosis and plays a major role in T- and B-cell homeostasis. Three different isoforms have been described on the protein level, including the long form c-FLIP(L) as well as 2 short forms, c-FLIP(S) and the recently identified c-FLIP(R). The mechanisms controlling c-FLIP isoform production are largely unknown. Here, we identified by sequence comparison in several mammals that c-FLIP(R) and not the widely studied c-FLIP(S) is the evolutionary ancestral short c-FLIP protein. Unexpectedly, the decision for production of either c-FLIP(S) or c-FLIP(R) in humans is defined by a single nucleotide polymorphism in a 3' splice site of the c-FLIP gene (rs10190751A/G). Whereas an intact splice site directs production of c-FLIP(S), the splice-dead variant causes production of c-FLIP(R). Interestingly, due to differences in protein translation rates, higher amounts of c-FLIP(S) protein compared with c-FLIP(R) are produced. Investigation of diverse human cell lines points to an increased frequency of c-FLIP(R) in transformed B-cell lines. A comparison of 183 patients with follicular lymphoma and 233 population controls revealed an increased lymphoma risk associated with the rs10190751 A genotype causing c-FLIP(R) expression.

Hormonal Contraception. Guideline of the DGGG, OEGGG and SGGG (S3 Level, AWMF Registry Number 015/015, January 2020).

Aims This is an official interdisciplinary guideline published and coordinated by the German Society for Gynecology and Obstetrics (DGGG), the Austrian Society for Gynecology and Obstetrics (OEGGG) and the Swiss Society for Gynecology and Obstetrics (SGGG). The guideline was developed for use in German-speaking regions and is backed by numerous professional societies and organizations. The aim of this guideline is to provide an evidence- and consensus-based overview of the diagnostic approach and the management of hormonal contraception based on a systematic evaluation of the relevant literature. Methods To compile this S3-guideline, a systematic search for evidence was carried out in PubMed and the Cochrane Library to adapt existing guidelines and identify relevant reviews and meta-analyses. A structured evaluation of the evidence was subsequently carried out on behalf of the Guidelines Commission of the DGGG, and a structured consensus was achieved based on consensus conferences attended by representative members from the different specialist societies and professions. Recommendations Evidence-based recommendations about the advice given to women requesting contraception were compiled. The guideline particularly focuses on prescribing contraceptives which are appropriate to women's individual needs, take account of her personal circumstances, and have few or no side effects.

No evidence for increased intraoperative bleeding in aortic-valve stenosis: a comparative analysis of haemotherapy in 136 patients undergoing aortic-valve replacement.

OBJECTIVE: An association of aortic-valve stenosis and abnormal bleeding, particularly from gastrointestinal angiodysplasia, has been reported. In this setting, high-shear stress generated by the transvalvular gradient leads to a conformational change of plasmic von Willebrand factor, making this adhesive protein more susceptible for proteolytic cleavage. Consequently, highest-molecular weight multimers of the von Willebrand factor are degraded through a von Willebrand factor specific protease leading to impaired platelet-related haemostasis. METHODS AND RESULTS: To assess the role of aortic-valve stenosis as a factor predicting abnormal intraoperative bleeding in patients suffering from aortic-valve stenosis, we compared the number of intraoperatively administered blood components during aortic-valve replacement for aortic-valve stenosis (n = 50), aortic-valve insufficiency (n = 19) and combined aortic-valve defects (n = 67). As a result, the three subgroups did not differ significantly regarding the mean number of transfused red-blood cell units (0.94 +/- 1.36, 0.4 +/- 0.9, or 0.86 +/- 1.3, respectively) and plasma units (0.04 +/- 0.28, 0.21 +/- 0.71, or 0.15 +/- 0.61, respectively). None of the patients received platelet concentrates. A multivariate logistic regression model adjusted for age and gender did not show an influence of the presence and severity of aortic-valve stenosis on intraoperatively applied haemotherapy. CONCLUSION: Along with our findings, the presence or severity of aortic-valve stenosis does not predict an increased need for intraoperative transfusion of blood components. Thus, this cardiac defect does not seem to represent a major risk determinant for intraoperative bleeding despite the high prevalence of shear-stress induced von Willebrand factor abnormalities in this setting.

Prevention of Venous Thromboembolism during Pregnancy and the Puerperium with a Special Focus on Women with Hereditary Thrombophilia or Prior VTE-Position Paper of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH).

Venous thromboembolism (VTE) is a major cause of maternal morbidity during pregnancy and the postpartum period. Because there is a lack of adequate study data, management strategies for the prevention of VTE during pregnancy have mainly been deduced from case-control and observational studies and extrapolated from recommendations for non-pregnant patients. The decision for or against pharmacologic thromboprophylaxis must be made on an individual basis weighing the risk of VTE against the risk of adverse side effects such as severe bleeding complications. A comprehensive, multidisciplinary approach is often essential as the clinical scenario is made more complex by the specific obstetric context, especially in the peripartum period. As members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH), we summarize the evidence from the available literature and aim to establish a more uniform strategy for VTE risk assessment and thromboprophylaxis in pregnancy and the puerperium. In this document, we focus on women with hereditary thrombophilia, prior VTE and the use of anticoagulants that can safely be applied during pregnancy and the lactation period.

Causes, etiology and diagnosis of acquired von Willebrand disease: a prospective diagnostic workup to establish the most effective therapeutic strategies.

Acquired von Willebrand disease (aVWD) occurs in association with a variety of underlying disorders, most frequently in lymphoproliferative and myeloproliferative disorders, other malignancies, and cardiovascular disease. aVWD is a complex and heterogeneous defect with a multifactorial etiology and the pathophysiologic mechanisms remain unclear in many cases. Assays for anti-factor VIII (FVIII)/von Willebrand factor (VWF) activities often yield negative results although antibodies may be present in autoimmune disease and some lymphoproliferative disorders. Functional assays of VWF in patients' plasma and particularly in heart valve disease, VWF multimer analysis are important for aVWD diagnosis. In patients with normal partial thromboplastin times and normal VWF activity, the diagnosis of aVWD is based on clinical suspicion and a careful bleeding history, which should prompt the clinician to initiate further laboratory investigations. Management of bleeding in aVWD relies mainly on desmopressin, FVIII/VWF concentrates and high-dose intravenous immunoglobulin. The half-life of VWF may be very short, and in bleeding episodes high doses of FVIII/VWF concentrates at short intervals may be necessary even when high-dose intravenous immunoglobulin was applied before. Since the optimal treatment strategy has not yet been defined for aVWD of different etiology, controlled multicenter trials aiming at the development of standardized treatment protocols are urgently needed.