Treatment Of Thrombotic Events Research Articles

Association between gene polymorphisms and initial warfarin therapy in patients after heart valve surgery.

Warfarin is widely used for the prevention and treatment of thrombotic events. This study aimed to examine the influence of gene polymorphisms on the early stage of warfarin therapy in patients following heart valve surgery. Nine single nucleotide polymorphisms were genotyped using microarray chips, categorizing patients into three groups: normal responders (Group I), sensitive responders (Group II), and highly sensitive responders (Group III). The primary clinical outcomes examined were time in therapeutic range (TTR) and international normalized ratio (INR) variability. To investigate potential influencing factors, a generalized linear regression model was employed. Among 734 patients, the prevalence of CYP2C9*3-1075A > C, CYP2C19*3-636G > A, and CYP2C19*17-806C > T variants were 11.2%, 9.9%, and 1.9% of patients, respectively. VKORC1-1639G > A or the linked -1173C > T variant was observed in 99.0% of the patients. Generalized linear model analysis revealed an impact of sensitivity grouping on INR variability. Compared to Group I, Group II showed higher TTR values (p = 0.023), while INR variability was poorer in Group II (p < 0.001) and Group III (p < 0.001). Individual gene analysis identified significant associations between CYP2C9*3-1075A > C (p < 0.001), VKORC1-1639G > A or the linked -1173 C > T (p = 0.009) and GGCX-3261G > A (p = 0.019) with INR variability. The genotypes of CYP2C9, VKORC1, and GGCX were found to have a significant impact on INR variability during the initial phase of warfarin therapy. However, no significant association was observed between TTR and gene polymorphisms. These findings suggest that focusing on INR variability is crucial in clinical practice, and preoperative detection of gene polymorphisms should be considered to assist in the initiation of warfarin therapy.

Oral Anticoagulant Therapy in Patients with Philadelphia-Negative Myeloproliferative Neoplasms: A Real-Life Comparison between Vitamin K Antagonists and Direct Oral Anticoagulants

BACKGROUND Chronic myeloproliferative neoplasms (MPN) are characterized by an high risk of thrombosis and bleeding. Historically, vitamin K inhibitors (VKAs) have been the preferred oral anticoagulant therapy (OAT) for these patients (pts). However, nowadays, VKAs are being used less frequently, and direct oral anticoagulants (DOACs) are becoming more popular. Despite this trend, there is still limited evidence in the literature regarding the efficacy and safety of these drugs in the context of MPN. Specifically, there is a lack of data directly comparing VKAs and DOACs in a real-world clinical setting. AIMS The study aimed to conduct a real-world analysis comparing the efficacy and safety of DOACs and VKAs in patients with MPN. Both medications were prescribed for the treatment and secondary prevention of venous thromboembolism (VTE) or for the prevention of thrombosis in pts with atrial fibrillation (AF). The secondary endpoints were to assess the influence of common demographic, clinical, and hematological variables on the incidence of thrombotic events (TE) and bleeding events (BE) METHODS We conducted an observational retrospective monocentric study that enrolled all consecutive pts with MPN, followed at the MPN Clinic of the IRCCS Foundation S. Gerardo dei Tintori - Monza between 1993 and 2022, who received OAT with VKAs or DOACs for VTE or AF. For each pts, we collected demographic, clinical, biological, therapeutic, and hematological data. TE were categorized based on their type (arterial or venous) and location. BE were classified as minor, major, or clinically relevant non-major bleeding, according to the ISTH classification. Thrombosis-free survival (TFS) and bleeding-free survival (BFS) were assessed from the initiation of OAT until the occurrence of the first TE or BE, respectively, and estimated using Kaplan-Meier analysis. The other analyses were conducted using common statistical methods. Multivariable analyses included previously established risk factors for BE and TE. RESULTS A total of 156 pts were enrolled: 89 were women (57%). The median age was 69 years (range 25-92); 61 were affected by myelofibrosis, 35 by polycythemia vera, and 48 by essential thrombocythemia. 64 pts received OAT with VKAs (41%), and 92 with DOACs (59%). For 82 pts OAT was prescribed for AF (52.6%), and for 74 for VTE (47.4%). 17 pts treated with DOACs for VTE received a reduced-dose extended treatment (45.9%). The median exposure time to OAT was 5.8 years in the VKAs group (range 0.2-20 years) and 1.77 years in the DOACs group (range 0.2-10 years). After a median follow-up of 3,2 years, 14 TE were reported: 5 (35.7%) in the DOAC-treated group, of which 4 were arterial (80%), and 9 (64.3%) in the VKA-treated group (7 arterial - 77.8%). The incidence rate of TE was 2.11 thrombosis/pts/year in the VKAs group and 2.14 thrombosis/pts/year in the DOACs group. There were no significant differences in terms of TFS between the two groups, whether considering the entire population or analyzing the therapeutic indications separately (respectively p=0.72, p=0.53, p=0.55). Overall, there were 27 BE: 13 in the DOACs group (51.9%), 14 in the VKAs group (48.1%). Among these, we report 8 major BE, 4 in both groups. The incidence rate of BE was 5.6/pts/year in the DOACs group and 3.3/pts/year in the VKAs group. We did not observe significant differences in terms of BFS analyzing the whole population and the VTE group (respectively p=0.13 and p=0.75), while we found a trend for lower BFS in pts treated with DOACs for AF (p=0.08, Fig. 1). In a multivariate model, adjusted for time of exposition to OAT, age, gender and antiplatelet treatment, the risk of BE was associated solely with DOACs administration (hazard ratio 3.7, p=0.01) We found no significant differences in the risk of TE and BE when considering the various types of DOACs used. Moreover, 45 (28.8%) patients received concomitant antiplatelet therapy, and we found no significant differences in the risk of BE or TE compared to the other group (p=0.39 and p=0.41, respectively). CONCLUSIONS To our knowledge, this is the largest study investigating the safety and efficacy of DOACs compared to VKAs for the treatment and prevention of TE in pts with MPN and VTE or AF. Our findings suggest that DOACs are as effective as VKAs, but they appear to exhibit a trend towards a higher overall risk of BE, especially in the AF group. More data from prospective multicentric studies are necessary to validate our results.

