Low Risk Of Thrombosis Research Articles

Essential Thrombocythemia: A Review.

Essential thrombocythemia, a clonal myeloproliferative neoplasm with excessive platelet production, is associated with an increased risk of thrombosis and bleeding. The annual incidence rate of essential thrombocythemia in the US is 1.5/100 000 persons. Patients with essential thrombocythemia have a persistent platelet count of 450 × 109/L or greater. The differential diagnosis includes myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis, chronic myeloid leukemia); inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosus; infections; splenectomy; iron deficiency anemia; and solid tumors such as lung cancer. Approximately 90% of individuals with essential thrombocythemia have genetic variants that upregulate the JAK-STAT (signal transducer and activator of transcription 5) signaling pathway, including Janus kinase 2 (JAK2, 64%), calreticulin (CALR, 23%), and myeloproliferative leukemia virus oncogene (MPL, 4%). The median age at diagnosis of essential thrombocythemia is 59 years. The median overall survival exceeds 35 years in those diagnosed at 40 years or younger. Patients with essential thrombocythemia are at increased risk of arterial thrombosis (11%), venous thrombosis (7%), and hemorrhagic complications (8%). Thrombosis risk is increased among those with a history of thrombosis, age older than 60 years, a JAK2 gene variant, and cardiovascular risk factors (eg, hypertension, diabetes mellitus, hyperlipidemias, tobacco use). Use of aspirin (81-100 mg/d) is suggested for most patients with essential thrombocythemia to lower thrombosis risk. In a retrospective study of 300 affected patients with a low thrombosis risk (younger than 60 years with no prior thrombosis), those not taking aspirin (100 mg/d) had a risk of arterial thrombosis of 9.4/1000 patient-years and a venous thrombosis risk of 8.2/1000 patient years; cardiovascular risk factors were associated with a higher risk of arterial thrombi (incidence rate ratio, 2.5 [95% CI, 1.02-6.1]), and a JAK2 gene variant was associated with increased risk of venous thrombosis (incidence rate ratio, 4.0 [95% CI, 1.2-12.9]). In a randomized trial of 114 patients at higher risk for thrombosis (age older than 60 years or a prior thrombotic event), cytoreduction with hydroxyurea significantly lowered the risk of arterial or venous thrombotic events compared with no cytoreductive therapy (3.6% vs 24%; P < .01). At a median of 8.5 years from diagnosis, approximately 10% of patients with essential thrombocythemia develop myelofibrosis and about 3% develop acute myeloid leukemia. Essential thrombocythemia is a rare clonal myeloproliferative neoplasm associated with an increased risk of venous and arterial thrombosis, hemorrhage, myelofibrosis, and acute myeloid leukemia. Based on individual risk factors for thrombosis, persons with essential thrombocythemia may be treated with low-dose aspirin, either alone or in combination with a cytoreductive drug such as hydroxyurea.

Anticoagulant Management After Emergency Surgery or Major Bleeding in Anticoagulated Patients—Results of the Prospective RADOA Registry

Background: Major bleeding or emergency surgery are the most frequently observed emergency situations in patients anticoagulated with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs). The restart of anticoagulation after these situations is a therapeutic dilemma. Methods: The prospective RADOA registry is an observational, noninterventional multicenter registry that documents the management of severe bleeding or emergency surgery in patients treated with VKAs or DOACs. In this substudy, we analyzed time point, type, and dosage of anticoagulant resumption after emergency situations. Results: Overall, 78 emergency surgery patients and 193 major bleeding patients were analyzed. Median age was similar in the VKA- and DOAC-treated groups (emergency surgery: 77 years, major bleeding: 79 years). Anticoagulants were restarted significantly earlier after emergency surgery compared to major bleeding, with no difference between the VKA and DOAC groups. While patients after cardiothoracic surgery received UFH intravenously, patients with trauma or having received abdominal surgery were mainly treated with prophylactic LMWH s.c.. After major bleeding, the majority of patients were treated with prophylactic LMWH. None of the patients in the emergency surgery group and 17% (4/24) of the major bleeding group with recurrent bleeding (12%, 24/193) experienced recurrent bleeding after restart of anticoagulation. Thromboembolism occurred rarely in both patient groups (emergency surgery: 3%, major bleeding 4%). Conclusions: Time points of restart, type, and dosage of anticoagulants are highly diverse in this high-risk patient population. Resumption of prophylactic anticoagulation is associated with a low risk of thrombosis and should be initiated as soon as possible.

Reduced Platelet Activation in Triple-Negative Essential Thrombocythemia Compared with JAK2V617F-Mutated Essential Thrombocythemia.

