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Background: Cancer-associated venous thromboembolism (CAT) has detrimental impact on patients' clinical outcomes and quality of life. Data on CAT education, communication, and awareness among the general cancer population are scanty. Methods: We present the preliminary results of an ongoing patient-centered survey including 27 items covering major spheres of CAT. The survey, available in 14 languages, was promoted and disseminated online through social networks, email newsletters, websites, and media. Results: As of September 20, 2022, 749 participants from 27 countries completed the survey. Overall, 61.8% (n = 460) of responders were not aware of their risk of CAT. Among those who received information on CAT, 26.2% (n = 56) were informed only at the time of CAT diagnosis. Over two thirds (69.1%, n = 501) of participants received no education on signs and symptoms of venous thromboembolism (VTE); among those who were educated about the possible clinical manifestations, 58.9% (n = 119) were given instructions to seek consultation in case of VTE suspicion. Two hundred twenty-four respondents (30.9%) had a chance to discuss the potential use of primary thromboprophylaxis with health-care providers. Just over half (58.7%, n = 309) were unaware of the risks of bleeding associated with anticoagulation, despite being involved in anticoagulant-related discussions or exposed to anticoagulants. Most responders (85%, n = 612) valued receiving CAT education as highly relevant; however, 51.7% (n = 375) expressed concerns about insufficient time spent and clarity of education received. Conclusions: This ongoing survey involving cancer patients with diverse ethnic, cultural, and geographical backgrounds highlights important patient knowledge gaps. These findings warrant urgent interventions to improve education and awareness, and reduce CAT burden.

Background Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. Method and results This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). Conclusions Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

Management of adult patients with immune thrombocytopenia (ITP) is often unsatisfactory, due to variable efficacy of treatment, risk of life-threatening bleeding if disease control is poor, and side effects associated with treatment. Lack of data on the platelet count threshold associated with bleeding and infection risk associated with ITP treatment limits risk/benefit clinical decision making. We reviewed medical records of all ITP patients who were admitted to our hospital between 2012 and 2017 to evaluate the platelet count threshold for bleeding, infection burden associated with treatment, and real-world efficacy of second-line treatment. We demonstrated fair discrimination between platelet count and occurrence of bleeding, with 15 × 109/L being the optimal cut-off for predicting any bleeding while 20 × 109/L had the highest negative predictive value for severe bleeding. In multivariable analyses, patients who were treated with corticosteroids for at least 2 months were 5.3 times as likely to have an infection. In addition, rituximab response was strongly associated with response to frontline corticosteroids and infection was associated with older age ≥ 65 years and corticosteroid dependence. If corticosteroids are initiated, physicians should aim for the shortest duration of treatment before switching to effective second-line agents for hemostatic platelet counts.

Objectives Pregnancy-associated venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is associated with increased risk of maternal mortality and morbidity. This study aimed to assess potential risk factors for pregnancy-associated VTE. Methods In this case-control study, women with pregnancy-associated VTE were identified via International Classification of Diseases codes and included if they had been objectively diagnosed with VTE during pregnancy or within six weeks postpartum, from 2004 to 2016, at KK Women’s and Children’s Hospital or Singapore General Hospital in Singapore. Controls, i.e. pregnant women without VTE, were selected from a prospective longitudinal study. The odds ratio (OR) for VTE was computed for a range of maternal and obstetric factors. Results and conclusions From 2004 to 2016, 89 cases of pregnancy-associated VTE and 926 controls were identifed and analysed using logistic regression. The most significant risk factors for pregnancy-associated VTE were smoking (OR 5.44, p=0.0002) and preterm delivery (OR 5.06, p=0.023). Malay race, multiparity, non-O blood group and caesarean section, were also identified to be of higher risk. These risk factors should be useful in the development of thromboprophylaxis strategies for pregnancy and the postpartum period, especially in Singapore.

The disease burden of AF is greater in Asia-Pacific than other areas of the world. Direct oral anticoagulants (DOACs) have emerged as effective alternatives to vitamin K antagonists (VKA) for preventing thromboembolic events in patients with AF. The Asian Pacific Society of Cardiology developed this consensus statement to guide physicians in the management of AF in Asian populations. Statements were developed by an expert consensus panel who reviewed the available data from patients in Asia-Pacific. Consensus statements were developed then put to an online vote. The resulting 17 statements provide guidance on the assessment of stroke risk of AF patients in the region, the appropriate use of DOACs in these patients, as well as the concomitant use of DOACs and antiplatelets, and the transition to DOACs from VKAs and vice versa. The periprocedural management of patients on DOAC therapy and the management of patients with bleeding while on DOACs are also discussed. ispartof: EUROPEAN CARDIOLOGY REVIEW vol:16 ispartof: location:England status: published

COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and other respiratory viral (non-CoV-2-RV) infections are associated with thrombotic complications. The differences in prothrombotic potential between SARS-CoV-2 and non-CoV-2-RV have not been well characterised. We compared the thrombotic rates between these two groups of patients directly and further delved into their coagulation profiles. In this single-center, retrospective cohort study, all consecutive COVID-19 and non-CoV-2-RV patients admitted between January 15th and April 10th 2020 were included. Coagulation parameters studied were prothrombin time and activated partial thromboplastin time and its associated clot waveform analysis (CWA) parameter, min1, min2 and max2. In the COVID-19 (n = 181) group there were two (1.0 event/1000-hospital-days) myocardial infarction events while one (1.8 event/1000-hospital-day) was reported in the non-CoV-2-RV (n = 165) group. These events occurred in patients who were severely ill. There were no venous thrombotic events. Coagulation parameters did not differ throughout the course of mild COVID-19. However, CWA parameters were significantly higher in severe COVID-19 compared with mild disease, suggesting hypercoagulability (min1: 6.48%/s vs 5.05%/s, P 2 vs 0.74%/s2, P = 0.033). In conclusion, the thrombotic rates were low and did not differ between COVID-19 and non-CoV-2-RV patients. The hypercoagulability in COVID-19 is a highly dynamic process with the highest risk occurring when patients were most severely ill. Such changes in haemostasis could be detected by CWA. In our population, a more individualized thromboprophylaxis approach, considering clinical and laboratory factors, is preferred over universal pharmacological thromboprophylaxis for all hospitalized COVID-19 patients and such personalized approach warrants further research.

Testing for polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene is still a standard part of thrombophilia testing in many laboratories. However, it is clear that these polymorphisms are not risk factors for arterial or venous thrombosis and therefore should not be part of thrombophilia testing. Eliminating MTHFR from thrombophilia testing will reduce patient concerns and health care costs.

OBJECTIVE: We investigated patient-reported roles of families, physicians, and patients themselves in treatment decision making and whether discordance between perceived and preferred roles is associated with psychological distress and perceived quality of care among patients with cancer.METHODS: We analyzed cross-sectional survey data from 599 adults with stage IV solid malignancy in Singapore. Stuart-Maxwell tests were used to compare patients' perceived and preferred roles in decision making. Types of discordance were categorized as follows: involvement at a lesser level than preferred, involvement at a greater level than preferred, and no change in patient involvement. Ordinary least squares regressions examined the associations between types of discordance and patient outcomes, controlling for patient characteristics.RESULTS: Discordance between perceived and preferred roles was observed in 16% of patients. Amongst patients with discordance, 33% reported being involved at a lesser level than they preferred, 47% reported being involved at a greater level than they preferred, and 19% reported discordance where level of patient involvement did not change. Multivariable analyses showed that lesser involvement than preferred and discordance with no change in patient involvement were associated with poorer quality of physician communication (β = - 9.478 [95% confidence interval {CI} - 16.303 to - 2.653] and β = - 9.184 [95% CI - 18.066 to - 0.301]) and poorer care coordination (β = - 11.658 [95% CI - 17.718 to - 5.597] and β = - 8.856 [95% CI - 16.744 to - 0.968]) compared with concordance.CONCLUSIONS: Most patients reported participating at their desired level. Despite this finding, our results suggest that involving patients at a lesser level than they prefer can lead to poorer perceived quality of physician communication and care coordination and that encouraging patient participation is a safe approach to minimizing poor outcomes.

Infections cause varying degrees of haemostatic dysfunction which can be detected by clot waveform analysis (CWA), a global haemostatic marker. CWA has been shown to predict poor outcomes in severe infections with disseminated intravascular coagulopathy. The effect of less severe bacterial and viral infections on CWA has not been established. We hypothesized that different infections influence CWA distinctively. Patients admitted with bacterial infections, dengue and upper respiratory tract viral infections were recruited if they had an activated partial thromboplastin time (aPTT) measured on admission. APTT-based CWA was performed on Sysmex CS2100i automated analyser using Dade Actin FSL reagent. CWA parameters [(maximum velocity (min1), maximum acceleration (min2) and maximum deceleration (max2)] were compared against control patients. Infected patients (n = 101) had longer aPTT than controls (n = 112) (34.37 ± 7.72 s vs 27.80 ± 1.59 s, p 2; 0.74 ± 0.16%/s2), bacterial infection has higher CWA results (6.92 ± 1.60%/s; 1.04 ± 0.28%/s2; 0.82 ± 0.24%/s2, all p 2; 0.43 ± 0.14%/s2, all p 2; 0.73 ± 0.18%/s2, all p > 0.05). CWA parameters demonstrated positive correlation with C-reactive protein levels (min1: r = 0.54, min2: r = 0.44, max2: r = 0.34; all p

Background: COVID-19 caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and other respiratory viral (non-CoV-2-RV) infections are associated with thrombotic complications. The differences in prothrombotic potential between SARS-CoV-2 and non-CoV-2-RV have not been well characterised. We compared the thrombotic rates between these two groups of patients directly and further delved into their coagulation profiles. Methods: In this single-center, retrospective cohort study, all consecutive COVID-19 and non-CoV-2-RV patients admitted between January 15th and April 10th 2020 were included. Coagulation parameters studied were prothrombin time and activated partial thromboplastin time and its associated clot waveform analysis (CWA) parameter, min1, min2 and max2. Findings: In the COVID-19 (n=181) group there were two (1.0 event/1000-hospital-days) thrombotic events while one (1.8 event/1000-hospital-day) was reported in the non-CoV-2-RV (n=165) group. All of these events were myocardial infarction occurring in the intensive care unit. Coagulation parameters did not differ throughout the course of mild COVID-19. However, CWA parameters were significantly higher in severe COVID-19 compared with mild disease, suggesting hypercoagulability (min1: 6.48%/s vs 5.05%/s, P