Pharmacogenetic substantiation of personalized prescription of oral anticoagulants in clinical practice

Thromboembolic diseases are of great clinical concern because of their high prevalence and consequences, which are often fatal. Despite significant progress in the prevention and treatment of thrombotic events, patients remain at risk of life-threatening bleeding episodes and other side effects arising from anticoagulant therapy, so the issue of personalizing prescriptions taking into account the genetic characteristics of patients has become urgent. The purpose of the study is to substantiate the need for patient genotype analysis in order to increase the effectiveness and safety of individual pharmacotherapy. The article has a conceptual nature, therefore the following research methods were chosen: systematization and generalization; analysis and specification; abstract and logical. For the search, we used PubMed, PubMedCentral, Google Scholar, dbSNP, Elsevier, Springer from September 2000 to November 2022. The review included studies written in English and Ukrainian. There were analyzed literature data on two main subclasses of oral antithrombotic agents, including oral anticoagulants and antiplatelet agents, namely warfarin, apixaban, rivaroxaban, and clopidogrel. Prognostically significant for evaluating the effectiveness and safety of anticoagulant use, as well as the most studied in this aspect, are CYP2C9 (rs1799853, rs1057910), CYP2C19 (rs4244285, rs4986893, rs12248560), VKORC1 (rs9923231, rs7294, rs9934438), MDR1 (rs4148738, rs2032582, rs1045642), FGB (rs1800787), PAI-1 (rs1799889) genes. The results of CYP2B6, CYP3A4/5 (rs776746), CYP4F2 (rs2108622) genes analysis indicate a certain influence on the anticoagulants metabolism and require further detailed study. Factors such as age, race, sex, smoking, diet, and other medications are known to influence the effectiveness of antithrombotic therapy, but the most influential factor is genetics, which accounts a significant percentage of interindividual variability. Future research should focus on the study of known and novel genetic variants that influence drug metabolism, as well as the molecular mechanisms that contribute to changes in plasma anticoagulant levels. The article provides a brief overview of action mechanisms, pharmacogenetics, and interactions between drugs and the genes responsible for their metabolism. The results indicate the need for studies of gene variants considered in this review before starting anticoagulant therapy, and attention should also be paid to the possibility of inhibitors and inductors influence on components of the metabolic pathway of anticoagulants and gene expression products that participate in their metabolism. The totality of these measures will ensure an increase in the efficiency and safety of individual pharmacotherapy and allow optimizing the choice and dosage of anticoagulants.

