Search

Introduction: Acute pulmonary embolism (PE) is a disease with a broad spectrum of clinical presentations. While some patients can be treated at home or may even be left untreated, other patients require an aggressive approach with reperfusion treatment. Areas covered: (1) Advanced reperfusion treatment in hemodynamically stable acute PE patients considered to be at high risk of decompensation and death, (2) the treatment of subsegmental pulmonary embolism, (3) outpatient treatment for hemodynamically stable PE patients with signs of right ventricle (RV) dysfunction, and (4) the optimal approach to identify and treatpost-PE syndrome. Expert opinion: Outside clinical trials, hemodynamically stable acute PE patients should not be treated with primary reperfusion therapy. Thrombolysis and/or catheter-directed therapy are only to be considered as rescue treatment. Subsegmental PE can be left untreated in selected low-risk patients, after proximal deep vein thrombosis has been ruled out. Patients with an sPESI or Hestia score of 0 criteria can be treated at home, independent of the presence of RV overload. Finally, health-care providers should be aware of post-PE syndrome and diagnose chronic thromboembolic pulmonary disease (CTEPD) as early as possible. Persistently symptomatic patients without CTEPD benefit from exercise training and cardiopulmonary rehabilitation.

The gut microbiome affects the development and progress of various types of disease such as obesity, diabetes, atherosclerosis and arterial thrombosis. Gut microbiome derived metabolites have been established to be predictive of arterial thrombosis in epidemiological studies. In these studies atherosclerosis and prothrombotic effect cannot be distinguished but preclinical studies show gut derived metabolites can induce platelet hyperreactivity and increase thrombotic potential. Gut commensals can also influence platelets through serotonin synthesis and may enhance Von Willebrand factor production. The effects on secondary haemostasis are less studied. In antiphospholipid syndrome, a thrombotic auto-immune disorder, autoreactive T cells and antibodies cross-react with auto-antigen mimicking peptides from gut commensals which appears to contribute to the pathophysiology. This review focusses on the prothrombotic effect of the gut microbiome and aims to provide insight into its influence on thromboembolic disease and the haemostatic system.

Objectives: This is a protocol for a Cochrane Review (diagnostic). The objectives are as follows:. To determine and compare the diagnostic accuracy of the clinically used tests for pregnancy-related DVT. This is a generic protocol that covers two separate reviews. The primary objectives of each review will be the following. Review one:. To determine the diagnostic accuracy of CDRs and D-dimer as triage tests for diagnosis of lower-extremity DVT during pregnancy and the postpartum period. CDR and D-dimer are analyzed as triage tests and will not be directly compared to each other since they are not alternatives but potentially complimentary. Review two:. To determine and compare the accuracy of US and MRI for diagnosis of lower-extremity DVT during pregnancy and the postpartum period. US and MRI are alternatives for the diagnosis of lower-extremity DVT in pregnancy and the postpartum period and will, therefore, be compared for diagnostic superiority if sufficient data are available, as will alternative CDRs. Secondary objectives Secondary objectives will be the following. To investigate the effects of different technological aspects of D-dimer assays, US, and MRI on test accuracy. These will include D-dimer assay types; use of Doppler flow measurement in US; MRI scanner type and scanning technique. To investigate the effect of different thrombus locations on US and MRI accuracy: distal (distal from popliteal vein), proximal (including and proximal from popliteal vein, but below the groin), and pelvic (above the groin). To investigate the effects of varying D-dimer cut-off values on test accuracy. To investigate the effect of trimester on test accuracy. To determine the number of inconclusive test results for US and MRI, defined as neither showing nor excluding DVT.

