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Aims: Anticoagulation was associated with improved survival of hospitalized coronavirus disease 2019 (COVID-19) patients in large-scale studies. Yet, the development of COVID-19-associated coagulopathy (CAC) and the mechanism responsible for improved survival of anticoagulated patients with COVID-19 remain largely elusive. This investigation aimed to explore the effects of anticoagulation and low-molecular-weight heparin (LMWH) in particular on patient outcome, CAC development, thromboinflammation, cell death, and viral persistence., Methods and Results: Data of 586 hospitalized COVID-19 patients from three different regions of Austria were evaluated retrospectively. Of these, 419 (71.5%) patients received LMWH and 62 (10.5%) received non-vitamin-K oral anticoagulants (NOACs) during hospitalization. Plasma was collected at different time points in a subset of 106 patients in order to evaluate markers of thromboinflammation (H3Cit-DNA) and the cell death marker cell-free DNA (cfDNA). Use of LMWH was associated with improved survival upon multivariable Cox regression (hazard ratio = 0.561, 95% confidence interval: 0.348-0.906). Interestingly, neither LMWH nor NOAC was associated with attenuation of D-dimer increase over time, or thromboinflammation. In contrast, anticoagulation was associated with a decrease in cfDNA during hospitalization, and curtailed viral persistence was observed in patients using LMWH leading to a 4-day reduction of virus positivity upon quantitative polymerase chain reaction [13 (interquartile range: 6-24) vs. 9 (interquartile range: 5-16) days, P = 0.009]., Conclusion: Time courses of haemostatic and thromboinflammatory biomarkers were similar in patients with and without LMWH, indicating either no effects of LMWH on haemostasis or that LMWH reduced hypercoagulability to levels of patients without LMWH. Nonetheless, anticoagulation with LMWH was associated with reduced mortality, improved markers of cell death, and curtailed viral persistence, indicating potential beneficial effects of LMWH beyond haemostasis, which encourages use of LMWH in COVID-19 patients without contraindications., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Genetic predispositions to venous thromboembolism (VTE) are relatively frequent in the general population and comprise a heterogeneous group of disorders. Whereas the most frequent congenital risk factors for thrombosis only moderately increase the risk, a deficiency in antithrombin (AT), one of the most important natural inhibitors of blood coagulation, carries a higher risk. Congenital AT deficiency is an infrequently encountered genetic risk factor for VTE, and different subtypes vary with regard to their thrombotic risk. Patients with congenital AT deficiency, especially those with quantitative deficiency (type 1), may develop thrombosis early in life and often have a conspicuous family history of first- and second-degree relatives with VTE. Women are particularly affected because of the risk potentiation by combined estrogen/progestogen oral contraceptive use or pregnancy. The lack of controlled trials or even observational studies of large cohorts does not allow therapeutic decisions to be based on scientific evidence. In this review, we will discuss cases with thrombotic manifestations and the tailored management of patients with this congenital thrombosis risk factor., (© 2019 by The American Society of Hematology.)

Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Anticoagulation for cancer-associated venous thromboembolism (VTE) can be challenging due to complications-including bleeding and potential drug-drug interactions with chemotherapy-associated with vitamin K antagonists and inconvenience of low-molecular-weight heparin (LMWH). Direct oral anticoagulants (DOACs) could partially overcome these issues, but until recently there were no large clinical trials assessing their efficacy and safety in cancer patients. This review summarizes clinical treatment guidelines, prior clinical and real-world evidence for anticoagulant choice, recent clinical trials assessing DOACs for cancer-associated VTE (i.e. Hokusai-VTE Cancer, SELECT-D, CARAVAGGIO, and ADAM VTE), and special considerations for DOAC use. Based on established data, clinical guidelines recommend patients with cancer-associated VTE receive LMWH treatment of at least 3-6 months. Nevertheless, LMWH is underused and associated with poor compliance and persistence in these patients relative to oral anticoagulants. Clinical data supporting DOAC use in cancer patients are becoming available. In Hokusai-VTE Cancer, edoxaban was noninferior to dalteparin for the composite of recurrent VTE and major bleeding (12.8% versus 13.5%), with numerically lower recurrent VTE (7.9% versus 11.3%) and significantly higher major bleeding (6.9% versus 4.0%); only patients with gastrointestinal cancer had significantly higher risk of bleeding with edoxaban. In SELECT-D, rivaroxaban had numerically lower VTE recurrence (4% versus 11%), comparable major bleeding (6% versus 4%), and numerically higher clinically relevant nonmajor bleeding (13% versus 4%) versus dalteparin. Most bleeding events were gastrointestinal or urologic; patients with esophageal/gastroesophageal cancer had higher rates of major bleeding with rivaroxaban (36% versus 11%). For comparison of apixaban versus dalteparin, CARAVAGGIO is ongoing, and preliminary results from ADAM VTE are favorable. This review concludes that DOACs appear to be reasonable alternatives to LMWH for treatment of cancer-associated VTE. In patients with gastrointestinal cancer, DOAC use should be considered on a case-by-case basis with consideration of the relative risks and benefits., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

