Pregnancy outcomes in women with Budd-Chiari syndrome or portal vein thrombosis A multicentre retrospective cohort study

OBJECTIVE: To evaluate current practice and outcomes of pregnancy in women previously diagnosed with Budd-Chiari syndrome and/or portal vein thrombosis, with and without concomitant portal hypertension. DESIGN AND SETTING: Multicentre retrospective cohort study between 2008-2021. POPULATION: Women who conceived in the predefined period after the diagnosis of Budd-Chiari syndrome and/or portal vein thrombosis. METHODS AND MAIN OUTCOME MEASURES: We collected data on diagnosis and clinical features. The primary outcomes were maternal mortality and live birth rate. Secondary outcomes included maternal, neonatal and obstetric complications. RESULTS: Forty-five women (12 Budd-Chiari syndrome, 33 portal vein thrombosis; 76 pregnancies) were included. Underlying prothrombotic disorders were present in 23 of 45 women (51%). Thirty-eight women (84%) received low-molecular-weight heparin during pregnancy. Of 45 first pregnancies, 11 (24%) ended in pregnancy loss and 34 (76%) resulted in live birth of which 27 at term age (79% of live births and 60% of pregnancies). No maternal deaths were observed, one woman developed pulmonary embolism during pregnancy and two women (4%) had variceal bleeding requiring intervention. CONCLUSIONS: The high number of term live births (79%) and lower than expected risk of pregnancy-related maternal and neonatal morbidity in our cohort suggest that Budd-Chiari syndrome and/or portal vein thrombosis should not be considered as an absolute contra-indication for pregnancy. Individualized, nuanced counselling and a multidisciplinary pregnancy surveillance approach are essential in this patient population

The role of tunneling in enzyme catalysis of C–H activation

AbstractRecent data from studies of enzyme catalyzed hydrogen transfer reactions implicate a new theoretical context in which to understand C–H activation. This is much closer to the Marcus theory of electron transfer, in that environmental factors influence the probability of effective wave function overlap from donor to acceptor atoms. The larger size of hydrogen and the availability of three isotopes (H, D and T) introduce a dimension to the kinetic analysis that is not available for electron transfer. This concerns the role of gating between donor and acceptor atoms, in particular whether the system in question is able to tune distance between reactants to achieve maximal tunneling efficiency. Analysis of enzyme systems is providing increasing evidence of a role for active site residues in optimizing the inter-nuclear distance for nuclear tunneling. The ease with which this optimization can be perturbed, through site-specific mutagenesis or an alteration in reaction conditions, is also readily apparent from an analysis of the changes in the temperature dependence of hydrogen isotope effects

Relevance of the JAK2V617F mutation in patients with deep vein thrombosis of the leg

Venous thromboembolism (VTE) can be the first presenting symptom in myeloproliferative neoplasms (MPN). Studies have demonstrated a high prevalence of the JAK2V617F mutation in patients with splanchnic vein thrombosis. Fewer studies have been done in patients with thrombosis outside the splanchnic area, showing a lower prevalence although the clinical relevance of the mutation in these patients, e.g., progression to overt MPN, remains unknown. The objective of this study was to determine the effect size of JAK2V617F in prospectively collected DNA samples of patients objectively diagnosed with deep vein thrombosis (DVT) of the leg and controls without DVT, with follow-up on JAK2V617F-positive patients to assess clinical relevance. Presence of JAK2V617F was determined in DNA samples from 187 patients with DVT and 201 controls, using quantitative RT-PCR. Hematological parameters were also analyzed. All initially JAK2V617F-positive patients were reassessed. Of 187 patients with DVT, 178 were analyzed for JAK2V617F, and in four (2.3%; 95% CI 0.1–4.4), JAK2V617F was present. Of 201 controls, 198 were analyzed; one was JAK2V617F positive (0.5%; 95% CI −0.5–1.5, OR 4.5; 95% CI 0.5–40.9). None had MPN features, nor upon reassessment after a median follow-up of 68.5 months. Four JAK2V617F-positive patients with DVT and one control without DVT did not develop overt MPN after a median follow-up of nearly 6 years. Thus, in patients with non-splanchnic venous thrombosis, JAK2V617F appears not to be clinically relevant

Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent

The results of early trials evaluating the tolerability, efficacy,and safety of specific antidotes for the DOACs are promising (Table 2), but none of these agents are as yet approved for clinical use. Until they are approved, clinicians attempting to reverse the anticoagulant effects of DOACs will be limited to the use of general hemostatic agents, such as(activated) PCCs or rFVIIa,3-12 and to hemodialysis or hemofiltration for removal of DOACs that are not highly protein-bound.The overall goal of using reversal agents is to prevent morbidity and mortality.23 Even without specific antidotes, the randomized trials have demonstrated that DOACs compared with standard therapies are associated with similar or lower rates of major bleeding and lower rates of intracranial bleeding,2,24 with similar or lower mortality rates after bleeding.25,26 In order to be approved for clinical use, future trials with specific antidotes will need to demonstrate their efficacy in clinical studies involving patients treated with DOACs. At this stage however, it is unclear whether regulatory agencies will require evidence of control of bleeding or whether demonstration of reversal of anticoagulant effects of DOACs will be sufficient for their approval. Demonstration of hemostatic efficacy will be challenging because bleeding of sufficient severity to require reversal of DOACs is uncommon, the half-life of DOACs are short, creating a limited window to administer the antidote, and the appropriate outcome measure for such studies is uncertain.However, because the overall goal of reversal agents is to prevent morbidity and mortality rather than to normalize prolonged coagulation tests, demonstration of hemostatic efficacy will be essential to establish that specific antidotes for DOACs can also make a clinically important differenc