Background The intestinal microbiome plays a versatile role in the etiology of arterial thrombosis. In venous thrombosis, driven chiefly by plasma coagulation, no such role has yet been established. We hypothesized that the intestinal microbiome composition affects coagulation in humans. Methods We used healthy donor fecal microbiota transplant (FMT) to experimentally change the microbiome composition in metabolic syndrome patients. Thirty‐five subjects were randomized in a blinded fashion to healthy donor FMT or autologous FMT as a control in a 2:1 ratio. We measured thrombin generation at baseline and after 6 weeks using automated calibrated thrombinography, and we determined plasma abundance of 32 coagulation related proteins using a targeted mass spectrometry‐based quantitative proteomics assay with heavy labeled internal standards. Results Healthy donor FMT prolonged the thrombinography lag time (median delta 0.0 versus 0.25 minutes, P = .039). The other thrombinography parameters showed no significant difference. Unsupervised cluster analysis suggested overall downregulation of coagulation related plasma proteins in subject clusters containing predominantly subjects that had a metabolic response to healthy donor FMT. FMT treatment status itself showed no clear clustering pattern with up‐ or downregulation, however, and proteins did not cluster according to an apparent biological grouping. Discussion A single healthy donor FMT tends to modestly suppress the onset thrombin generation in metabolic syndrome patients, representing initial proof‐of‐principle that the intestinal microbiota composition might affect the coagulation system in humans. The findings merit external validation as a role for intestinal microbiota in coagulation can have clinically important implications.

Summary The rate of identified isolated subsegmental pulmonary embolism (ssPE) has doubled with advances in computed tomography pulmonary angiography (CTPA) technology, but its clinical relevance is debated. The YEARS diagnostic algorithm was shown to safely reduce the number of required CTPAs in the diagnostic management of PE. We hypothesized that the higher threshold for performing CTPA in YEARS was associated with a lower prevalence of ssPE compared to the conventional diagnostic algorithm. We compared 2291 consecutive patients with suspected PE managed according to YEARS to 3306 consecutive control patients managed according to the Wells score for the prevalence of isolated ssPE. In the YEARS cohort, 52% were managed without CTPA, 12% had pulmonary embolism (PE) of which 10% were isolated ssPE, and the 3‐month diagnostic failure rate was 0·35%. In the control cohort, 32% were managed without CTPA, 20% had PE of which 16% were isolated ssPE, and the 3‐month failure rate was 0·73%. The isolated ssPE prevalence was significantly lower in YEARS (absolute difference 6·2% (95% confidence interval [CI] 1·4–10), Odds Ratio 0·58 (95% CI 0·37–0·90). In conclusion, YEARS is associated with a lower prevalence of isolated ssPE, due to reduction in CTPAs by the higher D‐dimer threshold. This was however not associated with a higher risk of recurrent VTE during follow‐up.

Pulmonary embolism, although rare, is a leading cause of maternal mortality. There is no strong evidence base for the diagnosis and management of pregnancy-related pulmonary embolism, hampering firm recommendations. In women with a suspicion of pulmonary embolism, the diagnosis is confirmed in 1 in 25–30 women only. However, imaging is always necessary to exclude pulmonary embolism, as no clinical decision rules or D-dimer-based strategies have been validated in pregnancy. Computed tomography pulmonary angiography and pulmonary scintigraphy are both suitable modalities, unless deep vein thrombosis is confirmed by compression ultrasonography of lower limb veins. Low-molecular-weight heparin (LMWH) in therapeutic doses is the treatment of choice during pregnancy, and anticoagulation should be continued until 6 weeks after delivery with a minimum total duration of 3 months. Use of LMWH or vitamin K antagonists does not preclude breastfeeding. Whether dosing should be based on weight or anti-Xa levels is unknown, and practices differ between centres. Management of delivery, including the type of anaesthesia if deemed necessary, requires a multidisciplinary approach, and several options are possible, depending on local preferences and patient-specific conditions. Prevention of pulmonary embolism with LMWH is indicated in all postpartum women with a history of venous thromboembolism, and in most women also during pregnancy.

Thrombomodulin (Thbd) exerts pleiotropic effects on blood coagulation, fibrinolysis, and complement system activity by facilitating the thrombin-mediated activation of protein C and thrombin-activatable fibrinolysis inhibitor and may have additional thrombin- and protein C (pC)-independent functions. In mice, complete Thbd deficiency causes embryonic death due to defective placental development. In this study, we used tissue-selective and temporally controlled Thbd gene ablation to examine the function of Thbd in adult mice. Selective preservation of Thbd function in the extraembryonic ectoderm and primitive endoderm via the Meox2Cre-transgene enabled normal intrauterine development of Thbd-deficient (Thbd(-/-)) mice to term. Half of the Thbd(-/-) offspring expired perinatally due to thrombohemorrhagic lesions. Surviving Thbd(-/-) animals only rarely developed overt thrombotic lesions, exhibited low-grade compensated consumptive coagulopathy, and yet exhibited marked, sudden-onset mortality. A corresponding pathology was seen in mice in which the Thbd gene was ablated after reaching adulthood. Supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen prevented the pathologies of Thbd(-/-) mice. However, Thbd(-/-) females expressing the PC transgene exhibited pregnancy-induced morbidity and mortality with near-complete penetrance. These findings suggest that Thbd function in nonendothelial embryonic tissues of the placenta and yolk sac affects through as-yet-unknown mechanisms the penetrance and severity of thrombosis after birth and provide novel opportunities to study the role of the natural Thbd-pC pathway in adult mice and during pregnancy