Triple-negative (TN) essential thrombocytopenia (ET) is characterized by the absence of driver mutations while retaining histologic and phenotypic characteristics sufficient for an ET diagnosis. Our understanding of TN-ET and its platelet activation remains incomplete. We carried out a large-scale multicenter clinical analysis to analyze the clinical and molecular characteristics and thrombotic complications of TN-ET. We also related the above characteristics to platelet activation to further explore the thrombosis mechanism of TN-ET. A retrospective multicenter study was conducted on 138 patients with TN-ET and 759 patients with ET with driver mutations from March 1, 2012 to December 1, 2021. The clinical and molecular characteristics of the patients with TN-ET were summarized. Additionally, platelet activation, apoptosis, and reactive oxygen species (ROS) levels were analyzed in 73 patients with TN-ET from this cohort and compared with 41 age- and sex-matched healthy donors. Compared with patients with the JAK2V617F mutation, those with TN mutation were younger (P < 0.001) and exhibited fewer thrombotic events before diagnosis (P < 0.001) and during follow-up (P = 0.039). Patients with TN mutation also presented with significantly reduced CD62P expression in platelets (P = 0.031), slightly reduced calcium concentration in platelets (P = 0.063), increased mitochondrial membrane potential (P = 0.011), reduced phosphatidylserine exposure (P = 0.015), reduced levels of ROS (P = 0.043) and MitoSOX in platelets (P = 0.047). In comparison with JAK2V617F-mutated ET, TN-ET is associated with lower platelet ROS levels, which leads to reduced platelet activation and consequently a lower risk of thrombosis.

Incidence and outcomes of prosthetic valve thrombosis during peripheral extracorporeal membrane oxygenation.

In the context of postcardiotomy cardiogenic shock (PCCS) following valve replacement surgery, it may be necessary to implant a peripheral veno-arterial extracorporeal membrane oxygenation (pVA-ECMO). This procedure, however, carries a risk of prosthetic valve thrombosis. The aim of this retrospective study was to describe the incidence and outcomes of prosthetic valve thrombosis after VA-ECMO support for PCCS and to report the associated risk factors. All consecutive adult patients who received pVA-ECMO for PCCS following a valve replacement procedure between January 2015 and October 2019 in our institution were included in this retrospective study. Outcome variables were prosthetic valve thrombosis, 30-day and hospital survival, pVA-ECMO-associated adverse events and surgery-related adverse events. During the 4-year study period, 549 patients received pVA-ECMO for PCCS. Among them, 152 had undergone a valve replacement procedure and 9 of these developed prosthetic valve thrombosis. The incidence of valve thrombosis at 30 days was 7.5 ± 2%. The cumulative incidence of prosthetic valve thrombosis was significantly lower with pVA-ECMO + intra-aortic balloon pump versus VA-ECMO alone (1.4 ± 1.4% vs 13.7 ± 4.7%, P = 0.021, respectively). Intra-aortic balloon pump use associated with pVA-ECMO (versus pVA-ECMO alone) was an independent protective factor against hospital death [odds ratio = 0.180 (0.068-0.478), P = 0.001]. After PCCS following valve replacement surgery, peripheral femoro-femoral VA-ECMO is associated with a low risk of acute valve thrombosis especially when associated with an intra-aortic balloon pump.

Odds and associated factors for thrombosis development among Lebanese COVID-19 patients: a case-control retrospective study.

Thromboembolism is reported to be up to 27% in COVID-19 patients due to SARS-CoV-2 infection. Dysregulated systemic inflammation and various patient traits play a vital role in thrombosis progression. To assess odds and associated factors for thrombosis development among Lebanese COVID-19 patients. This was a case-control retrospective study conducted in January-May 2021. Patients infected with COVID-19 and developed thrombosis were classified as cases and patients who were thrombosis-free identified as control. A questionnaire assessed socio-demographics, clinical parameters, and WHO COVID-19 disease severity. Among 267 patients, 26 (9.7%) developed thrombosis and the majority of thrombosis 34.6% was myocardial infarction, and the least (3.8%) was for catheter-related thrombosis. Results showed that the risk of thrombosis development is higher in patients with previous thromboembolic event (OR = 9.160) and previous intake of anti-hypertensive medications at home (OR = 3.116). However, females (OR = 0.330; CI: 0.118-0.925), intake of anticoagulants during hospital admission (OR = 0.126; CI: 0.053-0.300) and non-severe COVID-19 were at lower thrombosis risk (OR = 0.273). Patients who developed thromboembolic events had longer hospital stay (OR = 0.077). Patients with COVID-19 and thromboembolism were at higher risk of mortality as compared to patients with COVID-19 but without thromboembolism. The use of anticoagulants significantly reduced the risk for thromboembolism.

Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study.

Coronavirus disease 2019 (COVID-19) and thrombosis are linked, but the biomolecular mechanism is unclear. We aimed to investigate the causal relationship between COVID-19 and thrombotic biomarkers. We used two-sample Mendelian randomization (MR) to assess the effect of COVID-19 on 20 thrombotic biomarkers. We estimated causality using inverse variance weighting with multiplicative random effect, and performed sensitivity analysis using weighted median, MR-Egger regression and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods. All the results were examined by false discovery rate (FDR) with the Benjamin and Hochberg method for this correction to minimize false positives. We used R language for the analysis. All COVID-19 classes showed lower levels of tissue factor pathway inhibitor (TFPI) and interleukin-1 receptor type 1 (IL-1R1). COVID-19 significantly reduced TFPI (odds ratio [OR] = 0.639, 95% confidence interval [CI]: 0.435-0.938) and IL-1R1 (OR = 0.603, 95% CI = 0.417-0.872), nearly doubling the odds. We also found that COVID-19 lowered multiple coagulation factor deficiency protein 2 and increased C-C motif chemokine 3. Hospitalized COVID-19 cases had less plasminogen activator, tissue type (tPA) and P-selectin glycoprotein ligand 1 (PSGL-1), while severe cases had higher mean platelet volume (MPV) and lower platelet count. These changes in TFPI, tPA, IL-1R1, MPV, and platelet count suggested a higher risk of thrombosis. Decreased PSGL-1 indicated a lower risk of thrombosis. TFPI, IL-1R, and seven other indicators provide causal clues of the pathogenesis of COVID-19 and thrombosis. This study demonstrated that COVID-19 causally influences thrombosis at the biomolecular level.