Vascular Involvement in Behcet's Disease: An Evaluation of 147 Cases and Literature Review.

Behcet's disease (BD) is characterized by systemic vasculitis with inflammation that can affect various body organs. In BD, vasculitis primarily manifests with venous involvement, distinguishing it from other forms of systemic vasculitis. We retrospectively analyzed the demographic and clinical characteristics of 147 patients diagnosed with vascular BD in our center. Vascular BD cases accounted for 25.0% (147 out of 589) of all BD patients. A statistically significant correlation was found between gender and vascular involvement that was seen predominantly in males (76.9%). In 71 patients, a vascular event developed during follow-up for BD, while in 76 patients the disease was diagnosed after the occurrence of a vascular event (51.7%). The most common vascular event was deep vein thrombosis in the lower extremities (69.4%). Arterial involvement was primarily observed in the pulmonary arteries (12.9%). Patients with lower extremity deep vein thrombosis tended to be younger, while those with pulmonary artery involvement were typically older. Overall, veins were affected 4.5 times more frequently than arteries. The prevalent type of venous involvement was deep vein thrombosis in the lower extremities. Thrombotic events in BD cannot be solely attributed to abnormalities in thrombotic factors. The treatment of thrombotic events in BD remains contentious, with anticoagulant efficacy being debated and immunosuppressive therapy representing the primary treatment approach. Behcet's disease should be considered when a young male patient presents with an arterial or venous vascular event, especially if it is recurrent.

Women’s values and preferences on low-molecular-weight heparin and pregnancy: a mixed-methods systematic review

BackgroundVenous thromboembolism (VTE) in pregnancy is an important cause of maternal morbidity and mortality. Low-molecular-weight heparin (LMWH) is the cornerstone of prophylaxis and treatment of thrombotic events during pregnancy. LMWH has fewer adverse effects than other anticoagulants, does not cross the placenta, and is safe for the fetus. However, the use of LMWH during pregnancy is sensitive to womens’ underlying preferences. The objective of this review is to systematically assess women’s values and preferences research evidence on this topic.MethodsWe searched four electronic databases from inception to March 2022, and included studies examining values and preferences of using LMWH among pregnant women at risk of VTE. We followed a convergent integrated mixed-methods design to compare and contrast quantitative outcomes (utility and non-utility measures) and qualitative findings. We assessed the certainty of the values and preferences evidence with the GRADE approach for quantitative findings, and with GRADE-CERqual for qualitative evidence. Results were presented in a conjoint display.ResultsWe screened 3,393 references and identified seven eligible studies. The mixed methods analysis resulted in four themes. Datasets confirmed each other in that: 1) the majority of women consider that benefits of treatment outweigh the inconveniences of daily injections; and 2) main concerns around medication are safety and injections administration. Quantitative outcomes expanded on the qualitative findings in that: 3) participants who perceived a higher risk of VTE were more willing to take LMWH. Finally, we found a discrepancy between the datasets around: 4) the amount of information preferred to make the decision; however, qualitative data expanded to clarify that women prefer making informed decisions and receive support from their clinician in their decision-making process.ConclusionsWe are moderately confident that in the context of pregnancy, using LMWH is preferred by women given its net beneficial balance. Integrating data from different sources of evidence, and representing them in a jointly manner helps to identify patient’s values and preferences. Our results may inform clinical practice guidelines and support shared decision-making process in the clinical encounter for the management of VTE in the context of pregnancy.