Background: Inherited thrombophilias are genetic disorders in which mutation carriers have an elevated risk of venous thromboembolism through abnormalities in the coagulation cascade. These abnormalities all lead to increased thrombin generation. The mutations, of which factor V Leiden and prothrombin G20210A are the most common, therefore likely increase thrombin mediated protein C activation in plasma. Previous findings have however been inconsistent. Increased activation of protein C in inherited thrombophilia would be interesting in light of various unexplained phenotypes described in thrombophilia carriers. Examples of such phenotypes include improved fertility, increased risk of miscarriage, protection from diabetic nephropathy, decreased susceptibility to and mortality from sepsis and decreased mortality in acute respiratory distress syndrome. These do not appear directly related to increased coagulation in carriers. Activated protein C (APC) possesses a wide range of signaling functions and interactions with multiple pathways. These result in anti-apoptotic, anti-inflammatory, gene-expression, regenerative and endothelial stabilizing effects. Such properties can easily be thought to play a role in the above described phenotypes. APC has indeed been shown to possess beneficial properties in numerous animal injury models. Due to its pleiotropic nature, APC might be a promising candidate for further research into the unexplained phenotypes observed in inherited thrombophilia. Aim: To investigate if plasma APC concentrations are higher in thrombophilia carriers as compared to non-carriers. Methods: We performed a cross-sectional observational study comparing the APC plasma levels of factor V Leiden and prothrombin G20210A mutation hetero- and homozygotes with non-carriers. Exclusion criteria comprised use of anticoagulant medication and recent venous thrombosis or risk factors for venous thrombosis. We measured APC using a recently developed highly sensitive oligonucleotide-based capture assay, with a limit of detection of 0.022 ng/ml and the ability to quantify APC upward of 0.116 ng/ml (lower limit of quantification) (Müller et al., 2012). In addition we determined APC-protein C inhibitor complex (APC-PCI) as a secondary measure of protein C activation, and prothrombin fragment 1+2 (F1+2) concentration as a measure of thrombin generation using immunoassays. Parametric and non-parametric descriptive and inferential statistics were applied as appropriate. Results: We included 19 thrombophilia carriers and 18 non-carriers (Table 1). APC was detectable in 47% of carriers and in 39% of non-carriers (p = 0.74). APC was above the lower limit of quantification in only 19% of all subjects, with no difference between the groups (Figure 1). The median APC-PCI concentration in carriers and non-carriers were 5 AU (IQR 3.5-10.5) vs. 5 AU (IQR 3.0-8.0) (p = 0.338); and mean F1+2 concentrations were 266 pmol/L and 194 pmol/L in carriers and non-carriers respectively (p = 0.075). Discussion: We did not find increased circulating APC concentrations in thrombophilia carriers. Given the low number of subjects with quantifiable APC in the study, elevated APC levels in carriers versus non-carriers cannot be fully excluded. Local elevation at the site of thrombin formation still seems plausible, and our data do show a trend towards increased thrombin generation in thrombophilia carriers. However, we also show that systemic concentrations are generally below 0.116 ng/ml, which is an order of magnitude lower than concentrations previously reported as physiological levels. A prominent role for APC in non-coagulation related thrombophilia phenotypes might therefore be questioned. References Müller, J. et al. (2012). Journal of Thrombosis and Haemostasis : JTH, 10(3), 390-8. Measured APC concentrations above the limit of quantification, according to thrombophilia carriership status. Measured APC concentrations above the limit of quantification, according to thrombophilia carriership status. Figure 1 Figure 1. Disclosures Middeldorp: Boehringer Ingelheim: Consultancy; GSK: Consultancy, Honoraria; Aspen: Consultancy, Honoraria; BMS/Pfizer: Consultancy, Honoraria; Bayer: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Sanquin: Consultancy.