Comparisons of Impact of Vein Grafting with Different Indications on Outcomes of Reconstruction with Free Flaps.

Prior studies have shown an increased risk of complications and flap loss with the use of vein grafts in microsurgery. We hypothesize that indication for use of a vein graft can affect flap complications and loss rates. We performed a retrospective review of all patients at our institution from 2010 to 2020 who underwent free flap reconstruction and required use of a vein graft. Indications for vein grafting included: salvage of flap during primary operation after microvascular compromise, augmentation of flow during primary operation, lengthening of the flap pedicle during the primary operation, and salvage of the flap during a secondary salvage operation after microvascular compromise. A total of 79 patients met the study inclusion criteria. There were significant differences among the vein graft indication groups and the following: area of reconstruction (p = 0.002), vein graft length (p = 0.018), vessels grafted (p = 0.001), vein graft donor site (p = 0.011), and total flap loss (p = 0.047). Of the four indications for vein grafting, salvage of the flap during secondary salvage operation after microvascular compromise had the highest rate of total flap loss (26.7%). There were no significant associations between other flap complications and vein graft indications. Vein graft use in the primary reconstructive setting is efficacious, with low risk of thrombosis. Use in secondary procedures, however, is associated with higher rates of total flap loss, likely due to the thrombotic process, which was initiated prior to the use of the graft resulting in the salvage procedure and not secondary to the graft itself.

Milvexian: A Focus on a New Oral Anticoagulant that Targets Factor XIa for Thromboembolism Prophylaxis.

Drugs that target factor XI and/or XIa have been evaluated as alternatives to existing anticoagulants, in light of studies that indicate that a decrease in Factor XI/XIa levels or activity may result in a lower risk of thrombosis without a significant increase in bleeding risk. Milvexian is an investigational small-molecule factor XIa inhibitor that has recently completed phase 2 clinical trials. Preclinical studies were suggestive of its potential to prevent arterial and venous thrombosis. It was well-tolerated in healthy participants, as well as in participants with mild or moderate hepatic impairment and moderate or severe renal impairment. Notably, patients who received milvexian after knee arthroplasty had a dose-proportional lower incidence of venous thromboembolism compared to patients who received postoperative enoxaparin, and they had a lower incidence of clinically relevant bleeding. A separate phase 2 trial was conducted that assessed the use of milvexian for secondary stroke prevention in patients who had ischemic stroke or transient ischemic attack. It failed its primary objective of establishing a dose-response relationship between milvexian and a composite endpoint of symptomatic ischemic stroke or covert brain infarction. The trial did, however, show a reduction in the relative risk of symptomatic ischemic stroke across most of the treatment groups receiving various dosages of milvexian compared to placebo. The efficacy of milvexian in secondary stroke prevention will be further assessed in an upcoming phase 3 trial. Additional upcoming phase 3 trials will also assess its efficacy in stroke prevention in patients with atrial fibrillation as well as in event reduction in patients with acute coronary syndrome.

Comparison of different direct oral anticoagulant regimens in atrial fibrillation patients with high bleeding risk

BackgroundThe optimal dose of direct oral anticoagulants (DOACs) to prevent ischemic stroke (IS) and systemic thromboembolism (STE) in atrial fibrillation (AF) patients with a predisposing bleeding risk remains unclear. ObjectiveThe purpose of this study was to compare the effectiveness and safety of different DOAC dosage regimens in AF patients with high bleeding risk but low thrombosis risk. MethodsThis retrospective observational study was conducted with the National Health Insurance claims database in Taiwan to include AF patients aged 20 up to 75 years, under DOAC therapy, with CHA2DS2-VASc score of 1 for males and 2 for females and HAS-BLED score ≥3. Standard-dose regimen was defined as dabigatran 300 mg, rivaroxaban 20 mg, apixaban 10 mg, or edoxaban 60 mg per day. Any other lower-dose regimen were defined as the low-dose regimen. The primary outcomes were IS and major bleeding (MB). The secondary outcomes were STE, gastrointestinal bleeding, intracranial hemorrhage, and cardiovascular death. ResultsA total of 964 patients were included (52.1% standard-dose regimen). Median HAS-BLED score was 3 [interquartile range 3–3]. Compared with standard-dose group, patients in the low-dose group had a significantly increased risk of IS (adjusted hazard ratio [aHR] 5.13; 95% confidence interval 1.37–19.22) and STE (aHR 3.14 [1.05–9.37]) but similar risk of MB (aHR 0.45 [0.12–1.67]). The risks of other hemorrhage and cardiovascular death were similar between the 2 dose groups. ConclusionAmong patients with a predominant bleeding risk but relatively low thrombosis risk, the low-dose DOAC regimen is not a more appropriate selection than standard-dose regimen.