Complicaciones tromboembólicas en pacientes con COVID-19: una revisión narrativa

La pandemia de la enfermedad por coronavirus (COVID-19) ha generado una grave crisis en la salud pública global y ha ocasionado el ingreso de pacientes a la Unidad de Cuidados Intensivos (UCI) de varios hospitales alrededor del mundo, provocando incremento de la mortalidad debido a diversas complicaciones. El objetivo de este artículo es brindar información basada en evidencia actualizada acerca de la fisiopatología, diagnóstico y sobre todo el tratamiento de los eventos trombóticos que se presentan en pacientes con COVID-19. Se utilizaron buscadores como Pubmed, NCBI, Scielo, Cochrane Library y Google Académico. Se incluyeron los artículos enmarcados en las complicaciones tromboembólicas en los pacientes con COVID-19. Para la búsqueda se utilizaron los términos: “COVID-19”, “SARS-CoV-2”, “Complicaciones”, “Trombosis”, “Coagulación”. Además, se utilizaron operadores Booleanos, tales como “AND”, “NOT” y “OR”. En particular, el diagnóstico de las complicaciones tromboembólicas, dependiendo de su origen arterial o venoso, debe corroborarse con pruebas de laboratorio e imagen para que el médico pueda optar por el tratamiento más oportuno para el paciente de acuerdo a la naturaleza del trombo. Cabe recalcar, que los consensos sobre la profilaxis y tratamiento de las complicaciones tromboembólicas publicados hasta la fecha no se encuentran exentos de limitaciones. Sin embargo, la mayoría de las referencias bibliográficas indica que la heparina de bajo peso molecular ha presentado resultados satisfactorios para el manejo de eventos tromboembólicos en gran parte de la población afectada por COVID-19.

New Anticoagulants in Neonates, Children, and Adolescents.

Thrombotic events are an increasing challenge in pediatrics. Standard-of-care anticoagulants for pediatric thrombosis have several disadvantages which could be overcome by using direct oral anticoagulants (DOACs). Until recently, there was not enough evidence from clinical trials to recommend for or against the use of any of the four DOACs in children with thrombosis. In this literature review, we looked at the latest clinical trials in this field. On clinicaltrials.gov, we found 13 current studies with published results. For two of the four DOACs, namely dabigatran and rivaroxaban, we found successful phase III studies which led to the approval for the use in children. The results of these pivotal phase III studies allow to finally recommend rivaroxaban and dabigatran for the prophylaxis and treatment of thrombotic events in children.

Recent Advances in Anticoagulant Treatment of Immune Thrombosis: A Focus on Direct Oral Anticoagulants in Heparin-Induced Thrombocytopenia and Anti-Phospholipid Syndrome.

For more than 10 years, direct oral anticoagulants (DOACs) have been increasingly prescribed for the prevention and treatment of thrombotic events. However, their use in immunothrombotic disorders, namely heparin-induced thrombocytopenia (HIT) and antiphospholipid syndrome (APS), is still under investigation. The prothrombotic state resulting from the autoimmune mechanism, multicellular activation, and platelet count decrease, constitutes similarities between HIT and APS. Moreover, they both share the complexity of the biological diagnosis. Current treatment of HIT firstly relies on parenteral non-heparin therapies, but DOACs have been included in American and French guidelines for a few years, providing the advantage of limiting the need for treatment monitoring. In APS, vitamin K antagonists are conversely the main treatment (+/− anti-platelet agents), and the use of DOACs is either subject to precautionary recommendations or is not recommended in severe APS. While some randomized controlled trials have been conducted regarding the use of DOACs in APS, only retrospective studies have examined HIT. In addition, vaccine-induced immune thrombotic thrombocytopenia (VITT) is now a part of immunothrombotic disorders, and guidelines have been created concerning an anticoagulant strategy in this case. This literature review aims to summarize available data on HIT, APS, and VITT treatments and define the use of DOACs in therapeutic strategies.

Targeted Nanotherapeutics in The Prophylaxis and Treatment of Thrombosis

Currently available anti-thrombotic therapy for the prophylaxis and treatment of arterial and venous thrombosis includes intravenous administration of anti-thrombotic drugs which lead to severe bleeding risks such as cerebral hemorrhage and stroke. Targeting approaches that utilize nanosystems to reach the thrombus sites are emerging to increase the local effect of anti-thrombotic drugs, as well as to decrease these severe bleeding complications by diminishing the systemic availability of these drugs. This review emphasizes the emerging targeted nanomedicines (liposomes, micelles, polymeric nanoparticles, material bases nanoparticles and other biological vectors) for the prophylaxis and treatment of thrombotic events as well as multifunctional nanomedicines for theranostic applications. Nanomedicine offers a promising platform for a smart, safe, and effective approach for the management of thrombosis.