The non-vitamin K antagonist oral anticoagulants (NOACs) have considerably changed clinical practice and are increasingly being used as an alternative to vitamin K antagonists (VKAs) for 3 main reasons: 1) an improved benefit-risk ratio (in particular lower rates of intracranial bleeding), 2) a more predictable effect without the need for routine monitoring, and 3) fewer food and drug interactions compared with VKAs. Currently, there are four NOACs available: the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, and the thrombin inhibitor dabigatran. This consensus paper reviews the properties and usage of NOACs in a number of high-risk patient populations, such as patients with chronic kidney disease, patients ≥80 years of age and others and provides guidance for the use of NOACs in patients at risk of bleeding.

The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations.

Data on specific studies in cancer patients using direct oral anticoagulants (DOACs) for the prevention and treatment of venous thromboembolism (VTE) are still scarce. For preventing VTE with DOACs, current experience is still very limited, so definite conclusions cannot yet be drawn. However, DOACs have so far been compared with vitamin K antagonists (VKAs) in patients with acute VTE in 5 studies, and several hundreds of patients included in these studies had either active cancer, a history of cancer, or a new occurrence of cancer during the course of disease. Meta-analyses have revealed an at least similar efficacy and safety profile of DOACs compared with VKAs. A number of studies of cancer patients investigating primary prevention and treatment are underway, and some will be finalized soon. Nevertheless, we might need further trials, specifically on the prevention of VTE in patients who are at particularly high risk. This article also includes a personal opinion on the use of DOACs in cancer patients. In conclusion, the currently available data show that DOACs might be safe and efficacious in the treatment of VTE, however, this has yet to be proven in specifically designed trials in patients with cancer. With regard to prevention, thus far, even less data exist, and the outcomes of the ongoing studies have to be evaluated before DOACs may be used for primary prevention., (© 2016 by The American Society of Hematology. All rights reserved.)

Introduction: Lupus anticoagulant (LAC) testing is challenging. Most data are derived from a well-controlled study environment with potential alterations to daily routines. The aim of this retrospective cohort study was to assess the capacity of various LAC screening tests and derived mixing tests to predict a positive result in subsequent confirmation tests in a large cohort of patients., Materials and Methods: In 5832 individuals, we retrospectively evaluated the accuracy of the aPTT-A, aPTT-LA screen , aPTT-FS and dRVVT screen and of their derived mixing tests in detecting a positive confirmation test result within the same blood specimen. The group differences, degree of correlation and the predictive accuracy of LAC coagulation tests were analysed using the Mann-Whitney U test, the Spearman-rank-correlation and by area under the receiver operating characteristic curve (ROC-AUC) analysis. ROC-AUCs were compared with the Venkatraman´s permutation test., Results: The pre-test probability of patients with clinically suspected LAC was 36% in patients without factor deficiency or anticoagulation therapy. The aPTT-LA screen showed the best diagnostic accuracy with a ROC-AUC of 0.84 (95% CI: 0.82 - 0.86). No clear advantage of the dRVVT-derived mixing test was detectable when compared to the dRVVT screen (P = 0.829). Usage of the index of circulating anticoagulant (ICA) did not improve the diagnostic power of respective mixing tests., Conclusions: Among the parameters evaluated, aPTT-LA screen and derived mixing test parameters were the most accurate tests. In our study cohort, neither other mixing test nor the ICA presented any further advantage in LAC diagnostics., Competing Interests: Potential conflict of interest: None declared.