Background Pulmonary embolism is a leading cause of pregnancy-related death. An accurate diagnosis in pregnant patients is crucial to prevent untreated pulmonary embolism as well as unnecessary anticoagulant treatment and future preventive measures. Applied imaging techniques might perform differently in these younger patients with less comorbidity and altered physiology, who largely have been excluded from diagnostic studies. Objectives To determine the diagnostic accuracy of computed tomography pulmonary angiography (CTPA), lung scintigraphy and magnetic resonance angiography (MRA) for the diagnosis of pulmonary embolism during pregnancy. Search methods We searched MEDLINE and Embase until July 2015. We used included studies as seeds in citations searches and in 'find similar' functions and searched reference lists. We approached experts in the field to help us identify non-indexed studies. Selection criteria We included consecutive series of pregnant patients suspected of pulmonary embolism who had undergone one of the index tests (computed tomography (CT) pulmonary angiography, lung scintigraphy or MRA) and clinical follow-up or pulmonary angiography as a reference test. Data collection and analysis Two review authors performed data extraction and quality assessment. We contacted investigators of potentially eligible studies to obtain missing information. In the primary analysis, we regarded inconclusive index test results as a negative reference test, and treatment for pulmonary embolism after an inconclusive index test as a positive reference test. Main results We included 11 studies (four CTPA, five lung scintigraphy, two both) with a total of 695 CTPA and 665 lung scintigraphy results. Lung scintigraphy was applied by different techniques. No MRA studies matched our inclusion criteria. Overall, risk of bias and concerns regarding applicability were high in all studies as judged in light of the review research question, as was heterogeneity in study methods. We did not undertake meta-analysis. All studies used clinical follow-up as a reference standard, none in a manner that enabled reliable identification of false positives. Sensitivity and negative predictive value were therefore the only valid test accuracy measures. The median negative predictive value for CTPA was 100% (range 96% to 100%). Median sensitivity was 83% (range 0% to 100%). The median negative predictive value for lung scintigraphy was 100% (range 99% to 100%). Median sensitivity was 100% (range 0% to 100%). The median frequency of inconclusive results was 5.9% (range 0.9% to 36%) for CTPA and 4.0% (range 0% to 23%) for lung scintigraphy. The overall median prevalence of pulmonary embolism was 3.3% (range 0.0% to 8.7%). Authors' conclusions Both CTPA and lung scintigraphy seem appropriate for exclusion of pulmonary embolism during pregnancy. However, the quality of the evidence mandates cautious adoption of this conclusion. Important limitations included poor reference standards, necessary assumptions in the analysis regarding inconclusive test results and the inherent inability of included studies to identify false positives. It is unclear which test has the highest accuracy. There is a need for direct comparisons between diagnostic methods, including MR, in prospective randomized diagnostic studies.

In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir-boosted PI-containing regimen have virologic failure. We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load >500 copies/mL) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study. Ninety-three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients, 37 (40%) had virological failure, only 2 of them had had major PI mutations. The negative predictive values: probability of failure with lopinavir plasma concentration >1 µg/mL or hair concentrations >3.63 ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies per milliliter, of patients without PI resistance, could be explained by either having a low lopinavir concentration in plasma or hair. Most patients who fail a lopinavir/ritonavir regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent lopinavir/ritonavir use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing

International audience

a Maastricht University Medical Center, Laboratory for Clinical Thrombosis and Hemostasis, Cardiovascular Research Institute Maastricht (CARIM), Netherlands b Thrombosis Center, USA c McMaster University and Thrombosis and Atherosclerosis Research Institute, Canada d Vanderbilt University, Department of Pathology, Microbiology and Immunology, Nashville, USA e University of Groningen, University Medical Center Groningen, Department of Hematology, Netherlands f University of Leeds, Division of Cardiovascular and Diabetes Research, The LIGHT Labs, Leeds, UK g University of Amsterdam, Academic Medical Center, Department of Vascular Medicine, Netherlands h Erasmus University Medical Center, Rotterdam, Department of Hematology, Netherlands