A review of COVID-19-related thrombosis and anticoagulation strategies specific to the Asian population.

The coronavirus disease 2019 (COVID-19) pandemic has placed an immense burden on healthcare systems worldwide. There is intensive research targeted at better understanding of the virus pathogenicity, development of effective treatment strategies and vaccines against COVID-19. It is increasingly being recognised that the pathogenicity of COVID-19 extends beyond the respiratory system. In severe cases, there can be widespread activation of the immune system, vascular injury and a resultant pro-thrombotic state. Severe COVID-19 is widely regarded as a risk factor for venous thromboembolism. Interim European and American guidelines have been created to guide anticoagulation strategies in COVID-19 patients. However, it is unclear if these guidelines can be extrapolated directly to Asians, in whom there are differences in the baseline risk of thrombosis and bleeding. Our review article aimed to summarise the current understanding of arteriovenous thromboembolic complications in COVID-19 and discuss management strategies for prevention and treatment of thrombotic events in Asian COVID-19 patients.

A Review on the Use of Reversal Agents of Direct Oral Anticogulant Drugs in Case of Gastrointestinal Bleeding.

Major bleeding is a life-threatening condition and a medical emergency with high mortality risk. It is often the complication of anticoagulant's intake. Anticoagulants are commonly used for the prevention and treatment of thrombotic events. The standard therapy with vitamin K antagonist (warfarin) has been frequently replaced by direct oral anticoagulants (DOACs). The latter agents (rivaroxaban, apixaban, edoxaban, dabigatran, and betrixaban) showed better efficacy and safety compared to standard warfarin treatment and they are recommended for the reduction of ischemic stroke. Literature data reported a high risk of gastrointestinal bleeding with DOACs, in particular with dabigatran and rivaroxaban. In case of life-threatening gastrointestinal bleeding, these patients could benefit from the use of reversal agents. We performed an electronic search on PUBMED of the literature concerning reversal agents for DOACs and gastrointestinal bleeding in the Emergency Department from 2004 to 2020. This review summarizes the current evidence about three reversal agents idarucizumab, andexanet alfa and ciraparantag, and the use of the first two in the emergency setting in patients with active major bleeding or who need urgent surgery which physicians indicate for a better management approach in order to increase patient's safety. Although these agents have been marketed for five years (idarucizumab) and two years (andexanet alfa) respectively, and despite guidelines considering antidotes as first-line agents in treating life-threatening hemorrhage when available, these antidotes seem to gain access very slowly in the clinical practice. Cost, logistical aspects and need for plasma level determination of DOAC for an accurate therapeutic use probably have an impact on this phenomenon.. An expert multidisciplinary bleeding team should be established so as to implement international guidelines based on local resources and organization.

Antiphospholipid Syndrome: A Review

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by venous thromboembolism, arterial thrombosis, and obstetric morbidities in the setting of persistently positive levels of antiphospholipid antibodies. It may be primary or secondary. The latest classification criteria (Sydney 2006) recognize just three tests to define this syndrome- lupus anticoagulant, anticardiolipin antibodies and anti-?2-glycoprotein-1 antibodies. Treatment of thrombotic events involves lifelong anticoagulation with vitamin K antagonist warfarin. Antiphospholipid antibody syndrome (APS) with only pregnancy morbidity is treated with thromboprophylaxis with heparin during pregnancy and postpartum for 6 weeks. In this review we discuss the pathogenesis, diagnosis, treatment and prognosis of the APS.

Prophylaxis and Therapy of Venous Thrombotic Events (VTE) in Pregnancy and the Postpartum Period.