Venous thromboembolism (VTE) is a significant health problem in the general population but especially in cancer patients. In this review, we discuss the epidemiology and burden of the disease, the pathophysiology of cancer-associated VTE, and the clinical treatment options for both primary prevention and acute treatment. Overall, the development of VTE in cancer patients is related to increases in morbidity, mortality, and medical costs. However, the incidence of cancer-associated VTE varies due to patient-related factors (e.g. thrombophilia, comorbidities, performance status, history of venous diseases), tumour-related factors (e.g. cancer site, stage, grade), and treatment-related factors (e.g. surgery, chemotherapy, anti-angiogenesis treatment, hormonal and supportive treatment). Furthermore, blood count parameters (e.g. platelets and leukocytes) and biomarkers (e.g. soluble P-selectin and D-dimer) are predictive markers for the risk of VTE in cancer patients and have been used to enhance risk stratification. Evidence suggests that cancer itself is associated with a state of hypercoagulability, driven in part by the release of procoagulant factors, such as tissue factor, from malignant tissue as well as by inflammation-driven activation of endothelial cells, platelets, and leukocytes. In general, low-molecular-weight heparin (LWMH) monotherapy is the standard of care for the management of cancer-associated VTE, as vitamin K antagonists are less effective in cancer patients. Direct oral anticoagulants (DOACs) offer a potentially promising treatment option for cancer patients with VTE, but recommendations concerning the routine use of DOACs should await head-to-head studies with LMWH.

Background: Atrial fibrillation (AF) adds significant risk of stroke and thromboembolism in patients on hemodialysis (HD). The aim of this study was to investigate the prevalence of AF in a population-based cohort of HD patients and practice patterns of antithrombotic therapy for stroke prevention in AF., Methods: The Vienna InVestigation of AtriaL fibrillation and thromboembolism in patients on hemodialysis (VIVALDI), an ongoing prospective observational cohort study, investigates the prevalence of AF and the risk of thromboembolic events in HD patients in Vienna, Austria. We analyzed cross-sectional data of 626 patients (63.4% men, median age 66 years, approx. 73% of HD patients in Vienna), who provided informed consent. A structured interview with each patient was performed, recent and archived ECGs were viewed and medical histories were verified with electronic records., Results: The overall prevalence of AF was 26.5% (166 patients, 71.1% men, median age 72 years) of which 57.8% had paroxysmal AF, 3.0% persistent AF, 32.5% permanent AF, and 6.6% of patients had newly diagnosed AF. The median CHA2DS2-VASc Score was 4 [25th-75th percentile 3-5]. In multivariable analysis, AF was independently associated with age (odds ratio: 1.05 per year increase, 95% confidence interval: 1.03-1.07), male sex (1.7, 1.1-2.6), history of venous thromboembolism (2.0, 1.1-3.6), congestive heart failure (1.7, 1.1-2.5), history of or active cancer (1.5, 1.0-2.4) and time on HD (1.08 per year on HD, 1.03-1.13). Antithrombotic treatment was applied in 84.4% of AF patients (anticoagulant agents in 29.5%, antiplatelet agents in 33.7%, and both in 21.1%). In AF patients, vitamin-K-antagonists were used more often than low-molecular-weight heparins (30.1% and 19.9%)., Conclusions: The prevalence of AF is high amongst HD patients and is associated with age, sex, and distinct comorbidities. Practice patterns of antithrombotic treatment indicate a lack of consensus for stroke prevention in HD patients with AF., Competing Interests: The authors have declared that no competing interests exist.