Is the multinational, surveillance PRO-E2 study informative for all countries? The Italian data on VTE and contraceptive effectiveness

Purpose To evaluate whether the thromboembolic risk and contraceptive effectiveness of NOMAC-E2 observed in the PRO-E2 study can be extended to each participating country, as lifestyle, cardiovascular risk factors and prescribing habits may differ geographically. This analysis was performed on the PRO-E2 Italian subpopulation, where smoking habit and women over 35 years were more prevalent compared with the overall study population. Materials and methods Data from NOMAC-E2 or levonorgestrel-containing COCs (COCLNG) new users were descriptively analysed. Incidence rates of thrombosis (events/10,000 women-years [WY]) and the Pearl Index (pregnancies/100 WY) were calculated. Results Overall, 11,179 NOMAC-E2 and 8,504 COCLNG users were followed up to 2 years (34,869 WY). The NOMAC-E2 cohort included more women over 35 vs. COCLNG (37.7% vs. 31.8%; p = 0.001). A comparable low risk of combined deep venous thrombosis of lower extremities (DVT) and pulmonary embolism (PE) was observed in NOMAC-E2 (1.7/10,000 WY; 95% CI: 0.21–6.2) and COCLNG users (6.6/10,000 WY; 95% CI: 2.4–14.4). Similar results were obtained by considering all thromboembolic events (VTE). Unintended pregnancies did not differ between NOMAC-E2 (0.12/100 WY; 95% CI: 0.06–0.21) and COCLNG (0.15/100 WY; 95% CI: 0.08–0.26) cohorts. Conclusion Despite the higher age and tobacco use, findings from the Italian subpopulation were broadly consistent with overall PRO-E2 results, confirming a similar low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 and COCLNG. Short condensation This subgroup analysis of the PRO-E2 study provides comprehensive epidemiological data on the use of combined oral contraceptives in a large Italian cohort, with a higher prevalence of women over 35 years and smokers. The study confirms the low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 pill.

Mean Corpuscular Hemoglobin Optimizes the Thrombocytosis Risk Stratification in Polycythemia Vera: A Retrospective Multi-Center Study

Thrombosis was a common complication and the main cause of mobility of polycythemia vera (PV) with a lifetime incidence of 22%. Thrombosis risk was correlated with age, prior thrombosis, hypertension, red blood cell distribution width (RDW), leukocytosis, and JAK2V617F allele burden in previous studies, but only age≥65 years and prior thrombosis were included in thrombosis risk stratification. Finding independent thrombosis factors is significant to depict the landscape of PV and decrease the probability of thrombosis. Here, we aimed to find potential predictors to optimize the thrombocytosis risk stratification. Retrospectively reviewed 763 patients diagnosed with PV according to the 2016 WHO criteria from 17 hematology center in China from Jan 1, 2010, to July 1, 2023. Analyzed clinical characteristics and genetic features of thrombosis risk and compared the potential predictor in different risk stratification. The patients' clinical features are in table A.A total of 508(66.8%) subjects were male, the median age was 62 years (IQR, 53-70 years). The media follow-up was 45 months (IQR, 25-77 months). 84 (11.1%) subjects had thrombotic event pre-diagnosis, 25 (3.3%) of which were venous and 59 (7.9%) were arterial. 72 (9.6%) subjects had thrombotic events after diagnosis, 10 (1.3%) of which were venous and 62 (8.3%) were arterial (Figure B). Univariable analysis found thrombosis was associated with the thrombosis risk stratification (P=0.011), hypertension (P=0.017), diabetes (P=0.010), leukocytosis (P=0.026), mean corpuscular hemoglobin (MCH) (P=0.001), triglyceride (P=0.025), cholesterol (P=0.022), and splenomegaly (P=0.000). Thrombosis risk stratification (HR=1.74 [1.00, 3.02], P=0.026) and MCH (HR=0.92, [0.86, 0.98], P=0.010) were independently risk factors in multivariable variable analysis. We divided by MCH with cut-off point of 28.5pg, patients with MCH&amp;lt;28.5pg were associated with worse thrombosis-free survival (TFS) (Figure E). We further analyzed the effect of MCH in different thrombosis risk stratification. Results showed MCH &amp;lt;28.5pg was also meaningful in both low (P=0.0164) and high risk groups (P=0.0014) (Figure F, G). High risk stratification and MCH&amp;lt;28.5pg showed higher probability of thrombosis during the follow-up period (Figure C, D). In our study, potential risk factors from other studies such as JAK2V617F allele burden, hyperlipidemia, hypertension, leukocytosis, and RDW were not significant independent predictors of thrombosis. However, we found MHC&amp;lt;28.5pg was correlated with worse TFS both in low thrombosis risk stratification group and high thrombosis risk stratification group. Our study suggested that MCH&amp;lt; 28.8pg was an independent predictor and can increase the accuracy of predicting thrombosis. Acknowledgement: This research was funded by the Key R&amp;D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; Zhejiang Medical Association Clinical Medical Research special fund project, No. 2022ZYC-D09. Correspondence to: Dr Jian Huang, Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine. househuang@zju.edu.cn

Low Thrombosis Risk CALR Mutations Confer Higher Risk of Essential Thrombocythemia Progression