Venous thromboembolisms and pulmonary embolisms are one of the main causes of morbidity and mortality in pregnancy. The increased risk of thrombotic events caused by the physiological changes during pregnancy alone does not justify any medical antithrombotic prophylaxis. However, if there are also other risk factors such as a history of thromboses, hormonal stimulation as part of fertility treatment, thrombophilia, increased age of the pregnant woman, severe obesity or predisposing concomitant illnesses, the risk of thrombosis should be re-evaluated – if possible by a coagulation specialist – and drug prophylaxis should be initiated, where applicable. Low-molecular-weight heparins (LMWH) are the standard medication for the prophylaxis and treatment of thrombotic events in pregnancy and the postpartum period. Medical thrombosis prophylaxis started during pregnancy is generally continued for about six weeks following delivery due to the risk of thrombosis which peaks during the postpartum period. The same applies to therapeutic anticoagulation after the occurrence of a thrombotic event in pregnancy; here, a minimum duration of the therapy of three months should also be adhered to. During breastfeeding, LMWH or the oral anticoagulant warfarin can be considered; neither active substance passes into breast milk.

Research progress on pathophysiology of thrombosis formation in patients with paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic disease caused by an acquired mutation of hematopoietic stem cell gene, manifesting mainly with intravascular hemolytic anemia, pancytopenia and thrombosis. Above all, thrombosis formation is a severe complication, as well as a major cause of death. Clarifying its mechanism of propensity for thrombosis formation will benefit the prevention and treatment of thrombotic events in PNH patients. In this review, research progresses of associated mechanisms, such as complement system, free hemoglobin (fHb), NO, platelets and coagulation factors in thrombosis process of patients with PNH under hemolysis and non-hemolytic state were well reviewed, in order to clarify the pathophysiological mechanisms of thrombosis formation in PNH patients, and provide strategies for PNH related research and clinical treatment. Key words: Hemoglobinuria, paroxysmal; Thrombosis; Complement activation; Hemoglobins; Blood coagulation factors; Nitric oxide

Antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, such as lupus anticoagulant, anticardiolipin antibodies and anti-β2-glycoprotein 1 antibodies. APS can present with a variety of clinical phenotypes, including thrombosis in the veins, arteries and microvasculature as well as obstetrical complications. The pathophysiological hallmark is thrombosis, but other factors such as complement activation might be important. Prevention of thrombotic manifestations associated with APS includes lifestyle changes and, in individuals at high risk, low-dose aspirin. Prevention and treatment of thrombotic events are dependent mainly on the use of vitamin K antagonists. Immunosuppression and anticomplement therapy have been used anecdotally but have not been adequately tested. Pregnancy morbidity includes unexplained recurrent early miscarriage, fetal death and late obstetrical manifestation such as pre-eclampsia, premature birth or fetal growth restriction associated with placental insufficiency. Current treatment to prevent obstetrical morbidity is based on low-dose aspirin and/or low-molecular-weight heparin and has improved pregnancy outcomes to achieve successful live birth in >70% of pregnancies. Although hydroxychloroquine and pravastatin might further improve pregnancy outcomes, prospective clinical trials are required to confirm these findings.

Anticoagulation Therapy for Thrombotic Events in Paediatric Cancer Patients with Low Platelet Counts