Background: The clinical practice of stroke prevention in atrial fibrillation (AF) with direct oral anticoagulants (DOACS) differs from anticoagulation in randomized trial patients. We investigated the risk of thromboembolism, bleeding, and drug discontinuation in a hospital-based real-world setting., Methods: All-comer patients with non-valvular AF were recruited into a registry at an academic tertiary care center. After informed consent, patients underwent a personal structured interview including medical history, past and current anticoagulation, and returned for follow-up after 6-12 months., Results: The registry comprised 282 patients (42% women, median age 71 years) with a median CHA2DS2-Vasc-Score of 4 (25. to 75. percentile 2.5-5), who were prospectively followed 285 days in median. At inclusion, 118 patients took vitamin-K-antagonists, 33 dabigatran, 87 rivaroxaban, 30 apixaban, 5 low-molecular-weight heparin, and 9 were on no anticoagulant. Occurrence of stroke (rate 2.8/100 patient-years), was associated with prior stroke (hazard ratio [HR] 18.5, 95% confidence interval 2.16-159), increased HbA1c (HR per 1% increase 1.71, 1.20-2.45) and borderline significantly associated with vascular disease (HR 8.33, 0.97-71.3). Further we observed a high rate of major bleeding (2.8/100 patient-years), clinically relevant non-major bleeding (4.1/100 patient-years), and venous thromboembolism (2.8/100 patient-years). Anticoagulation was discontinued by 80 patients (36.9/100 patient-years), and diabetes (HR 2.31, 1.32-4.02), history of bleeding (HR 2.51, 1.44-4.37) and elevated leucocyte count (HR per 1G/l increase 1.02, 1.00-1.05) were associated with increased risk of discontinuation., Conclusions: In this hospital-based registry, patients with atrial fibrillation had an increased risk of thromboembolic events despite anticoagulation. The low drug persistence may be attributable to distinct comorbid conditions and bleeding complications.

Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at an increased risk of developing VTE and are more likely to have a recurrence of VTE and bleeding while taking anticoagulants. Management of VTE in patients with cancer is a major therapeutic challenge and remains suboptimal worldwide. In 2013, the International Initiative on Thrombosis and Cancer (ITAC-CME), established to reduce the global burden of VTE in patients with cancer, published international guidelines for the treatment and prophylaxis of VTE and central venous catheter-associated thrombosis. The rapid global adoption of direct oral anticoagulants for management of VTE in patients with cancer is an emerging treatment trend that needs to be addressed based on the current level of evidence. In this Review, we provide an update of the ITAC-CME consensus recommendations based on a systematic review of the literature ranked according to the Grading of Recommendations Assessment, Development, and Evaluation scale. These guidelines aim to address in-hospital and outpatient cancer-associated VTE in specific subgroups of patients with cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study., Methods: The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events., Conclusion: The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VTE., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE., Methods: A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model., Results: LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies., Conclusion: The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable., Funding: Austrian Science Fund (FWF-SFB-54)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low-molecular-weight heparin (LMWH) for at least 3-6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer-associated VTE., Methods: Patients with active cancer and newly diagnosed VTE were enrolled in a prospective, multicenter study and received subcutaneous dalteparin for 12 months. The rates of bleeding and recurrent VTE were evaluated at months 1, 2-6 and 7-12., Findings: Of 334 patients enrolled, 185 and 109 completed 6 and 12 months of therapy; 49.1% had deep vein thrombosis (DVT); 38.9% had pulmonary embolism (PE); and 12.0% had both on presentation. The overall frequency of major bleeding was 10.2% (34/334). Major bleeding occurred in 3.6% (12/334) in the first month, and 1.1% (14/1237) and 0.7% (8/1086) per patient-month during months 2-6 and 7-12, respectively. Recurrent VTE occurred in 11.1% (37/334); the incidence rate was 5.7% (19/334) for month 1, 3.4% (10/296) during months 2-6, and 4.1% (8/194) during months 7-12. One hundred and sixteen patients died, four due to recurrent VTE and two due to bleeding., Conclusion: Major bleeding was less frequent during dalteparin therapy beyond 6 months. The risk of developing major bleeding complications or VTE recurrence was greatest in the first month of therapy and lower over the subsequent 11 months., (© 2015 International Society on Thrombosis and Haemostasis.)