Background: Patients (pts) with essential thrombocythemia (ET) face increased risk of thrombosis and the prospect of progression to myelofibrosis (MF) or acute leukemia. ET treatment recommendations from ELN 1 and NCCN 2 are largely governed by the revised IPSET-thrombosis score that identifies 4 risk categories from “very low” to “high” based on age, thrombosis history, and the presence of a JAK2 V617F mutation 3. Pts with CALR-mutated ET are known to have a lower risk of thrombosis than those with a JAK2 mutation, and for this reason, are often considered to have lower risk ET. Yet previous study of pts with clinically diagnosed ET found that CALR mutations may negatively impact progression risk 4. For this reason, we evaluated the impact of driver mutations on the risks of thromboembolic events, disease progression, and overall mortality for a cohort of pts with rigorously defined WHO ET treated at our institution. Methods: Medical records were queried for pts with the diagnosis (dx) of ET, as per ICD, code versions 9-10. The dx of ET and dx date were confirmed by manual review. All pts met the 2022 WHO criteria for ET, including a diagnostic marrow in all cases. Confounding diagnoses, including pre-fibrotic MF, polycythemia vera, or presumed ET in pts lacking a marrow biopsy, were strictly excluded by thorough review of the rich data available. Structured query language supplemented by manual review was used to extract clinical, laboratory, molecular, and marrow findings and treatment course. Overall (OS), MF-free (MFS), and thrombosis-free (TFS) survival were estimated using Kaplan-Meier methods. Univariable and multivariable analysis of post-ET MF (PETMF), thrombosis and mortality risk were performed using Cox proportional-hazards models using IPSET-survival 5 and revised IPSET-thrombosis variables as covariates. Results: The query returned 751 pts but only 338 met our strict criteria for ET with diagnostic marrows and had annotated driver mutations. Of these, 216 (64%) were positive for JAK2 V617F, 85 (25%) CALR, 19 (6%) MPL, and 18 (5%) triple negative (TN). We identified no significant differences among the driver mutation cohorts in dx age, sex, or median follow up duration. Semi-quantitative features of the diagnostic marrow biopsies, including age-adjusted cellularity and reticulin fibrosis score, were not significantly different among the groups. Red cell parameters at dx were mildly higher in the JAK2 pts (HCT, HGB, RBC all with p&amp;lt;0.001), WBC count was highest in TN pts ( p=0.012), and PLT count was not significantly different ( p=0.064). 20-year TFS for JAK2 was 71%, CALR 100%, MPL 90% and TN 83% ( p=0.0027, Figure 1); 20-year MFS for JAK2 was 87%, CALR 48%, MPL 65% and TN 94% ( p=0.00053, Figure 2); 20-year OS for JAK2 was 76%, CALR 86%, MPL 89% and TN 90% ( p=0.66). Multivariable analysis showed that CALR was associated with a significantly higher risk of PETMF as compared to JAK2 (HR 11.52, CI 1.88-70.51, p=0.008), independent of age, sex, WBC, and thrombosis history. Conversely, CALR was associated with a lower risk of thrombosis (HR 0.08, CI 0.01-0.58, p=0.013) when adjusting for sex and revised-IPSET thrombosis parameters. Discussion: We found that although pts with CALR-mutated ET have lower thrombosis risk, they experience higher risk of progression to MF. Current risk models for thrombosis yield treatment recommendations well suited to reducing thrombosis risk 3. With this success, pts are expected to live with ET for decades, thereby exposing them to other ET risks, most notably that of malignant disease progression. These risks are of particular concern for younger pts who suffer the greatest relative risk 6. It is important that thrombosis risk and fibrosis risk are not conflated as our data suggest that pts with low or very low risk CALR-mutated ET can be at higher risk of progression. Our findings reinforce the need for long-term data to guide therapy for ET based not only on the near-term thrombotic risk, but also on the long-term risk of progression.

No Increased Incidence of Bleeding in Essential Thrombocythemia Patients with Extreme Thrombocytosis