The 2020 Congress of the International Society of Thrombosis and Haemostasis (ISTH) was held virtually July 12-15, 2019, due to the coronavirus disease 2019 pandemic. The congress convenes annually to discuss clinical and basic topics in hemostasis and thrombosis. Each year, the program includes State of Art (SOA) lectures given by prominent scientists. Presenters are asked to create Illustrated Capsules of their talks, which are concise illustrations with minimal explanatory text. Capsules cover major themes of the presentation, and these undergo formal peer review for inclusion in this article. Owing to the shift to a virtual congress this year, organizers reduced the program size. There were 39 SOA lectures virtually presented, and 29 capsules (9 from talks omitted from the virtual congress) were both submitted and successful in peer review, and are included in this article. Topics include the roles of the hemostatic system in inflammation, infection, immunity, and cancer, platelet function and signaling, platelet function disorders, megakaryocyte biology, hemophilia including gene therapy, phenotype tests in hemostasis, von Willebrand factor, anticoagulant factor V, computational driven discovery, endothelium, clinical and basic aspects of thrombotic microangiopathies, fibrinolysis and thrombolysis, antithrombotics in pediatrics, direct oral anticoagulant management, and thrombosis and hemostasis in pregnancy. Capsule authors invite virtual congress attendees to refer to these capsules during the live presentations and participate on Twitter in discussion. Research and Practice in Haemostasis and Thrombosis will release 2 tweets from @RPTHJournal during each presentation, using #IllustratedReview, #CoagCapsule and #ISTH2020. Readers are also welcome to utilize capsules for teaching and ongoing education., peer-reviewed

Race is touted as an independent risk factor for venous thromboembolism (VTE), although the basis for this is varied and contentious. Comparison of plasma thrombin generation (TG) using calibrated automated thrombogram (CAT) across races offers a modality that objectively measures global hemostatic function to evaluate this influence. Direct comparative data across races are currently not available. Aim is to establish the influence of race on plasma TG. Sixty normal participants, matched for age and gender, equally representing 4 races—Caucasian, Chinese, Indian, and Malay—were recruited. Thrombin generation parameters (lag time, time to peak, peak, and endogenous thrombin potential [ETP]) in platelet-poor plasma were measured using CAT. The mean ETP (standard deviation) for the different races were Caucasians: 1338.18 (194.19) nM·min; Chinese, 1318.91 (108.90) nM·min; Indians, 1389.81 (182.61) nM·min; and Malays, 1436.21 (184.24) nM·min. Caucasians had the longest mean lag time of 2.59 ± 0.37 seconds; Indians had the highest mean peak of 284.22 ± 30.74 nM, and Malays had the longest mean time to peak of 5.47 ± 0.59 seconds. Analysis based on race did not demonstrate any significant difference for all TG parameters. The greatest mean difference of ETP between any 2 races (Malays and Chinese) was 117.30 nM·min (95% confidence interval: −45.86 to 280.46 nM·min) which was within the predefined limit of equivalence. In a cohort of healthy participants, TG mediated by plasma factors is not influenced by race and does not explain the reported racial differences in VTE incidence. For the 4 racial groups studied, the use of separate normal ranges for plasma TG might not be essential.