Introduction: Prothrombin complex concentrates (PCCs) are a common treatment option for the reversal of oral anticoagulation with vitamin K antagonists (VKAs). This study assessed efficacy and safety of Prothromplex Total®., Materials and Methods: Patients (≥18 years) with acquired prothrombin complex coagulation factor deficiency (international normalized ratio [INR] ≥ 2 at screening) due to oral VKAs, requiring reversal of anticoagulation, were treated with 25, 35, or 50 IU/kg BW PCC. After infusion, efficacy was assessed for 72 ± 4 hours. Adverse events (AEs) were captured for 15 days., Results: Sixty-one subjects, 48 requiring interventional procedures and 13 with acute bleeds, received a single infusion of PCC. Of 59 subjects analyzed, all achieved normalization of INR (≤ 1.3) within 30 ± 5 minutes of infusion, demonstrating effective anticoagulant reversal. IVRs of factors II, VII, IX, and X ranged from 1.12-2.03 IU/dL:IU/kg. Median INRs remained between 1.00 and 1.18 for up to 6 hours. Overall efficacy of treatment was rated "excellent" for 60 subjects. Three AEs were deemed possibly related to treatment: 1 serious AE (SAE) of acute myocardial infarction (rated severe), 1 SAE of deep vein thrombosis (rated mild), and 1 AE of pyrexia (rated mild). Thrombotic adverse events (2/61, 3.3%) reported here are comparable to rates observed in other PCC studies., Conclusions: While there is a risk of thromboembolic events following treatment with PCC products, the number of events reported here was low and could have occurred without PCC treatment. The individualized, INR-based dosing of PCC used here for VKA anticoagulant reversal produces rapid normalization of INR to ≤ 1.3 within 30 minutes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The introduction of new direct oral anticoagulants has changed the treatment of nonvalvular atrial fibrillation. However, these changes are not yet fully reflected in current guidelines.This consensus statement, endorsed by six Austrian medical societies, provides guidance to current prophylactic approaches of thromboembolic events in nonvalvular atrial fibrillation on the basis of current evidence and published guidelines. Furthermore, some special subjects are treated, like changes in laboratory parameters and their interpretation under treatment with direct oral anticoagulants, treatment of bleedings, approach to operations, cardioversion and ablation, and specific neurological aspects. For a CHA2DS2-VASc-Score of ≥ 2, anticoagulation is recommended with a high level of evidence (1A). At the end of the consensus statement, recommendations for a number of specific patient subgroups can be found, in order to help treating physicians to arrive at appropriate therapeutic decisions.

Patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) like polycythemia vera and essential thrombocythemia are at increased risk of arterial and venous thrombosis. Strategies of prevention may consist of platelet aggregation inhibitors and/or cytoreductive agents depending on the underlying disease and the individual risk. Clinical evidence for management of acute venous thromboembolic events in MPN patients is limited. Modality and duration of therapeutic anticoagulation after venous thrombosis has to be evaluated critically with special regard to the increased risk for spontaneous bleeding events associated with the underlying diseases. Both for therapy of the acute event and for secondary prophylaxis, low-molecular-weight heparins should preferentially be used. A prolongation of the therapeutic anticoagulation beyond the usual 3 to 6 months can only be recommended in high-risk settings and after careful evaluation of potential risks and benefits for the individual patient. New direct oral anticoagulants (NOAC) should not preferentially be used due to lack of clinical experience in patients with MPN and potential drug interactions (e.g. with JAK inhibitors). Consequent treatment of the underlying myeloproliferative disease and periodical evaluation of the response to therapy is crucial for optimal secondary prophylaxis of thromboembolic events in those patients.