CONCLUSIONS About 25% of essential thrombocythemia (ET) patients present with extreme thrombocytosis (ExT), defined as having a platelet count ≥1000 x 10^9/L. ExT patients may have an increased bleeding risk, at least in part associated with acquired von Willebrand disease. There are no specific guidelines for managing ExT patients, and many are started on cytoreduction, even if they are younger and otherwise at low thrombotic risk by the revised International Prognostic Score of Thrombosis for ET (R-IPSET). We analyzed the risk of bleeding and thrombosis in ExT vs. non-ExT ET patients to inform treatment decisions. METHODS : We retrospectively analyzed patients who received targeted gene sequencing at Massachusetts General Brigham / Dana-Farber Cancer Institute from 2014-2021 and met WHO 2016 criteria for ET. We performed medical record review and recorded information on treatment, diagnosis, blood counts, and von Willebrand antigen and activity levels. We abstracted the first major bleed, clinically relevant non-major bleed (CRNMB), and thrombotic event in a patient's disease course. Bleeding was categorized using the International Society on Thrombosis &amp; Haemostasis definitions.We determined the cumulative incidence rates of bleeding and thrombosis in ExT and non-ExT patients with death as a competing event and compared these rates using a Gray test. Risk factors for bleeding and thrombosis were evaluated using univariate and multivariate Fine Gray models. We identified 408 patients diagnosed with ET, of which 344 had a platelet count reported at diagnosis. There were 96 ExT patients and 248 non-ExT patients. Median follow-up was 11 and 6 years, and median platelet count at ET diagnosis was 1194 and 651, respectively. ExT patients, compared with non-ExT patients, were more likely to be younger (51 vs. 58 years old, p&amp;lt;.001), have the CALR mutation (49% vs. 23%, p&amp;lt;.001), have lower IPSET-thrombosis risk (65% vs. 49% very low or low risk, p&amp;lt;.001), and have lower von Willebrand activity levels at diagnosis or in disease course (60% vs. 94%, p&amp;lt;.001, Table 1). There were 7 (7%) major bleeds and 7 (7%) CRNMBs in the 96 ExT patients, and 11 (4%) major bleeds and 22 (9%) CRNMBs in the 248 non-ExT patients (p=.29 for major bleeding, p=.83 for CRNMB). 10 year cumulative incidence of major bleed and CRNMB was not different in ExT vs. non-ExT patients (4% vs. 5%, p=.68 for major bleed; 3% vs. 10%, p=.27 for CRNMB, Figure 1). Despite 65% of ExT patients in our sample categorized as very low or low risk for thrombosis, these patients were more likely to be treated with cytoreduction compared to non-ExT patients (63% vs. 50%, p=.21 for very low risk; 81% vs. 51%, p=.022 for low risk). However, there was no difference in the 10 year cumulative incidence of major bleeding and CRNMB in ExT patients who were treated vs. not treated with cytoreduction (6% vs. 0%, p=.13 for major bleed; 2% vs. 8%, p=.13 for CRNMB). There was also no difference in the cumulative incidence of bleeding in ExT and non-ExT patients who were not treated with cytoreduction (untreated or aspirin alone, 0% vs. 4%, p=.34 for major bleed; 8% vs. 9%, p=.75 for CRNMB). In univariate analysis, diabetes mellitus and thrombosis during disease course were significantly associated with increased combined major bleeding and CRNMB. In a multivariable analysis adjusting for these factors in addition to platelet count ≥1000 x 10^9/L and age at ET diagnosis, first von Willebrand factor activity, aspirin and cytoreduction during disease course, and JAK2 mutation status, diabetes mellitus (HR 3.45, 95% CI 1.31-8.72) and thrombosis during disease course (HR 2.92, 95% CI 1.41-6.03) remained as significant risk factors for bleeding. Cytoreduction was not significantly associated with a lower rate of bleeding in multivariable analysis (HR .42, 95% CI .09-3.06). 10 year cumulative incidence of thrombosis was not different in ExT vs. non-ExT patients (22% vs. 26%, p=.94). We found no difference in the cumulative incidence of bleeding and thrombosis in ET patients with ExT and importantly, no clear role for initiation of cytoreductive therapy in these patients who are otherwise low risk by R-IPSET. This confirms the current recommendations to initiate cytoreduction based on thrombotic risk and suggests that ExT alone should not be an indicator for cytoreduction.

Attitudes of Hematologists in the Midwestern United States Toward Evaluating and Managing Thrombosis Risk in Transgender Youth Starting Gender Affirming Hormone Therapy

Background: Transgender and gender nonconforming (TG) youth who are at increased risk of thrombosis may be evaluated by a hematologist to discuss thromboprophylaxis prior to starting gender-affirming hormone therapy (GAHT). However, in the absence of guidelines to inform the delivery of hematologic care to such youth, variations in practice patterns may lead to suboptimal care for these individuals. Aim: Determine hematologists' recommendations about which TG youth should be considered at higher risk of thrombosis, laboratory evaluation and medical management of such youth, and which youth should be referred for hematologic evaluation prior to starting GAHT. Methods: From 6/2022-2/2023, we recruited hematologists caring for patients 13-22 years-old and practicing in the Midwestern U.S. for individual semi-structured interviews. Hematologists were recruited from the institutions in the footprint of the Midwest Transgender Research Collaborative. Interviews assessed demographics, practice characteristics, comfort recommending and prescribing thromboprophylaxis to TG youth, and recommendations for 1) which youth TG youth would be considered at higher risk of thrombosis; 2) laboratory evaluation; 3) recommended thromboprophylactic medication and duration; and 4) which TG youth should undergo hematologic evaluation prior to GAHT. Transcripts were analyzed using team-based framework analysis. The study was IRB approved; informed consent was obtained. Results: Eleven hematologists from 4 academic centers participated. Mean age was 50.5 years (SD 7.2); 9 participants identified as white; 2 were Latino/a. Ten participants had provided care to TG adolescents (13-17 years-old); all 11 had provided care to TG young adults (18-22 years-old). Participants reported on average 2.8 (SD 3.3) TG adolescents and 2.5 (SD 2.9) TG young adults in their practices. Ten participants reported comfort with recommending and prescribing thromboprophylaxis to patients at higher risk of thrombosis starting estrogen for GAHT; counseling about knowledge gaps and engaging in shared decision making were important elements in the process. One participant reported preference for non-medication interventions, such as compression stockings and using lower doses or transdermal formulations of estrogen. There was less consensus around attitudes toward prophylaxis for youth starting testosterone for GAHT: 4 participants reported lower likelihood of recommending thromboprophylaxis due to low risk of thrombosis with testosterone use; 3 participants discussed risk of erythrocytosis/polycythemia due to testosterone use (although there was no consensus on whether prophylaxis would be recommended); 3 participants reported comfort prescribing prophylaxis to youth starting testosterone; and 2 participants reported insufficient knowledge about the thrombotic risks of testosterone. Hematologists reported various factors that would lead to TG youth being considered high risk, as well as recommended lab testing (Table 1). If prophylaxis is needed, 10 participants would recommend a direct anticoagulant, while 1 would recommend aspirin. Five participants anticipated that long term prophylaxis would be needed for the duration of GAHT, while 6 reported duration would be individualized. Ten participants would not recommend against estrogen due to thrombosis risk, emphasizing the importance of gender care and the role of the hematologist in making GAHT as safe as possible. No participant would recommend against testosterone. Participants offered recommendations for which TG youth should be evaluated by a hematologist prior to starting GAHT (Table 2). Conclusion: Overall, hematologists voiced comfort with recommending and prescribing thromboprophylaxis to TG youth at higher risk of thrombosis starting estrogen. However, there was lack of consensus about evaluation of youth at higher risk of thrombosis starting testosterone and whether mitigation of risk would be needed. Developing guidance for gender care teams for which youth should be considered at higher risk of thrombosis and referred for hematologic evaluation would help optimize the safe delivery of gender-affirming hormone care. Additional data and guidance about the thrombosis risks associated with GAHT is needed to better inform hematologic care. Funding: NIH R01HL161153; Cincinnati Children's Hospital Medical Center Gap Funding