Background Thrombocytopenia is common in children receiving cancer chemotherapy. In addition, children with cancer are also at increased risk of acute thrombotic events (TE). When these two complications occur simultaneously, TE management with anticoagulants (ACT) poses a unique challenge, as ACT use in thrombocytopenic patients increases their bleeding risk. Current guidelines provide only best practice recommendations on how to manage this treatment conundrum, and even these recommendations vary on optimal management due to the lack of evidence to guide treatment. To date, no systematic literature review summarizing the available paediatric data on treatment of TE in the presence of thrombocytopenia has been conducted. The aim of our systematic review was to summarize the data available to evaluate the safety of ACT for management of TE in paediatric oncology patients during periods of thrombocytopenia. Methods We systematically searched MEDLINE and EMBASE from the OVID platform from inception to April 15th 2016 for studies that included children aged less than 18 years with diagnosis of cancer complicated by an objectively confirmed TE, whose anticoagulation therapy was complicated by a period of thrombocytopenia (as defined by the study author). We included all study designs. Two authors (LB and AA) screened the data at title then full-text level to select eligible studies. Disputes were arbitrated by a third author (UA) until a consensus was reached. Our primary outcome was haemorrhagic complications, categorized as minor or major according to paediatric ISTH criteria. Bleeding episodes were divided according to anticoagulation intensity (age-appropriate, agent-specific full dose vs. half-dose, as per CHEST guidelines) and degree of thrombocytopenia (i.e. severe &lt;/=50 x109/L, moderate 51-99 x109/L, mild &gt;/=100 x109/L). Our secondary outcome was the identification of platelet transfusion triggers according to degree of anticoagulation intensity. Results Our search yielded 244 articles, of which 13 were screened at a full text level. Four manuscripts were selected for inclusion, as follows: case report (n=1), case series (n=2), and prospective cohort study (n=1). Details of included studies are described inTable 1 and patient information in table 2. The studies included 39 patients with malignancies, of which the most common were acute lymphoblastic leukaemia (n=13), CNS malignancies (n=6), non-hodgkinlymphoma(n=4). All patients had venous TE. Type and regimen of ACT, and author definitions of thrombocytopenia and bleeding were variable. Thirty-five patients received low-molecular weight heparin (LMWH), of whom 33 received therapeutic dose, and no dose was recorded for two. Three patients received unfractionated heparin (UFH) with antithrombin(AT) supplementation; however, UFH wasstopped in periods of low platelet counts, and one received a reduced dose UFH. According to our definition, 36/39 (92.3%) experienced severe thrombocytopenia, 1 (2.6%) developed moderate thrombocytopenia, platelet count was not stated in 2(5.1%). Using the ISTH bleeding criteria, one patient (2.6%) developed major bleeding, and seven (17.9%) developed minor bleeding (n=2 intestinal bleeding, n=5 injection site/port bleeding). Only one study reported our secondary outcome, which used a platelet transfusion trigger of &lt;40x109/L if receiving therapeutic LMWH and &lt;20x109/L if receiving prophylactic LMWH. Given the heterogeneity, we were unable to statistically aggregate any data. Discussion The results of this systematic review highlight the paucity of high-quality data to assess the use and safety of ACT for TE in paediatric cancer patients during periods of thrombocytopenia. We identified only observational studies- one prospective and three retrospective in design. These studies included very few patients (total n=39), and had variable patients, disease and treatment-related factors. Evidence-based recommendations cannot be generated to guide an optimal ACT management in such situations. Further research using standardized definitions is needed to identify optimal strategies for treating thrombotic events during periods of thrombocytopenia. Such research will help on the development of evidence-based clinical practice guidelines to improve patient care. Disclosures Brandão: Boehringer Ingelheim: Consultancy.

Minimisation of Bleeding Risks Due to Direct Oral Anticoagulants

Direct oral anticoagulants (DOAC) are used in several indications for the prevention and treatment of thrombotic events. As highlighted by data from clinical trials and case studies, all DOAC carry the risk of bleeding despite careful selection and patient management. Previous publications have demonstrated the limited knowledge of many physicians concerning the indications for, and correct management of, these anticoagulants. Health institutions should develop risk minimisation strategies and educational materials to prevent major adverse events related to DOAC administration. Major bleeding events are reported in clinical practice and specific antidotes are emerging from Phase III trials. Some antidotes are licensed but their high cost might limit routine use. We therefore illustrate approaches and tools that can help physicians prescribe DOAC appropriately. We focus on screening for modifiable bleeding risk factors and adapting doses according to the individual benefit-risk profile. We also provide recommendations on managing a missed dose, switching, bridging, and resumption.

The Role of Fibrinogen and Factor XIII in Hemostasis, and the Identification and Treatment of Associated Disorders