Cancer is a major and independent risk factor of venous thromboembolism (VTE). In clinical practice, a high number of VTE events occurs in patients with cancer, and treatment of cancer-associated VTE differs in several aspects from treatment of VTE in the general population. However, treatment in cancer patients remains a major challenge, as the risk of recurrence of VTE as well as the risk of major bleeding during anticoagulation is substantially higher in patients with cancer than in those without cancer. In several clinical trials, different anticoagulants and regimens have been investigated for treatment of acute VTE and secondary prophylaxis in cancer patients to prevent recurrence. Based on the results of these trials, anticoagulant therapy with low-molecular-weight heparins (LMWH) has become the treatment of choice in cancer patients with acute VTE in the initial period and for extended and long-term anticoagulation for 3-6 months. New oral anticoagulants directly inhibiting thrombin or factor Xa, have been developed in the past decade and studied in large phase III clinical trials. Results from currently completed trials are promising and indicate their potential use for treatment of VTE also in cancer patients. However, the role of the new oral thrombin and factor Xa inhibitors for VTE treatment in cancer patients still has to be clarified in further studies specifically focusing on cancer-associated VTE. This brief review will summarize the current strategies of initial and long-term VTE treatment in patients with cancer and discuss the potential use of the new oral anticoagulants.

Venous thrombembolism (VTE) is one of the most frequent complication in cancer patients. The current options in prophylaxis and therapy have to be balanced against the risks of major bleeding and the burden for the patients. The Gesellschaft für Thrombose- und Hämostaseforschung, the Deutsche Gesellschaft für Palliativmedizin and the German speaking Societies of Hematology and Oncology have recently published guidelines on VTE in cancer patients. Recommendations include diagnostics, individual prophylaxis and treatment.

Background: Prothrombin complex concentrate (PCC) can substantially shorten the time needed to reverse antivitamin K oral anticoagulant therapy (OAT). OBJECTIVES. To determine the effectiveness and safety of emergency OAT reversal by a balanced pasteurized nanofiltered PCC (Beriplex P/N) containing coagulation factors II, VII, IX, and X, and anticoagulant proteins C and S., Patients and Methods: Patients receiving OAT were eligible for this prospective multinational study if their International Normalized Ratio (INR) exceeded 2 and they required either an emergency surgical or urgent invasive diagnostic intervention or INR normalization due to acute bleeding. Stratified 25, 35, or 50 IU kg(-1) PCC doses were infused based on initial INR. Study endpoints included INR normalization (

Prothrombin complex concentrates (PCCs) are widely administered for emergency oral anticoagulation reversal and for coagulation defects in liver disease. Pharmacokinetic data may help to optimize treatment. The objective of this study was to characterize the pharmacokinetics of a PCC (Beriplex P/N) containing coagulation factors II (FII), VII (FVII), IX (FIX) and X (FX) and anticoagulant proteins C and S. Fifteen healthy volunteers received a single rapid 50 IU/kg infusion of PCC and underwent frequent blood sampling until 144 hours (h) after infusion. Coagulation factors and anticoagulant protein pharmacokinetic parameters were estimated by non-linear regression. The mean infusion rate of PCC was 7.9 ml/min, equivalent to 196.4 IU/min. By the earliest post-infusion sampling point at 5 minutes (min), plasma FIX concentration increased by a median of 73%. Median increases in FII, FVII and FX at 5 min were 122%, 62% and 158%, respectively. Proteins C and S also increased rapidly. The median terminal half-life of FIX was 16.7 h, FII 59.7 h, FVII 4.2 h and FX 30.7 h. The median in-vivo recovery of FIX was 1.57 %/IU/kg and that of the other three coagulation factors > 2 %/IU/kg. Plasma concentration of thrombogenicity marker D-dimer did not increase, and there was no clinical evidence of thrombosis. Through up to 12 weeks follow-up there were no laboratory findings indicating PCC-related viral exposure. Rapid PCC infusion produced prompt sustained increases in coagulation factors and anticoagulant proteins with no clinical evidence of thrombosis or viral transmission.

Background: As the placental vessels are dependent on the normal balance of procoagulant and anticoagulant mechanisms, inherited thrombophilia may be associated with fetal loss., Objectives: We performed a prospective study to investigate the relation between inherited thrombophilia and fetal loss, and the influence of thromboprophylaxis on pregnancy outcome., Patients and Methods: Women were enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). These included women with factor (F)V Leiden or a deficiency of antithrombin, protein C or protein S. Controls were partners or acquaintances of thrombophilic individuals. A total of 191 women (131 with thrombophilia, 60 controls) had a pregnancy outcome during prospective follow-up. Risk of fetal loss and effect of thromboprophylaxis were estimated by frequency calculation and Cox regression modelling., Results: The risk of fetal loss appeared slightly increased in women with thrombophilia without a previous history of fetal loss who did not use any anticoagulants during pregnancy (7/39 vs. 7/51; relative risk 1.4; 95% confidence interval 0.4, 4.7). Per type of defect the relative risk varied only minimally from 1.4 for FV Leiden to 1.6 for antithrombin deficiency compared with control women. Prophylactic anticoagulant treatment during pregnancy in 83 women with thrombophilia differed greatly in type, dose and duration, precluding solid conclusions on the effect of thromboprophylaxis on fetal loss. No clear benefit of anticoagulant prophylaxis was apparent., Conclusions: Women with thrombophilia appear to have an increased risk of fetal loss, although the likelihood of a positive outcome is high in both women with thrombophilia and in controls.

Venous thromboembolism (VTE) occurs infrequently but is a leading cause of illness and death during pregnancy and the puerperium. In the general population the incidence of pregnancy-associated VTE is approximately 1 in 1500 deliveries. The risk of VTE is five times higher in a pregnant than in a nonpregnant woman. Postpartum the VTE risk is even higher. Women with congenital abnormalities or persistent presence of antiphospholipid antibodies have an increased risk of VTE during pregnancy and the puerperium. Women with previous VTE have an approximately 3.5-fold increased risk of recurrent VTE during pregnancy. Heparin does not cross the placenta and is therefore the anticoagulant of choice. In case of acute thrombosis during pregnancy, treatment is performed in the same manner as for nonpregnant patients. There is an ongoing debate whether pregnant women with previous venous thrombosis should routinely receive prophylactic anticoagulation. Patients who have hereditary antithrombin deficiency, antiphospholipid antibodies, a combined abnormality, or a history of a severe thrombotic event (pulmonary embolism or extended deep vein thrombosis) should be advised to use prophylactic heparin during pregnancy, starting during the first trimester. Postpartum prophylaxis should be given to all women with an increased risk for VTE. A large body of evidence has been presented that hypercoagulability may cause recurrent abortions, stillbirth, and preeclampsia. There is no doubt that the antiphospholipid syndrome is strongly associated with fetal loss. The combination of heparin and aspirin significantly decreases the fetal loss rate during pregnancy and thus this is the treatment of choice in this patient group. Several studies indicate that women with recurrent miscarriage may benefit from heparin administration during pregnancy, however, data from controlled trials have not yet been published. In women with artificial heart valves, maternal and fetal complications are frequent despite anticoagulation, but oral anticoagulants can reduce the risk for maternal complications.

Background: Subcutaneously administered low-molecular-weight heparins are widely used for prevention of venous thromboembolism. The appropriateness of the subcutaneous route in critically ill patients has never been established., Objective: To determine anti-Xa activities in critically ill patients and in noncritically ill patients receiving prophylactic doses of subcutaneous enoxaparin., Design: Prospective, controlled, open-labeled study., Setting: Tertiary medical-cardiologic-postoperative intensive care unit and a general medical ward at a university hospital., Patients: A total of 16 intensive care unit patients (group 1; age, 61.1 +/- 16 yrs; male/female ratio, 7/9; Acute Physiology and Chronic Health Evaluation II score, 20.9 +/- 7; mechanical ventilation, n = 15; vasopressors, n = 13) and 13 noncritically ill medical patients (group 2; age, 61.7 +/- 9 yrs; male/female ratio, 7/6) were studied. Body mass index (25.7 +/- 5 vs. 24 +/- 6 kg/m2, p = not significant) was comparable and serum creatinine levels (0.83 +/- 0.25 vs. 1.07 +/- 0.3 mg/dL, group 1 vs. 2) were within the normal range in both groups. Patients with impaired renal function, receiving hemofiltration, or requiring therapeutic anticoagulation were not eligible., Interventions: None., Measurements and Main Results: Anti-Xa activities were determined at 0, 1, 3, 6, and 12 hrs after a single daily subcutaneous dose of 40 mg enoxaparin on day 1 and at 3 hrs after 40 mg of enoxaparin on days 2-5. Mean anti-Xa levels at 0 to 12 hrs were consistently lower in group 1 compared with group 2 by analysis of variance (p =.001 between groups and over time), as was the area under the curve at 0 to 12 hrs (2.6 +/- 1 vs. 4.2 +/- 1.7 units x mL(-1) x hr(-1), group 1 vs. 2, p =.008). Significant differences in anti-Xa activity were also found on days 2-5 (p =.001). Peak anti-Xa activities at 3 hrs after administration were negatively correlated with the body mass index (r = -.41, p <.03). No correlation was found between the anti-Xa activity at 3 hrs and the dose of norepinephrine (r =.12, p =.7)., Conclusion: Critically ill patients with normal renal function demonstrated significantly lower anti-Xa levels in response to a single daily dose of subcutaneous enoxaparin when compared with medical patients in the normal ward.