Introduction An increasing number of evidence have reported the association of COVID-19 with increased incidence of thrombotic events. High incidences were initially reported in critically ill COVID-19 patients, but subsequently an increased incidence was also noticed in non-critically ill general ward patients. This has led to a universal recommendation of thromboprophylaxis for all COVID-19 patients by ASH and ISTH. As the data on COVID-19 and thrombosis continue to develop and evolve, we examined the data in two aspects. Firstly, other non-SARS-CoV-2 viral respiratory infections have also been reported to be associated with thrombotic events, be it arterial or venous. Thus, we aimed to compare the thrombotic rates between these two groups of patients directly to hopefully ascertain the actual thrombotic tendency in COVID-19 infections. Secondly, global hemostatic assays such as thromboelastogram and clot waveform analysis (CWA) have been used to demonstrate hypercoagulability in COVID-19 patients, albeit in a small group of patients and only in the critically ill. Incorporating these laboratory results into the management of thromboprophylaxis in COVID-19 is an attractive notion but more data and studies are definitely needed. Here, we evaluate the dynamic changes of hemostatic assays in patients with COVID-19 to better understand the overall coagulation profiles of COVID-19 infection. Methods We performed a single center, retrospective cohort study. All consecutive patients admitted to our hospital between 15 January and 10 April 2020 that were tested positive for COVID-19 or other non-SARS-CoV-2 respiratory viruses were included in our study. The main coagulation assays studied were prothrombin time and activated partial thromboplastin time and its associated CWA, min1, min2 and max2. Findings We included a total of 181 COVID-19 patients and 165 patients with non-SARS-CoV-2 respiratory viral infections. The respiratory viruses were rhinovirus (n=65), influenza A and B (n=46), adenovirus (n=13), human coronavirus 229E/NL63/OC43 (n=15), human enterovirus (n=3), metapneumovirus (n=6), parainfluenza virus 1 to 4 (n=11), respiratory syncytial virus (n=6) and human bocavirus 1 to 4 (n=0). The median age of COVID-19 patients was 37 (interquartile range [IQR], 30.5-51 years) versus 35 (IQR, 29-51.5) in the non-SAR-CoV-2 respiratory viruses group (P=0.12). Comorbidities, assessed by Charlson score, was also not statistically different between both groups (median score 0 (IQR, 0-1) in both groups, P=0.39). Majority of our patients had relatively mild infection as reflected by the low proportions of them requiring oxygen supplementation (11.0% in COVID-19 vs 4.8% in non-SARS-COV-2, P=0.035). COVID-19 patients had longer hospital stay (7 days (IQR, 5.5-13) vs 3 days (IQR, 2-3), P Conclusion The thrombotic rates were low in both groups and did not differ significantly between COVID-19 and Non-SARS-CoV-2 patients. Nonetheless, our analysis of hemostatic parameters demonstrated hypercoagulability in COVID-19 as a dynamic process with the risk highest when the patients are critically ill. These changes in hemostasis could be detected by CWA. With our findings, we suggest that a more individualized thromboprophylaxis approach, considering clinical and laboratory factors, is probably preferred over universal pharmacological thromboprophylaxis for all hospitalized COVID-19 patients and warrants further research. Disclosures Lee: Sanofi: Honoraria, Other: travel grants; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: travel grants ; Medtronics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Objective Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. This study aims to describe the thrombotic and bleeding rates in COVID-19 patients admitted to intensive care units (ICU) in Singapore. Design Retrospective observational study involving all consecutive adult COVID-19 patients who required ICU admission between 23 January 2020 and 30 April 2020. Setting National multicenter study involving all eight public hospitals in Singapore. Patients 111 consecutive COVID-19 patients who required ICU admission were included. Measurements and Main Results Primary outcome was any venous or arterial thrombotic events occurred in ICU. Other measures included (1) the overall, venous and arterial thrombotic events throughout the hospitalisation, (2) major and minor bleeding events. The overall thrombotic rate in ICU was 11.7% (n=13), with 1.8% (n=2) venous and 9.9% (n=11) arterial events. The overall thrombotic rates throughout hospitalisation, censored at 30 April 2020, increased to 18.0% (n=20) with 6.3% (n=7) venous and 11.7% (n=13) arterial events. Major and minor bleeding rates were 14.8% (n=16) and 3.7% (n=4), respectively. Two-third of the patients received pharmacological thromboprophylaxis in ICU. Conclusions Critically ill COVID-19 patients in Singapore have lower VTE but higher arterial thrombosis rates with higher bleeding manifestations than other reported cohorts. Standard thromboprophylaxis may be sufficient to prevent thrombotic complications in patients with similar demographics. Disclosures No relevant conflicts of interest to declare.

International audience; 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.

Introduction: A hypercoagulable state is a predisposition for venous thromboembolism (VTE). The activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA) is a global haemostatic measure but its role in assessment of hypercoagulability and thrombotic disorders is uncertain. We aimed to study the changes of CWA parameters in acute VTE. We hypothesized that patients with acute VTE would demonstrate higher CWA values than control patients without VTE and having elevated CWA parameters is associated with acute VTE. Materials and methods: Clot waveform analysis data from patients (N = 45) with objectively proven acute VTE who had an aPTT performed prior to initiation of anticoagulation were compared with controls (N = 111). The CWA parameters measured were min1, min2, max2 and delta change. Results: While the mean aPTT between VTE patients and controls did not differ (P = 0.830), the mean CWA parameters were significantly higher among VTE patients than controls (min1, P < 0.001; min2, P = 0.001; max2, P = 0.002; delta change, P < 0.001). There were significantly more cases within the VTE group exhibiting CWA values above their reference intervals than the control group (all P < 0.001), with the odds ratios for VTE of 8.0, 5.2, 4.8 and 18.6 for min1, min2, max2 and delta change, respectively (all P < 0.001). Conclusions: Patients with acute VTE had elevated aPTT-based CWA parameters than controls. Higher CWA parameters were significantly associated with acute VTE.

Non-transfusion-dependent thalassaemia (NTDT) is associated with a hypercoagulable state with thrombotic risk highest after splenectomy. Various mechanisms have been proposed. Although an antiplatelet agent is commonly recommended as thromboprophylaxis in NTDT, the role of platelets contributing to this hypercoagulable state is not well-defined. This study aims to evaluate the role of platelets contributing to hypercoagulability in NTDT patients using thrombin generation (TG). Platelet-rich (PRP) and platelet-poor plasma (PPP) were collected from NTDT patients (n = 30) and normal controls (n = 20) for TG measurement and compared. Controls had higher endogenous thrombin potential (ETP) in PPP (1204.97 nM.min vs 911.62 nM.min, p

With increasing usage of thrombolysis in the treatment of acute ischemic strokes within 4.5- hour window, it is becoming more important to recognize stroke mimics. Though the incidence of stroke mimics being thrombolysed is less than 3%, it is essential to diagnose them so as to avoid wrong thrombolytic treatment which carries potential complications of bleeding. We describe the case of a 17 year old girl with acute lymphoblastic leukemia, who developed stroke like episodes on two consecutive challenges with a chemotherapeutic regime which included intravenous and intrathecal methotrexate. She had MRI changes consistent with acute ischemic stroke on both occasions. Her deficits recovered completely and spontaneously, as did the MRI changes. She did not have any further episodes when methotrexate was excluded from the chemotherapeutic regime.