Hybrid green bionanocomposites based on chitosan/starch/gelatin and metallic nanoparticles for biological applications

Multicomponent composites based on natural biopolymers: chitosan, starch and gelatin in two different ratios (0.5:1:1 and 1:1:1) were in situ crosslinked by intermolecular interactions and used as matrices for zinc oxide and magnetite fillers. The bionanocomposite films have been evaluated by spectral and microscopy methods: Fourier-Transform Infrared spectrometry (FT-IR), Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) confirming the electrostatic and hydrogen bonding interactions between the components of the polymeric matrices and the inorganic fillers and the crosslinking process. AFM and SEM images showed a compact, non-porous and homogenous morphology of the hybrid films, proving a good miscibility of the blends. At lower concentrations of embedded filler, the composites were less hardened and more ductile due to the interaction with the polymeric matrix. Increased amounts of inorganic NPs led to the reduced mechanical properties of the prepared materials and increased thermal stability. The bionanocomposites revealed a similar behavior of the dielectric constant with frequency and increased values at higher temperatures. The wettability of the films' surface and the values of the water sorption capacity revealed a slight hydrophilicity of the bionanocomposites as compared with the initial matrices. The biocompatibility, evaluated by means of the surface free energy components and the interfacial tension with blood, and the hemolysis analysis demonstrated that the bionanocomposites possess a low risk of thrombosis, being promising materials for in vivo biomedical applications.

Primary prevention of cancer-associated venous thrombosis: Rationale and challenges in clinical practice

Cancer-associated venous thrombosis (CAT) is a common, multifactor event known to complicate the course of cancer and jeopardize a patient's prognosis. The current guidelines regarding the prevention of CAT are sometimes considered insufficiently precise about specific situations, or are poorly applied. The expected benefits of thromboprophylaxis are balanced by the risk of major bleeding induced by anticoagulation, which implies a need to accurately identify ambulatory patients at high risk of thrombosis or hemorrhage. The Khorana score is commonly used for this, but is limited by the non-reproducibility of predicted performance across cancer types, and by the fact that antitumor treatment and cardiovascular risks are not included. The COMPASS-CAT score, which includes those two aspects, was found to be a more accurate predictor of venous thromboembolism in patients with lung cancer, and to better distinguish between patients at low or high risk of thrombosis. The frailty of patients with cancer is also a major issue, and should be taken into account when thromboprophylaxis is considered. According to current guidelines, CAT prophylaxis should be considered for hospitalized patients, those for whom surgery is scheduled, or those with pancreatic cancers. In ambulatory patients, decisions should be made according to patient, cancer and antitumoral treatment characteristics. Low molecular weight heparin is the gold standard of CAT prophylaxis. Despite increased risks of bleeding or drug-drug interactions in cancer patients, direct oral anticoagulants could be alternate options for high-risk ambulatory patients that should be accompanied by a careful global analysis of benefits, harms, and patient preferences.