Oral anticoagulants are highly effective for the prevention of recurrence of venous thromboembolism and of thromboembolic complications in rheumatic and non-rheumatic atrial fibrillation, dilated cardiomyopathy and in patients with prosthetic heart valves, but less effective for prevention of arterial thrombosis. Bleeding is the main side effect, the risk of fatal bleeding is 0.2 to 0.4% per year, depending on the intensity of treatment. The problem of the standardization of the prothrombin time determination has been solved by the introduction of the international normalized ratio. Recent studies have shown that a lesser degree of anticoagulation (INR 2.0 to 3.0) is sufficient to prevent venous thromboembolism and cardiac emboli. The measurement of activation markers of coagulation will probably allow a more rational monitoring in the near future.

Although the antithrombotic potential of oral anticoagulants is undisputed, bleeding complications constitute a serious problem. One of the main causes for these complications has been a lack of standardization of the prothrombin time. The introduction of the International Normalized Ratio (INR) has led to a better standardization of prothrombin time. Thus, the same level of anticoagulation can be reached using different reagents and therefore over- and undercoagulation can be avoided. Furthermore, the benefit/risk ratio can be improved by adapting the intensity of anticoagulation to the indication. The following clinical conditions are established indications for treatment with oral anticoagulants: Prevention of cardiac emboli in acute anterior myocardial infarction with atrial thrombus, in patients with atrial fibrillation with or without mitral valve disease, in patients with prosthetic heart valves and in patients with dilated cardiomyopathy. Furthermore, oral anticoagulants should be given to patients after femoropopliteal bypass. A relatively mild oral anticoagulant treatment (INR 2-3) is sufficient to prevent recurrences of venous thrombosis and pulmonary emboli. The duration of treatment in patients with venous thromboembolism depends on some clinical features and the results of clotting tests which indicate an increased tendency to thrombosis.

Splenic marginal zone lymphoma (SMZL) is a rare low-malignant Non-Hodgkin lymphoma (NHL), in which immune mediated paraneoplastic phenomena such as autoimmune hemolytic anemia (AIHA), autoimmune thrombocytopenia (ITP) and C1 esterase inhibitor deficiency are relatively common. Materials and Methods We performed a multicenter retrospective study in 70 patients on the prevalence and clinical features of antiphospholipid antibodies (aPLA) in SMZL. Results and Conclusions Nine patients (13%) had the diagnosis of a lupus anticoagulant (LA). The occurrence of venous thromboembolic events was significantly higher in LA positive patients compared to LA negative patients (4/9 [44%] vs 5/61 [8%], p=0.002), especially within 12months after splenectomy (3/6 [50%] vs 2/28 [7%], p=0.007). None of the patients with LA had a persistent complete remission of LA after splenectomy, but complete remission of LA was achieved in 2/2 patients after rituximab-bendamustine immuno-chemotherapy. In conclusion, our data show a relatively high prevalence of aPLA in SMZL and an increased risk of postsplenectomy thrombosis in these patients. The fact that rituximab-bendamustine was effective for eradicating LA may be considered as an argument for using immuno-chemotherapy as first line therapy in SMZL patients with LA. [ABSTRACT FROM AUTHOR]