Preeclampsia and small-for-gestational-age pregnancy are major causes of maternal and perinatal morbidity and mortality. Women with a previous pregnancy affected by these conditions are at an increased risk of recurrence in a future pregnancy. Past trials evaluating the effect of low-molecular-weight heparin for the prevention of recurrence of preeclampsia and small-for-gestational-age pregnancy have shown conflicting results with high levels of heterogeneity displayed when trials were compared. We sought to assess the effectiveness of enoxaparin in addition to high-risk care for the prevention of preeclampsia and small-for-gestational-age pregnancy in women with a history of these conditions. This was an open-label randomized controlled trial in 5 tertiary care centers in 3 countries. Women with a viable singleton pregnancy were invited to participate between >6(+0) and

BACKGROUND AND APPROACH: Thrombomodulin (Thbd) is a multifunctional transmembrane molecule expressed on endothelial, hematopoietic, placental trophoblast, and various other cells. Thbd facilitates protein C and TAFI activation by thrombin, but also exerts thrombin- and protein C-independent functions to regulate complement activity and inflammatory signaling. Complete Thbd deficiency causes embryonic death through as yet unclear mechanisms, while ablation of the lectin-like Thbd domain, reduction of Thbd cofactor activity for protein C (pC) activation, or truncation of the cytoplasmic domain do not impair embryonic development1-3. Here we applied in vivo structure-function and genetic complementation analyses to differentiate between pC-dependent and -independent Thbd functions. RESULTS: Three mouse strains with various function-selective Thbd mutations were generated, i.e. ThbdPro/ΔCS, ThbdEGF4-6, and ThbdLT (Table 1). Of these, only the latter mutant with defective thrombin-binding reproduced the embryonic lethal phenotype of complete Thbd deficiency. To examine the developmental role of Thbd expression in cell types other than placental trophoblast, Thbd LoxP mice carrying a conditional Thbd allele were crossed with mice expressing Cre recombinase under control of the endogenous Meox2 gene promotor, resulting in selective ablation of Thbd in the embryo proper, but preservation in extra-embryonic placental tissue. This yielded a normal number of Thbd-deficient embryos at term pregnancy. Preservation of Thbd function in the embryonic placenta therefore was sufficient to prevent intrauterine lethality until birth. Immunohistochemistry of term embryos and adult mice (week 10-16) confirmed persistent absence of Thbd expression. Half of Thbd-null mice were lost prior to weaning (3 weeks). Surviving mice were smaller, yet exhibited normal weight gain thereafter. By 4 weeks of age, 19 of 28 Thbd-deficient animals developed grossly observable lesions, i.e. purple discoloration and swelling of tail segments, followed by, edematic swelling and discoloration of the tail and hind limb digits, distal tail necrosis and/or uni- or bilateral eye degeneration. More than half of the Thbd-null mice expired within the first 10 weeks of life, and only 2 of 28 mice survived to week 40. Neither gross anatomical inspection nor histological surveys of internal organs revealed evidence of severe thrombotic organ damage, and except for elevated IL-6, cytokine plasma levels were normal. Tamoxifen-induced Thbd LoxP gene ablation in adult mice (10-12 week old) reproduced the phenotype of Meox2Cre-Thbd-null mice. Genetic supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen variant (“hyperactivatable” protein C4), prevented perinatal lethality, partially restored normal birth weight, and largely prevented the phenotype of Thbd-null mice. However, Thbd-null females expressing the pC transgene exhibited pregnancy-induced morbidity and mortality with complete penetrance. When mated to wild type males (embryonic placenta expresses Thbd), 8 of 8 pregnancies ended in death or severe distress during gestation or postpartum. CONCLUSIONS: These findings indicate that the lack of protein C activation by Thbd-bound thrombin is the sole cause of lethality of embryonic and adult Thbd-null mice; and that Thbd expression in extra-embryonic placental tissue is sufficient to prevent intra-uterine lethality. The mortality of pregnant Thbd-null females expressing the protein C transgene constitutes a novel model for pregnancy-specific complications associated with defects in the function of natural anticoagulant pathways. REFERENCES: 1. Isermann B et al. Nat Med. 2003;9(3):331-337. 2. Conway EM et al. Blood. 1999;93(10):3442-3450. 3. Conway EM et al. J Exp Med. 2002;196(5):565-577. 4. Isermann B et al. Nat Med. 2007;13(11):1349-1358. Figure. Survival of Thbd-null mice with and without the hyperactivatable PC transgene (hmPC). Figure. Survival of Thbd-null mice with and without the hyperactivatable PC transgene (hmPC). Disclosures No relevant conflicts of interest to declare.