Cerebral venous thrombosis and thrombophilia: a systematic review and meta-analysis

Cerebral venous thrombosis (CVT) is a rare manifestation of venous thromboembolism (VTE) and stroke. The aim of our systematic review was to provide an updated summary of the strength of association between CVT and thrombophilia and to explore the relevance of thrombophilia for recurrence of CVT or other VTE, or other outcome variables. MEDLINE (via PubMed), EMBASE (via Ovid), and CENTRAL were systematically searched, including references of retrieved articles. Cohort studies of ≥ 40 patients and case-control studies comparing the prevalence of thrombophilia in patients with CVT and unrelated controls were eligible. Two reviewers independently selected studies, assessed quality, and extracted data. A meta-analysis was performed for high quality case-control studies with unselected cases and healthy controls. Odds ratios with 95% confidence intervals were calculated and pooled. We included 23 cohort studies and 33 case-control studies. A significant association was demonstrated between CVT and all inherited thrombophilic factors, as well as increased levels of homocysteine. Inconclusive results were found on the relevance of thrombophilia for recurrent CVT or other VTE. Although there is a strong association between CVT and thrombophilia, the clinical relevance of thrombophilia testing in patients with CVT seems limited, similarly to other forms of VT

Cancer and venous thrombosis: current comprehensions and future perspectives

Venous thromboembolism (VTE) is a common complication in all types of cancer and adversely impacts cancer prognosis. Randomized controlled trials with primary thromboprophylaxis in cancer patients generally show effective VTE relative risk reductions of up to 60%. However, absolute risks of VTE were fairly low. Thromboprophylaxis should therefore only be recommended to cancer patients at highest risk of VTE, who may benefit most from prophylaxis. Predictive risk models to identify patients at a high risk of VTE are promising, however additional validation is required. An increasing proportion of cancer-associated VTE is formed by incidental VTE, with similar risk factors and clinical consequences. Randomized trials are not yet available, but it seems reasonable to treat incidental VTE similarly to symptomatic VTE. In a substantial proportion of patients with unprovoked VTE without known cancer at the time of VTE diagnosis, concomitant or occult cancer is identified. Studies have investigated the value of extensive screening over routine examinations alone for occult cancer. Although extensive screening may be able to identify more occult cancers, its clinical benefit over routine screening has not been demonstrate

Stroke and Thromboembolism in Patients with Heart Failure and Sinus Rhythm: A Matter of Risk Stratification?

Patients with heart failure (HF) in sinus rhythm (SR) experience an increased incidence of thromboembolic events including stroke. Among patients with HF, high-quality evidence supports the use of oral anticoagulation when atrial fibrillation is present, but the benefit of anticoagulation in SR in the absence of other known indications for anticoagulation is unclear. In four randomized controlled trials (RCTs), warfarin did not improve a composite of clinical outcomes compared with aspirin or placebo in patients with HF with reduced ejection fraction (HFrEF) and SR. A recent RCT assessed the efficacy of the direct oral anticoagulant rivaroxaban versus placebo in patients with HFrEF (including mildly reduced ejection fraction), SR, and coronary artery disease. While rivaroxaban had a neutral effect on the primary composite outcome of myocardial infarction, stroke, or all-cause mortality, exploratory analyses revealed a significant reduction in strokes. It is thus possible that a subgroup of patients with HFrEF who are at high risk of stroke may benefit from anticoagulation. The challenge is to adequately identify this subgroup and to balance the potential benefit of anticoagulation with the risk of major bleeding. There is also an unmet need for evidence around anticoagulation in HF with preserved ejection fraction and SR. This review explores the current evidence around anticoagulation in patients with HF and SR, identifies challenges regarding outcome definitions and patient selection, and offers suggestions for future research

Venous thromboembolism in adults treated for acute lymphoblastic leukaemia: Effect of fresh frozen plasma supplementation

Treatment of acute lymphoblastic leukaemia (ALL) is frequently complicated by venous thromboembolism (VTE). The efficacy and optimal approach of VTE prevention are unclear, particularly in adult patients. We assessed the effect of thromboprophylaxis on symptomatic VTE incidence in cycle 1 of ALL treatment in adult patients. Secondly, we explored potential etiologic factors for VTE and the clinical impact of VTE on ALL outcome. We retrospectively assessed symptomatic VTE incidence and use of thromboprophylaxis in 240 adults treated for newly diagnosed ALL in the Dutch-Belgian HOVON-37 multicentre study (1999-2005). Potential etiologic factors were explored by analysis of patient and disease characteristics, impact of VTE on ALL outcome by analysis of complete remission and overall survival rates. Symptomatic VTE was observed in 24 of 240 patients (10%). Thromboprophylaxis differed by centre (prophylactic fresh frozen plasma (FFP) supplementation or no thromboprophylaxis) and was applied only during L-asparaginase in cycle 1. VTE incidence was significantly lower with FFP supplementation than without FFP (6% vs. 19%; adjusted odds ratio [OR] 0.28; 95% confidence interval [CI] 0.10-0.73). FFP did not influence antithrombin or fibrinogen plasma levels. Patients with VTE in cycle 1 had a significantly poorer complete remission rate (adjusted OR 0.18; 95% CI 0.07-0.50), particularly patients with cerebral venous thrombosis (adjusted OR 0.17; 95% CI 0.04-0.65). Our study suggests that prophylactic FFP supplementation effectively reduces symptomatic VTE incidence during ALL treatment in adults. This should be confirmed in a randomised controlled tria