The group of new oral anticoagulants or NOACs, now termed direct oral anticoagulants or DOACs, with their favourable results from large scale phase III clinical trials, represent a major advancement and expanded armamentarium in antithrombotic therapy. Dabigatran, rivaroxaban, apixaban and edoxaban are now in clinical routine use for prevention and treatment of arterial and venous thrombotic diseases as addressed in their clinical trials. Usage of the DOACs is expected to increase as clinicians gain more experience and reassurance with data from the real world studies which are generally consistent with that from clinical trials. Development of specific antidotes in management of bleeding complications and development of coagulation assays for their plasma levels will further boost the confidence in the DOACs. Nonetheless, there are still limitations associated with the DOACs. Many patients in need of anticoagulant therapy for indications not studied in the clinical trials will not be eligible for treatment with a DOAC. Conditions where more data is required include DOACs use in the paediatric age group, patients with atrial fibrillation and valvular heart disease, thrombosis associated with the anti-phospholipid syndrome and cancer associated thrombosis. The affordability and access to these drugs may pose an issue for many patients under healthcare systems not providing for these medications. With four new anticoagulants coming onboard very quickly, the focus has shifted to the practical approach and management in real life as many clinicians are not yet familiar with the DOACs. Clinicians need to be educated on how to manage this new class for drugs, from choosing the appropriate drug to prevention and managing bleeding complications as a lack of knowledge and understanding in these drugs will lead to inappropriate use and compromise on patient safety.

Extramedullary leukaemic involvement is not uncommon as part of the presentation in acute myeloid leukaemia (AML). However, infiltrative peripheral neuropathy due to AML was rarely reported. We report a case of extramedullary leukaemic infiltration of the brachial plexus in a patient with relapsed AML.Akut miyeloid löseminin (AML) bir parçası olarak ekstramedüller lösemik tutulum nadir bir durum değildir. Ancak AML’ye bağlı infiltratif periferik nötropati nadiren bildirilmiştir. Burada, relaps AML’li bir hastada brakiyal pleksusun ekstramedüller lösemik infiltrasyonu vakasını sunuyoruz.

Purpose Herbs with “blood-activating” properties by traditional medicine theory often raise concerns for their possible anti-platelet or anticoagulation effects based on reports from in vitro studies. Such herbs have been implicated for bleeding manifestations based on only anecdotal reports. In particular, the combination of such herbs with anti-platelet agents is often empirically advised against despite lack of good clinical evidence. Here we studied 3 commonly used herbal preparations Curcuma longa, Angelica sinensis and Panax ginseng on their respective anti-platelet and anticoagulation effect, alone and in combination with aspirin. Study design This is a randomized, double-blind, placebo-controlled trial involving 25 healthy volunteers for each herbal preparation. Methods Each subject underwent 3 phases comprising of herbal product alone, aspirin alone and aspirin with herbal product, where each phase lasted for 3 weeks with 2 weeks of washout between phases. PT/APTT, platelet function by light transmission aggregometry and thrombin generation assay by calibrated automated thrombogram were measured at baseline and after each phase. Information on adverse reaction including bleeding manifestations was collected after each phase. Results On the whole there was no clinically relevant impact on platelet and coagulation function. With the exception of 5 of 24 subjects in the Curcuma longa group, 2 of 24 subjects in the Angelica sinensis group and 1 of 23 subjects in the Panax ginseng group who had an inhibition in arachidonic-acid induced platelet aggregation, there was no effect of these 3 herbals products on platelet aggregation by other agonists. Combination of these herbal products with aspirin respectively did not further aggravate platelet inhibition caused by aspirin. None of the herbs impaired PT/APTT or thrombin generation. There was no significant bleeding manifestation. Conclusions This study on healthy volunteers provides good evidence on the lack of bleeding risks of Curcuma longa, Angelica sinensis and Panax ginseng either used alone or in combination with aspirin.

Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able to overcome several high-risk features of myeloma, the validity of conventional risk-stratification and prognostication systems needs to be reevaluated. We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure. Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still discriminating of long-term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in predicting for a worse outcome on multivariate analysis (median survival 2.6 years, P = 0.001), suggesting that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyping provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high-risk FISH markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation.

Warfarin-induced bleeding complications and high inter-patient variability are major hindrances to oral anticoagulant therapy. The present study identifies the influence of VKORC1 diplotypes, CYP2C9 and CYP2C19 variants on warfarin disposition and dose requirements in Chinese patients (n=107). The study subjects were genotyped for VKORC1, CYP2C9 and CYP2C19 polymorphic variants. Weekly warfarin dose requirements and S-warfarin clearance were stratified by VKORC1, CYP2C9 and CYP2C19 pharmacogenetics. The major VKORC1 diplotypes were H1-H1 (62%), H1-H7 (18%) and H1-H(*)(b) (10%). Warfarin dose requirements were significantly lower in patients with VKORC1 H1-H1 and H1-H(*)(a) diplotypes compared to patients harboring the H1-H7 and H1-H(*)(b) diplotypes (P0.05). Hepatic tissues with H1-H1 diplotype had significantly lower expression of VKORC1 mRNA compared with liver tissues carrying the H1-H7 and H1-H(*)(b) diplotypes (P=0.006). The percent variability explained by VKORC1 diplotype status was 59.1% while the CYP2C9 genotype status accounted for 6.9% variability in warfarin dose requirements. Patient age and weight were significant covariates accounting for 29% and 8.6% of warfarin dose variability, respectively. The present study shows that VKORC1 diplotype status, CYP2C9 genotype, age and weight are significant covariates, accounting for 73.4% of interindividual variability in warfarin dose requirements among Chinese patients. Translation of these findings into clinical guidelines for warfarin dosing may be required to assess its impact on the safety and efficacy of warfarin.

What is already known about this subject • Recent studies on pharmacogenetics of warfarin have implicated apolipoproteinE (APOE) polymorphisms to influence the vitamin K dependent coagulation cascade and hence the efficacy of warfarin. • Studies among Caucasian and African Americans showed a significant but conflicting role of apolipoproteinE (APOE) isoforms in warfarin pharmacogenetics. • The contribution of APOE isoforms in influencing variations in warfarin requirements in Asian subjects remains to be investigated. What this study adds • This is the first report of a population study in Asians exploring the role of isoforms encoded by three APOE alleles (e2, e3, e4) in influencing warfarin dose requirements. • The present study showed that the APOE e3/e3 isoform is the predominant genotype in the Asian population. • The study also showed that APOE isoforms may not be important in affecting warfarin pharmacodynamics in Asian patients. It also suggested that the impact of different APOE isoforms depended on the frequency of APOE genotypes in the population, in particular the e4 allele containing genotypes. Aims To investigate the influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients. Methods A total of 174 Asian patients (Chinese, n = 96; Malays, n = 50; Indians, n = 28) who had stable daily warfarin doses for at least 1 month were recruited. Following genomic DNA extraction from venous blood, pharmacogenetic analysis of APOE and VKORC1 genes was done by DNA sequencing. Results The majority of the Asian patients (78%) harboured the APOE e3/e3 genotype. Different APOE genotypes were found not to have any significant influence on mean daily warfarin dose requirements. Warfarin dose requirements in the pooled Asian patients homozygous for the VKORC1 H1 haplotype were significantly lower compared with patients homozygous for the H7 haplotype (H1-H1 vs. H7-H7: 2.79 ± 1.06 mg day−1vs. 5.45 ± 2.3 mg day−1, P

Warfarin exhibits wide interpatient variability in dosing requirements. Recent studies have shown a novel polymorphism (rs2108622, V433M) in the CYP4F2 gene to be associated with variability in warfarin requirements in Caucasians. The purpose of this study was to evaluate the impact of rs2108622 on warfarin dose requirements in the Asian population. The mean warfarin dose was found to be significantly lower in patients carrying homozygous wild-type allele CC when compared with patients carrying variant alleles CT and TT (CC vs CT+TT: 3.0 mg/day vs 3.75 mg/day, p = 0.033). In patients harboring VKORC1 diplotypes associated with low warfarin requirements, a linear regression model which included age, weight, CYP2C9 and CYP4F2 variants accounted for 38% of the variability in warfarin dose. Approximately 11% of the dose variation was explained by CYP4F2 rs2108622 (p = 0.004). The influence of rs2108622 in patients harboring VKORC1 diplotypes associated with high warfarin requirements was not significant. This study suggests that CYP4F2 rs2108622 may significantly affect warfarin dose requirements in carriers of VKORC1 low-dose-associated diplotypes.

Point-of-care (POC) coagulometers are increasingly used by patients for self-monitoring of oral vitamin K antagonists therapy. We studied the feasibility of introducing POC international normalised ratio (INR) testing in place of standard laboratory assays in a hospital-based anticoagulation clinic with 250 active patients. The CoaguChek® XS system was first validated in 253 INR samples and found to have a correlation of r = 0.945 with standard assays. Variations increased with INR readings above 3.5 and this was chosen as the cutoff for acceptance of POC INR results. POC testing was done for 1,332 clinic visits during the subsequent 6-month study. Rate of rejections of INR over 3.5 was 4.3% (95% CI 3.3–5.5%). POC testing reduced clinic visit duration by 35 min (p

Background: The use of herbal medicine is prevalent worldwide. Curcuma longa(CL), Angelicae sinensis (AS) and Panax Ginseng(PG), commonly known as Tumeric, Dong Quai and Ginseng respectively, are frequently used herbal medicines but were cautioned to have "blood thinning" effects and generally advised not to be taken with anti-platelets and anticoagulants. However, their effects on haemostasis and interaction with aspirin are unknown and occurrence of bleeding symptoms rarely documented. Aim: To investigate the in-vivo effects of CL (Tumeric), AS (Dong Quai) and PG (Ginseng) with and without aspirin on platelet function and thrombin generation. Methods: A randomized, double-blind, placebo-controlled crossover study was carried out for each herb. 75 healthy volunteers were recruited with 25 assigned to each of the 3 herb-groups (Tumeric, Dong Quai and Ginseng). The study subjects were first assigned to {herbal only} for 3 weeks, followed by a 2-week wash out period, after which they were randomly assigned to {aspirin + herbal} or {aspirin + placebo} for 3 weeks. Following another 2 week washout, the subjects crossed over to receive {aspirin + placebo} and {aspirin + herbal capsule} respectively for next 3 weeks. Dosages of herbs are Tumeric 500mg, Dong Quai 1000mg or Ginseng 1000 mg and aspirin 100mg once daily. Blood samples were analysed at baseline and after each intervention phase for full blood counts (FBC), PT/aPTT, platelet function tests (PFT) and thrombin generation assays. PFT measured platelet aggregation using light transmission in platelet-rich plasma, induced with Adenosine diphosphate (ADP), Arachidonic acid (AA), Collagen, Epinephrine and Ristocetin. Thrombin generation (TG) assays on platelet poor plasma measured Endogenous Thrombin Potential(ETP), Time to peak (ttPeak), Peak height and Lag time (LT). All clinical events experienced by the subjects were recorded during each phase. Non-parametric statistical analysis was carried out through Wilcoxon-signed rank tests (SPSS Version 21, USA) and deemed significant if p Results: FBC, PT and aPTT were normal at baseline and for all 3 phases in all 3 herbs, with and without aspirin. For PFTs, Tumeric resulted in impaired AA-induced aggregation in 5, Dong Quai in 2 and Ginseng in 1 subjects. 2 other subjecys in Dong Quai group and 1 in Ginseng group also had reduction in Epinephrine-induced aggregation. Aspirin, as expected suppressed platelet aggregation to AA, Epinephrine, collegen and ADP but this was not further suppressed by concomitant administration of any of the 3 herbs. All TG assays were normal in all 3 herbs with one exception where Tumeric showed a significant proplongation in LT over baseline. Aspirin reduced ETP and peak height which was not further aggravated by concomitant administration of any of the 3 herbs. There was no significant clinical events reported, in particular no bleeding complications. Conclusion: Overall, there was no meaningful nor severe suppression of PFTs. Only a few subjects demonstrated decreased % platelet aggregation while on one of these herbs. In each of these subjects, this was restricted to platelet aggregation by 1 inducer and normal for the rest. Hence, the overall platelet hemostatic function should not be significantly compromised as to cause clinical events. Importantly, addition of herb did not further impair PFTs due to aspirin alone TG assays are more sensitive to subtle changes in global plasma hemostatic functions compared to conventional clotting times. Apart from a prolongation of LT seen in the Tumeric group, TG assays were largely unaffected by these herbs, indicating that these 3 herbs did not significantly affect the global plasma hemostatic function. Importantly, suppressed TG assays by aspirin was not further impaired by concomitant administration of any of the 3 herbs with aspirin, inferring that the herb addition to aspirin did not further impair hemostatic functions. The widely held notion of "blood thinning" properties of Tumeric, Dong Quai and Ginseng were not demonstrated through PFT and TG assays. The concurrent usage of aspirin with these herbs individually did not result in compromise of hemostatic functions and was safe with no clinical bleeding. These findings will help mitigate the anxiety over bleeding complications of these 3 herbs, especially for patients who are on aspirin. Larger studies with more numbers will be required for further verifications. Disclosures No relevant conflicts of interest to declare.

Acute leukemia is an uncommon complication of patients with essential thrombocythemia (ET). We describe a patient with ET, who transformed to acute biphenotypic leukemia 4 and 1/2 years after initial ET diagnosis. She had received hydroxyurea, anagrelide, and interferon, in different combinations and varying doses, before leukemic transformation. Acute biphenotypic leukemia was confirmed on bone marrow studies and immunophenotyping. Complete remission (CR) was achieved with induction chemotherapy for acute leukemia. This was followed with consolidation chemotherapy and the patient has remained in CR 9 months after initial induction chemotherapy. To our knowledge, this is a rare event of acute biphenotypic leukemic transformation of a patient with ET.

An end-stage renal failure patient with lupus nephritis was treated with low molecular weight heparin (LMWH) and aspirin for cardiac ischemia. She was then subjected to surgery to recreate a new arteriovenous fistula for dialysis 1 day after discontinuing LMWH and aspirin. Severe postsurgical bleeding required wound reexploration and multiple transfusions of blood products, which nevertheless, failed to arrest bleeding. Recombinant factor VIIa (rFVIIa) as a bolus dose of 120 microg/kg successfully secured hemostasis. Bleeding in this patient was attributed to the accumulation of low molecular weight heparin activity from poor renal clearance as well as the antiplatelet activity of aspirin. The potential of rFVIIa in securing hemostasis for excessive bleeding after use of these agents is promising.

Abstract 5060 Less than 20% of patients with essential thrombocythemia (ET) are diagnosed below the age of 60. Patients with ET have increased risk of thrombosis and bleeding and potential for progression to myelofibrosis (MF) or acute myeloid leukaemia (AML). In limited studies of young patients, the clinical course has been relatively benign with low rates of transformation to AML or MF. Thrombohemorrhagic events are generally few, but higher than that of the general population. This study aims to characterize of a group ET patients diagnosed at age ≤40, their thrombotic and hemorrhagic events, disease progression and treatment given. Patients were identified through a single institution MPN registry. This is an IRB approved registry that captures comprehensive information about patients with ET. Data on patient demographics, treatment, and disease-related events were obtained. Patients were diagnosed from 1975–2011, using either WHO or PVSG criteria depending on date of diagnosis. Kaplan-Meier method was used for survival analysis. 59 patients were diagnosed with ET at age ≤40. Median age of diagnosis was 31. 5years (range 16–40), with a median follow up of 7. 7years (0. 4–33. 8). All were of Asian descent: 81. 4% Chinese, 11. 9% Malay, 3. 4% Indian and 3. 4% Filipino. 40. 7% were male. JAK2 V617F mutation was screened for in 61%. Of these patients, 11 were positive, 25 negative for the mutation. Mean presenting counts were: WBC 10. 7 × 109/L (5. 9–21. 3), Hb 13. 6g/dL (9. 7–16. 4), platelets 957 × 109/L (449–2377). Splenomegaly was noted in 3 patients. 20. 3% had underlying hypertension, 16. 9% hyperlipidemia and 5. 1% diabetes mellitus. One patient had a prior stroke. Another had prior portal vein thrombosis. At diagnosis, 23. 7% were symptomatic, with microvascular symptoms of headache (11. 9%) and giddiness (6. 8%) being most common. The remainder were diagnosed incidentally, on health screening or when seeking medical attention for unrelated conditions. One patient presented with a myocardial infarction at diagnosis, while another had a significant bleeding post hemorrhoidectomy with drop in Hb by >2g/dL (platelet 2457 × 109/L). Based on a history of prior thrombosis, 3 patients were defined as high risk for thrombotic events. 67. 8% of patients had cytoreduction, indications being platelets ≥1500 × 109/L (n=16), presence of risk factors for atherosclerotic disease (n=11) and history/onset of thrombosis (n=5). In 8, the reason for cytoreduction could not be ascertained. Hydroxyurea was most commonly used (62. 7%), followed by anagrelide in 52. 5% and interferon 25. 4%. 5. 1% received busulphan, and 1. 7% 32P. Use of antiplatelet therapy was noted in 83. 8%, most frequently aspirin (76. 5%) and ticlopidine (11. 9%). On follow up, 2 arterial thromboses occurred (stroke, TIA), giving a thrombosis rate of 0. 39%/patients/year. Neither was a recurrent thrombosis. No venous thrombosis or major bleeds occurred. 20. 4% had minor mucocutaneous bleeding; 5 had platelets ≥1500 × 109/L at that time. 3. 4% had disease progression due to MF and another 3. 4% had AML. 3. 4% of patients died due to AML. Median survival was 33. 8years (95% confidence interval 30. 3–35. 5). Initial blood counts, presence of JAK2 and high risk disease status did not correlate with thrombotic risk, risk of death or disease progression. Use of antiplatelet agents and a platelet count ≥1500 × 109/L did not correlate with bleeding risk. Few studies have looked exclusively at young patients with ET. In this group, most patients were asymptomatic and well, ET being diagnosed incidentally. They were predominantly at low risk for thrombosis and other ET-related complications. The period of follow up was comparable to that of other studies and during that time, the rate of complications and risk of disease progression was low. The thrombosis rate of 0. 39% per patient year was less than that reported by other groups (2. 2–2. 6 thromboses/100patients/year) (Leukaemia 2007;21:1218–1223, Clin Appl Thrombosis/Hemostasis 2000;6(1):31–35) but similar to the 0. 74%/patient year reported by Barbui (Blood. Epub. June 13 2012). Overall findings generally complemented those reported by other groups. No risk factors were found to influence the occurrence of complications, but the number of events was small. Follow up of this group of patients over time is essential to see if their disease course remains benign or if complications will increase with time. Soli Deo Gloria Disclosures: Kam: Shire Pharmaceuticals: Consultancy, grant to support the MPN registry Other.

Introduction: Emerging good quality evidence has suggested that the prevalence of VTE among Asians is significant and was largely underestimated previously. Objective and methods: We conducted a study of thrombophilic markers among our population of VTE patients to determine their prevalence and help determine the best screening strategy among our increasing number of VTE patients. Three major hospitals in the country were involved in this study. Results: Of 254 patients recruited, ethnic distribution was as follows: Chinese 68.1%, Malays 17.3%, Indians 12.6%, Others 2%. The ratio of males to females was 2:3. Major risk factors such as surgery, trauma and malignancy was recordedand identified in about 80% of the population. Twenty-one percent of patients had pulmonary embolism. Positive results of thrombophilic markers were as follows: protein C deficiency, 4 patients (1.52%); protein S deficency, 26 (10.24%), antithrombin III deficiency, 11 (4.33%); lupus anticoagulant, 9 (3.54%); anticardiolipin antibody IgG, 3 (1.18%); anticardiolipin antibody IgM, 6 (2.36%); hyperhomocysteinemia, 32 (12.6%); factor V Leiden gene mutation, 0 (0%); prothrombin 20210 gene mutation, 0 (0%). The prevalence of at least one thrombophilic condition was found in about one third of our patients. The relative risks of these thrombophilic conditions will be compared with a healthy control population. Conclusion: Among our VTE patients, the most commonly associated thrombophilic conditions were protein S and antithrombin III deficiencies. The factor V Leiden and prothrombin G20210A mutation did not feature at all in our patient population and is consistent with other studies on Asian populations. These tests should not be included as part of our thrombophilic screening.