Long-term outcome in vaccine-induced immune thrombocytopenia and thrombosis

BackgroundRapid diagnosis and treatment has improved outcome of patients with vaccine-induced immune thrombocytopenia and thrombosis (VITT). However, after the acute episode, many questions on long-term management of VITT remained unanswered. ObjectivesTo analyze, in patients with VITT, the long-term course of anti–platelet factor 4 (PF4) antibodies; clinical outcomes, including risk of recurrent thrombosis and/or thrombocytopenia; and the effects of new vaccinations. Methods71 patients with serologically confirmed VITT in Germany were enrolled into a prospective longitudinal study and followed for a mean of 79 weeks from March 2021 to January 2023. The course of anti-PF4 antibodies was analyzed by consecutive anti-PF4/heparin immunoglobulin G enzyme-linked immunosorbent assay and PF4-enhanced platelet activation assay. ResultsPlatelet-activating anti-PF4 antibodies became undetectable in 62 of 71 patients (87.3%; 95% CI, 77.6%-93.2%). In 6 patients (8.5%), platelet-activating anti-PF4 antibodies persisted for >18 months. Five of 71 patients (7.0%) showed recurrent episodes of thrombocytopenia and/or thrombosis; in 4 of them (80.0%), alternative explanations beside VITT were present. After further COVID-19 vaccination with a messenger RNA vaccine, no reactivation of platelet-activating anti-PF4 antibodies or new thrombosis was observed. No adverse events occurred in our patients subsequently vaccinated against influenza, tick-borne encephalitis, varicella, tetanus, diphtheria, pertussis, and polio. No new thrombosis occurred in the 24 patients (33.8%) who developed symptomatic SARS-CoV-2 infection following recovery from acute VITT. ConclusionOnce the acute episode of VITT has passed, patients appear to be at low risk for recurrent thrombosis and/or thrombocytopenia.

Distinctive Attributes of Indian Patients With Classical BCR::ABL1 Negative Myeloproliferative Neoplasms: Unified Clinical and Laboratory Data.

We report one of the largest single center data from a mixed referral setting in India describing baseline characteristics and outcomes of patients with classical BCR::ABL1 negative myeloproliferative neoplasms (MPNs). Patients diagnosed from June 2019 to 2022 were included. Workup and treatment was as per current guidelines. Diagnosis comprised polycythemia vera (PV) in 51(49%), ET in 33(31.7%) and prefibrotic primary myelofibrosis (MF) pre fibrotic myelofibrosis (prePMF) and myelofibrosis in 10(9.6%) patients each. Median age at diagnosis was 52 years for PV and ET, 65.5 for MF and 79 years for prePMF. Diagnosis was incidental in 63(56.7%) and after thrombosis in 8(7.2%) patients. Baseline next generation sequencing (NGS) was available for 63(60.5%) patients. Driver mutations in PV: JAK2 in 80.3%; in ET: JAK2 in 41%, CALR in 26%, MPL in 2.9%; in prePMF JAK2 in 70%, CALR in 20%, MPL in 10%, and in MF: JAK2 in 10%, MPL in 30% and CALR in 40%. Seven novel mutations were detected of which 5 were potentially pathogenic on computational analysis. After median follow up of 30 months, 2 patients had disease transformation and none had new episodes of thrombosis. Ten patients died, most commonly with cardiovascular events(n=5,50%). Median overall survival was not reached. Mean OS time was 10.19 years(95%CI, 8.6 to 11.74) and mean time to transformation was 12.2 years(95% CI,11.8 to 12.6). Our data indicates comparatively indolent presentation of MPNs in India with younger age and lower risk of thrombosis. Further follow up will enable correlation with molecular data and guide modification of age based risk stratification models.

Revisiting the central aortopulmonary shunt procedure.

In this study, we present our experience with the central aortopulmonary shunt technique with interposing a polytetrafluoroethylene graft between main pulmonary artery (end-to-end) and the ascending aorta (side-to-side) in a variety of cyanotic congenital heart defects. Between January 2019 and June 2022, a total of 10 patients (6 males, 4 females; mean age: 4.3±2.8 months; range, 5 days to 10 months) with hypoplastic central pulmonary arteries who underwent central aortopulmonary shunt procedure were retrospectively analyzed. Demographic characteristics, preoperative, operative, and postoperative data of the patients were recorded. The Nakata indices of the patients were also noted before the procedure, as well as before the second stage of palliation or definitive repair. Four (40%) patients were operated as the first-step palliation for univentricular circulation. Six (60%) patients had well-developed ventricles and were palliated to be treated with total correction. The median follow-up after the procedure was 12 (range, 8 to 16) months. The mean systemic arterial saturation level at room air was 89.3±2.9% during follow-up. No mortality was observed in any patient. A central aortopulmonary shunt procedure provides a reliable antegrade blood flow with a relatively non-challenging surgical technique that offers sufficient growth for the hypoplastic and confluent central pulmonary arteries with a very low risk of shunt thrombosis and overflow.

An insight into the use of estetrol-drospirenone as effective oral contraceptive

Rise in population level is a major issue in today's world and according to United nations reports suggest the world population of 6 billion is expected to reach 9.7 billion by 2050. Contraception is an easy and direct method of reducing population growth. The popularity and success of contraception in the developed is testament to this. A total of 103 drugs were approved during the year 2020-2021 by the USFDA (United states food and drug administration) and the Estetrol-drospirenone (E4-DRSP) combination was one of them. E4-DRSP combination is the first oral contraceptive consisting of a natural estrogen Estetrol which is synthesized in the foetal liver. The other component is Drospirenone (DRSP) having anti-mineralocorticoid action and is a spironolactone derivative which makes the combination more effective. E4-DRSP is a combined oral contraceptive that is efficient, generally well-tolerated and may lower thrombosis risk. This review covers a detailed study of the E4-DRSP combination including its mechanism of action, pharmacology, adverse drug reactions, and clinical trials.