The thrombin-mediated conversion of fibrinogen to fibrin and the subsequent stabilization of thefibrin clot by activated FXIII are vital to adequate hemostasis. Once cross-linked, the fibrin clot is relatively resistant to fibrinolysis, ensuring longterm stability of the fibrin clot to permit repair of the damaged vessel. Indeed, qualitative or quantitative defects in either fibrinogen or FXIII may result in bleeding.1,2 Conversely, elevated fibrinogen levels are considered a risk factor for thrombotic disease, whereas FXIII may affect thrombotic risk in selected patient groups.3–5 Thus, thrombosis and hemostasis critically involve both fibrinogen and FXIII, which in turn are fascinating molecules in terms of structure and function, and clinical impact. The biochemical and biophysical properties of the fibrin clot have been partly elucidated and help us understand the mode of action of clot formation; moreover, determinants of (in)stability of the clot have been identified.6–8 FXIII is a complex molecule that exists in a different form in plasma (as a A2B2 heterotetramer) and within cells including platelets (as an A2 homodimer). Both fibrinogen and FXIII have properties beyond their well-recognized role in thrombosis and hemostasis.9–11 We are proud and pleased to present a comprehensive overview of new clinical and basic science developments in the field of fibrin formation and crosslinking. This issue of Seminars in Thrombosis & Haemostasis starts with a provocative paper by Litvinov andWeiselwho review the relevance of fibrin(ogen) for clinicians and biochemists.12 The relatively mild phenotype of thefibrinogen knockoutmicehas led some biochemists and clinicians to conclude that fibrinogen is not very important, but critical arguments against this conclusion are provided by Litvinov and Weisel. Subsequently, Macrae and coworkers present an update of biochemical and clinical studies on the fibrinogen gamma prime splice variant,13 which has biophysical and biochemical features that are markedly distinct from “normal” fibrinogen, and appears associated with thrombotic disease. Besides the fibrinogen gamma prime variant, which is present in all of us, rare mutations in fibrinogen leading to decreased plasma levels, decreased fibrinogen function, or both, can occur and are associated with both a bleeding tendency and thrombotic complications. Neerman-Arbez and coworkers provide a comprehensive description of the screening for, and molecular characterization of, congenital fibrinogen abnormalities, and provide an update on themutations that have so far been identified.14 Casini and colleagues then discuss therapeutic options in patients with congenital fibrinogen abnormalities and highlight difficult situations, including obstetric management and treatment of thrombotic events.15 The use of fibrinogen concentrate to treat acquired fibrinogen deficiencies, such as encountered in massive bleeding due to trauma, surgery, or due to postpartum bleeding, has gained popularity over the past decade. Samama argues against the liberal use of fibrinogen concentrates inmassively bleeding patients and calls for additional studies to clarify the role of fibrinogen concentrates in this setting.16 Subsequently, Undas provides in-depth information on commonly used laboratory tests to assessfibrin clot properties in both routine diagnostics and research settings.17 Fibrinogen is synthesized in the liver, and patients with liver diseases may acquire quantitative and qualitative defects in fibrinogen. The consequences of these changes are discussed by Lisman and Ariens, who provide evidence of qualitative improvements in fibrin structure in these patients despite quantitative defects.18 Alterations in fibrin(ogen) may contribute to thrombotic events that may occur in patients with liver diseases. In addition, fibrin(ogen) may play a role in the pathogenesis of liver diseases. Evidence from experimental animal models linking fibrin(ogen) to disease pathology is

The class I phosphoinositide 3-kinases α and β control antiphospholipid antibodies-induced platelet activation.

Antiphospholipid syndrome (APS) is an autoimmune disease characterised by the presence of antiphospholipid antibodies (aPL) associated with increased thrombotic risk and pregnancy morbidity. Although aPL are heterogeneous auto-antibodies, the major pathogenic target is the plasma protein β2-glycoprotein 1. The molecular mechanisms of platelet activation by aPL remain poorly understood. Here, we explored the role of the class IA phosphoinositide 3-kinase (PI3K) α and β isoforms in platelet activation by aPL. Compared to control IgG from healthy individuals, the IgG fraction isolated from patients with APS potentiates platelet aggregation induced by low dose of thrombin in vitro and increases platelet adhesion and thrombus growth on a collagen matrix under arterial shear rate through a mechanism involving glycoprotein Ib (GPIb) and Toll Like Receptor 2 (TLR-2). Using isoforms-selective pharmacological PI3K inhibitors and mice with megakaryocyte/platelet lineage-specific inactivation of class IA PI3K isoforms, we demonstrate a critical role of the PI3Kβ and PI3Kα isoforms in platelet activation induced by aPL. Our data show that aPL potentiate platelet activation through GPIbα and TLR-2 via a mechanism involving the class IA PI3Kα and β isoforms, which represent new potential therapeutic targets in the prevention or treatment of thrombotic events in patients with APS.

Preventive strategies against bleeding due to nonvitamin K antagonist oral anticoagulants.

Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC's dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures.