First described 100 years ago, von Willebrand disease (VWD) is the most common inherited bleeding disorder, characterized by a quantitative or qualitative deficiency of von Willebrand factor (VWF), a large multimeric glycoprotein central to hemostasis. Despite its prevalence, VWD remains globally underdiagnosed. Accurate diagnosis requires thorough clinical assessment and specialized laboratory evaluation. Although international evidence-based guidelines have advanced care, significant diagnostic and management challenges remain. Management focuses on treating and preventing bleeding, ensuring periprocedural safety, and improving quality of life through individualized strategies and the use of various hemostatic agents and therapeutic strategies. Optimal management approaches in complex clinical scenarios remain challenging. In this comprehensive illustrated review, we cover the biology and physiology of VWF, along with the pathophysiology, diagnosis, and management of VWD. We review current clinical practice recommendations and provide practical guidance for challenging scenarios such as surgery, pregnancy, cardiovascular disease, aging, and acquired von Willebrand syndrome. We also highlight emerging therapeutics and models of care in VWD.

Background: Hemophilia carriers (HCs) experience varied bleeding tendencies affecting their quality of life, yet their bleeding phenotype and management remain poorly understood. Since majority of the studies in carriers have focused on women of reproductive age, an unmet need exists to characterize their clinical, laboratory phenotype and treatment patterns across the lifespan. Objectives: The objective of our study was to investigate the age-dependent clinical and laboratory phenotype of hemophilia carriers across the lifespan. We also aimed to study the longitudinal treatment trends in HCs through analysis of the American Thrombosis and Hemostasis Network dataset. Methods: We investigated the age-dependent variation of bleeding phenotype, coagulation factor levels, and trends of utilization of factor concentrates and nonfactor hemostatic therapies (antifibrinolytics, 1-desamino-8-D-arginine vasopressin) in HCs using the American Thrombosis and Hemostasis Network dataset from 2010 to 2020. The study included 3663 HCs (2728 hemophilia A, 935 hemophilia B) divided into 3 age groups: 0 to 12, 13 to 49, and >50 years. Results: Joint bleeding was prevalent across all ages of HCs. While bleeding events were more frequent among HCs within the reproductive-age group, hemophilia B carriers received factor therapy more frequently than hemophilia A carriers (P = .03). Factor (F)VIII activity levels in hemophilia A carriers increased significantly with age (P < .001). Analysis of treatment trends from 2010 to 2020 showed increased utilization of factor concentrates and nonfactor hemostatic therapies among HCs (P < .001 and P = .02, respectively). Conclusion: Our study confirms prior reports of increased bleeding in reproductive-age HCs and identifies lifelong joint bleeding risk. While the rising trend in hemostatic therapy use suggests growing awareness of bleeding tendencies, age-dependent increase in FVIII levels in hemophilia A carriers emphasizes the need for developing tailored management strategies across the lifespan for this population.

AIMS:Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome caused by excessive immune activation, leading to severe inflammation and multi-organ failure. While adult-onset HLH is well documented, pregnancy-related HLH remains under investigated, with limited data on its triggers, presentation, and management. We systematically review cases of pregnancy-related HLH in the literature, focusing on presentations, triggers, utilized treatments, and outcomes. METHODS:A systematic search of PubMed and Embase identified case reports and series describing HLH during pregnancy or postpartum. Data were extracted and analyzed using standardized methods, including frequency distributions for categorical variables and means with standard deviations for continuous variables. Quality was assessed using the Joanna Briggs Institute checklist. Statistical analysis was conducted using IBM SPSS version 26. RESULTS:The initial search identified 838 records, from which 66 case reports and 7 case series were included, covering 104 unique patients. The mean age of the patients was 29 years (SD 5.6 years). Presentations occurred between 7 weeks of gestation and up to 7 months after delivery; of these, 82.5% presented antepartum at an average gestational age of 24 weeks (SD 7.9 weeks), while 17.5% presented postpartum. Fever (100%), anemia (90.7%), and elevated ferritin levels (> 1000 ng/mL in 95.1%) were the most common findings. Infections were the most frequent triggers (42 patients, 40.4%), with Epstein-Barr virus (EBV) being the most frequently implicated pathogen (10 patients, 9.6%). Other triggers included systemic lupus erythematosus (10 patients, 9.6%), Adult-onset Still's Disease (7 patients, 6.7%), lymphoma (6 patients, 5.8%), and no identifiable trigger in 42 patients (40.4%). Regarding treatment, corticosteroids were used in 93.3% of cases, etoposide in 35.6%, cyclosporine in 17.3%, and intravenous immunoglobulins (IVIG) in 26%. Delivery stabilized or reversed the disease in 40.4% of cases. However, 45.6% of patients with prepartum onset experienced pregnancy loss. Nineteen patients (18.3%) died due to HLH. CONCLUSION:This review highlights the distinct characteristics and challenges of HLH in pregnancy. Early diagnosis, a multidisciplinary approach, and individualized treatment strategies are crucial for improving maternal and fetal outcomes.

Neuraxial anesthesia is used for pain management in surgical and nonsurgical settings. Spinal/epidural hematomas likely occur in between 1:10 000 and 1:200 000 procedures. Risk is believed to be greater in patients with bleeding disorders/thrombocytopenia, and there are no existing comprehensive recommendations to guide neuraxial anesthesia in these patients. The study’s objective was to develop recommendations to advise clinicians on treatment thresholds for neuraxial anesthesia in patients with platelet disorders/coagulation defects. A 4-round electronic modified Delphi consensus study was conducted. A steering committee generated the original Delphi statements and refined them based on panelist feedback. Consensus was achieved if ≥70% of participants agreed/strongly agreed or disagreed/strongly disagreed with a statement. This project was endorsed by the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on von Willebrand Factor. Forty-five experts participated (42% response rate) with an essentially equal number of hematologists and anesthesiologists. Thirty consensus statements were developed for 11 disorders ranging from various causes of thrombocytopenia, inherited platelet function disorders, and single or multiple coagulation defects in obstetrical and nonobstetrical patients. Risk of sampling bias is present due to a predominantly North American sample, attrition (common in Delphi studies), and steering committee participation in the Delphi rounds. This is the first set of consensus recommendations for neuraxial anesthesia in adult patients with an array of platelet disorders/coagulation defects. These recommendations, based on the best available evidence and expert opinion, provide a decision framework for clinicians when faced with this challenging scenario.

Background: While bleeding around pregnancy is well described in von Willebrand disease (VWD), the risk of pregnancy loss is less certain. Objectives: We aimed to describe the frequency of pregnancy loss in females with VWD compared with those with a similar mucocutaneous bleeding phenotype and no VWD or compared with nonbleeding disorder controls. Methods: Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014 and 2023. The VWD group was defined as having von Willebrand factor (VWF) antigen and VWF activity levels, each <0.50 IU/mL on >= 2 occasions, and a condensed MCMDM-1 score of >= 4. The non-VWD mucocutaneous bleeding disorder group had VWF levels >= 0.50 IU/mL on >= 2 occasions and an MCMDM-1 score >= 4. A nonbleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic. Results: There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with >= 1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%; 82/145; -11.2%; 97.5% CI, -24.2%, 1.8%), and the nonbleeding disorder control group (37.2%; 51/137; 8.1%; 97.5% CI, -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group vs the non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared with the literature. Conclusion: There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and nonbleeding disorder controls.

INTRODUCTION:Gastrointestinal (GI) bleeding events (BEs) in von Willebrand disease (VWD) are difficult to diagnose and often recurrent. Limited data from clinical trials has led to lack of consensus on treatment options. AIM:Describe current treatments and outcomes for GI BEs in people with VWD. METHODS:This retrospective, observational, multicentre chart review study was conducted from January 2018 through December 2019 and included patients with inherited VWD with ≥1 GI BE in the preceding 5 years. Baseline characteristics, number and aetiology of BEs, associated GI-specific morbidities/lesions, treatment and outcomes were analysed descriptively. RESULTS:Sixty bleeds were reported in 20 patients with type 1 (20%), type 2 (50%) and type 3 (30%) VWD. During the 5-year study period, 31 (52%) BEs had one identified or suspected cause; multiple causes were reported in 11 (18%). Most GI BEs (72%) were treated with a combination of von Willebrand factor (VWF), antifibrinolytics and/or other haemostatic or non-haemostatic treatments. Time to resolution did not differ by VWF treatment use; however, BEs treated with non-VWF treatments tended to resolve later. In patients with GI-specific morbidities/lesions, 84% resolved with first-line treatment; time to resolution tended to be longer than in patients without such morbidities/lesions. Thirteen BEs occurred in patients receiving prophylaxis and 47 in patients receiving on-demand treatment; 18 BEs resulted in a switch to prophylaxis after bleed resolution. CONCLUSIONS:This study confirms the unmet need for the management of recurrent GI BEs in people with VWD and the need for prospective data, especially on prophylaxis.

In many patients referred with signi ficant bleeding phenotype, laboratory testing fails to de fine any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this patient cohort poses signi ficant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a signi ficant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical signi ficance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.

Introduction Left ventricular assist devices (LVADs) are being used increasingly for medical therapy-resistant heart failure, reducing mortality but associated with bleeding complications due to anticoagulation (AC) use. Vitamin K Antagonists (VKAs) are the standard of care in patients with LVADs, while the safety and efficacy of direct oral anticoagulants (DOACs) remains uncertain. We report our experience of using DOACs or discontinuing AC in patients with LVADs, followed by a systematic review of the literature. Methods We conducted a retrospective, single-center review, identifying patients with HeartMate III (HM3) LVAD, prescribed a DOAC or being monitored off AC after experiencing warfarin failure between 2018 and 2024. Demographics, therapy duration, reasons for change in AC, adverse events such as stroke, thromboembolism, pump thrombosis, major bleeding (MB), and life-threatening bleeding were recorded. A systematic search of PubMed, CINAHL, and OVID databases using the PRISMA guidelines identified studies evaluating the use of DOACs in patients with LVADs, excluding animal or ex-vivo studies. Results Six patients (4 males, average age of 71 ± 6 years, and BMI of 29.7 kg/m2) are included from our institution. Following warfarin failure, 3 patients were switched to apixaban 2.5 mg twice daily, 1 patient to rivaroxaban 20 mg once daily, and AC was discontinued for 2 patients. They remained on warfarin for 850 ± 558 days, DOACs for 345 ± 302 days (all 4 continue on DOAC to present), and were off AC for 646 ± 365 days. Previously, time within therapeutic range on warfarin averaged 37%. Reasons for change in AC included recurrent gastrointestinal bleeding (GIB), intracranial hemorrhage (ICH), and supra-therapeutic INR (more than 10 with no overt bleeding). Nine bleeding events occurred in patients while on warfarin (7 were life-threatening including ICHs and GIBs) whereas only 1 patient had a major GIB and ICH while on a DOAC. AC was discontinued for 2 patients after life-threatening GIBs on warfarin, with only 1 recurrence. Only 1 transient ischemic attack occurred on warfarin, with no other thrombotic events. 49 studies were screened, and 15 were included in the review (8 case reports with 1-7 patients, 4 retrospective single-center analyses (RSCA) with 7-63 patients, and 3 randomized controlled trials (RCTs) with 16-45 patients, totaling 222 patients). Three studies involved HeartWare LVAD patients, of which an RCT was halted early due to 50% (4/8) pump thrombosis on dabigatran vs. 12.5% (1/8) on VKA. Five studies involved the HeartMate II LVAD; 2 RSCAs with 7 patients each assessed dabigatran vs. VKA and apixaban/rivaroxaban vs VKA with similar incidence of bleeding and thrombotic complications in each group. Seven studies involved the HM3 LVAD. 2 RSCAs with 35 and 63 patients reported similar incidence of thrombotic events, 6% vs 10%, p = 1.0 and 24% vs. 15%, p=0.75, and clinically lower bleeding events or related admission, 5% vs. 30%, p=0.1, 2.2 vs. 9.7 admission per 1000 days on therapy, in patients on apixaban vs. VKA, respectively. 2 RCTs in HM3 LVAD patients reported no thrombosis on a VKA or a DOAC but demonstrated a clinical reduction in rates and severity of bleeding events (1/47 vs. 6/28) in patients on apixaban vs. VKA. Conclusion In our experience, albeit a very small sample size, the use of apixaban or rivaroxaban in LVAD patients following VKA failure was not associated with increase in thrombosis but with a clinical reduction in number and severity of bleeding events. In 2 LVAD patients for whom AC was discontinued due to life-threatening bleeding on a VKA, no thrombotic complications occurred for 2.5 and 0.75 years. Furthermore, review of literature supports our findings though total number of patients is relatively small. Nonetheless, there is growing evidence of the safety and efficacy of administering DOACs in patients with LVADs, although more extensive trials and registry studies are required to confirm this and further reassure clinicians given the prevailing standard of care of “never” administering a DOAC in a LVAD patient.

Background: Rapid clinical evaluation of immune thrombotic thrombocytopenic purpura (iTTP) is crucial due to its high mortality and the need for early intervention. Enhancing the accuracy of initial predictive models is important, as it could help improve early recognition and treatment of iTTP, and avoid unnecessary interventions in non-TTP patients. The PLASMIC score is a widely used clinical tool for predicting ADAMTS13 deficiency in suspected iTTP. However, subsequent studies have shown variability in its predictive performance across different populations. Machine learning, with its ability to analyze many continuous variables as well as the complex interactions between them, offers a promising approach to enhance predictive accuracy. We utilized XGBoost (extreme gradient boosting), a machine learning approach, to develop a novel tool that improves upon the PLASMIC score's ability to rapidly predict iTTP. Objectives: To develop a novel machine learning tool to predict iTTP diagnosis that improves upon the PLASMIC score. Methods: We identified all ADAMTS13 tests performed between 2012-2022 using data from four US institutions: University of Utah (Salt Lake City, UT), Case Western/University Hospitals (Cleveland, OH), Rochester Regional Health (Rochester, NY), and University of Illinois (Peoria, IL). iTTP was defined as ADAMTS13 activity level < 10%, and controls were defined as ADAMTS13 activity level > 20%. We included all presenting variables from the PLASMIC score and added hemoglobin, lactate dehydrogenase (LDH), age, sex, and the presence of any neurologic deficit as potential predictors. Instead of the composite variable of hemolysis in the PLASMIC score, we used its individual components of haptoglobin, reticulocyte percentage, and indirect bilirubin as separate variables. We developed a new predictive model using XGBoost implemented in the R package xgboost. Variable importance (VI) was reported for each predictor. The model's performance was assessed using repeated 10-fold cross-validated area under the receiver operating characteristic curve (AUC). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were reported at two thresholds for high and intermediate risk of TTP, respectively. Results We included 106 iTTP patients and 402 controls from four institutions. The machine learning model, named TTP-14, predicts the risk, or probability of iTTP diagnosis based on fourteen variables. The predictors, in order of highest VI were: Platelet count, LDH, creatinine, INR, reticulocyte percentage, active cancer, indirect bilirubin, MCV, total bilirubin, haptoglobin, neurologic deficit, hemoglobin, age, and history of transplant. TTP-14 achieved a cross-validated AUC of 0.91 (95% CI: 0.90-0.92), improving upon the PLASMIC score's AUC of 0.85 (95% CI: 0.81-0.89) in our dataset. We chose two risk cut-offs to define three risk categories: High risk (TTP-14 predicted risk ≥ 50%)Intermediate risk (TTP-14 predicted risk > 10% and < 50%)Low risk (TTP-14 predicted risk ≤ 10%) For the high risk group (15.4% of patients), TTP-14 predicted iTTP diagnosis with high specificity and PPV: Sensitivity0.64Specificity0.97PPV0.83NPV0.91Overall accuracy0.90 For the low risk group (39.2% of patients), TTP-14 effectively ruled out iTTP with high NPV and sensitivity: Sensitivity0.90Specificity0.74PPV0.48NPV0.97Overall accuracy0.77 Conclusion: Our predictive model, TTP-14, implemented machine learning technique to accurately predict the probability of iTTP diagnosis in suspected patients at initial presentation. With a cross-validated AUC of 0.91, our machine learning model offered enhanced predictive performance compared to the PLASMIC score in our dataset (AUC 0.85). TTP-14 identified low-risk patients with an NPV of 0.97 and could confidently rule out iTTP, and high-risk patients were identified with PPV of 83% and high specificity of 97%. External validation is warranted to confirm these findings and integrate TTP-14 into clinical practice. If externally validated, TTP-14 can help improve early recognition and treatment of iTTP and reduce unnecessary interventions for non-TTP patients.

Introduction: Severe hemophilia A (HA) in females is incredibly rare particularly if complicated by a high-titer factor VIII (FVIII) inhibitor. We report, to the best of our knowledge, the first-of-its-kind use of emicizumab (emi) ante/post-partum, its effect on the newborn, and its excretion in breast milk. Baseline details: 29-year-old-female was diagnosed with severe HA at age 1 following prolonged bleeding from a venipuncture site. She had no family history of HA. One stage FVIII activity (OSA) was less than 1%. She was compound heterozygous for F8 type 1 and type 2 intron 22 inversions. At 21 months of age, she developed a high-titer inhibitor (peak: 35 Bethesda unit[BU]). She was not treated with immune tolerance induction and had remained on factor eight inhibitor bypassing activity (FEIBA) as prophylaxis until transferring to our center. She was transitioned to monthly emi prophylaxis and recombinant FVIIa (rFVIIa, NovoSeven) for breakthrough bleeding at age 26. She was medically advised against pregnancy due to unclear safety profile of emi in pregnancy and theoretical concerns for an increased risk of bleeding and thrombotic complications associated with the use of bypassing agents in the peripartum setting. Nevertheless, she desired pregnancy and continued on emi prophylaxis every 4 weeks during her pregnancy. Clinical course in pregnancy: She had an uncomplicated antepartum course and did not require rFVIIa for breakthrough bleeds. Blood emi levels and FVIII inhibitor levels were measured in each trimester of pregnancy (Table 1). Her labor was induced with oxytocin while on rFVIIa and tranexamic acid (TXA) support. She had a spontaneous, unassisted vaginal delivery immediately complicated by post-partum hemorrhage resulting in estimated blood loss of 1100cc. She did not require blood transfusion. She continued on 90 mcg/kg rFVIIa support every 2 hours, gradually prolonging the dosing interval by 2 hours every 24 hours (q2, q4, q6, etc.), and experienced no further in-hospital bleeding. She delivered a healthy female newborn. The infant developed cephalhematoma but transcranial ultrasound was negative for intracranial bleeding. Cord blood was collected at the time of delivery and sent for emi level, FVIII activity and FVIII inhibitor titer (Table 2). FVIII inhibitor assay with bovine reagent (CBU) was performed using chromogenic substrate assay (CSA) after pre-analytical heat-inactivation of patient plasma. The infant's CSA FVIII level was measured using a bovine chromogenic FVIII assay, and FVIII was also assayed using a one-stage APTT-based assay. Mother opted to breast-feed the infant. Emi level was measured in breast milk (Table 1). Conclusion: In this highly unusual case, we demonstrate that emi crossed the placenta and is excreted in breast milk. We also demonstrate that the maternal FVIII inhibitor did not cross the placenta into the newborn. Drawing conclusions on the safety of emi despite placental and breast milk transmission and transmissibility of inhibitor based on a single case would be premature. The conglomeration of several rarities in a single case renders our report unique and insightful and provides a baseline experience for future cases.

The authors regret the affiliation of Clinical Pathology Department, Faculty of Medicine, Mansoura University, Egypt was omitted for Maha Othman. This has been corrected and added as below. The authors would like to apologise for any inconvenience caused. Examining international practices in the management of pregnant women with von Willebrand diseaseJournal of Thrombosis and HaemostasisVol. 20Issue 1PreviewThe management of pregnant women with von Willebrand disease (VWD) is complex as physiological pregnancy‐induced increases in plasma von Willebrand factor (VWF) may be blunted or absent. Women with VWD experience a heightened risk of postpartum hemorrhage (PPH) and special consideration must be given regarding neuraxial anesthesia (NA) and the need for prophylaxis at time of delivery. These challenges are compounded by a lack of robust evidence to guide clinical decision‐making. Full-Text PDF Open Access

Thrombosis is a common complication of Essential Thrombocythemia (ET) and is responsible for significant morbidity and mortality in affected individuals. The JAK2 V617F mutation is a well-established risk factor for thrombosis in ET, with a reported prevalence of approximately 50% in patients with ET. However, there is increasing evidence that other mutations, including CALR mutations, also independently confer increased thrombotic risk in ET. CALR functions as a chaperone protein that screens misfolded proteins in the endoplasmic reticulum and prevents transition to the Golgi apparatus and, ultimately, to the cell surface. CALR mutations are exon 9 frameshift mutations due to 52-base pair deletion in type 1 or 5-base pair insertion in type 2. JAK2 and CALR mutations have been proposed to represent two distinct subtypes of ET due to their significant differences in thrombosis risk and disease progression. Therefore, we conducted a systematic review and meta-analysis comparing the cumulative thrombotic risk between different CALR mutation types (type 1 and type 2), and JAK2 V617F mutation in ET. We searched PubMed, Google Scholar, MEDLINE OVID, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases to identify relevant peer-reviewed studies published from database inception to January 2023 without any language restrictions. The overall odds ratio (OR) was computed using the random-effects model to account for the expected heterogeneity among included studies. The meta-analysis included a total of 15 studies.1-15 There were 795 included patients with CALR1 mutations, 561 included patients with CALR2 mutations, and 3538 included patients with JAK2 mutations. Most of the studies were retrospective in design and conducted in different countries. The quality of studies was assessed by the JBI risk assessment tool. Most of the studies (10 out of 15) had a low risk of bias, while others had a moderate risk of bias. The rank correlation test for funnel plot asymmetry did not reveal publication bias. The pooled odds ratios for thrombosis in CALR1 versus JAK2, CALR2 versus JAK2, and CALR1 versus CALR2 were 0.65 (95% confidence interval [CI], 0.46–0.91), 0.45 (95% CI, 0.32–0.62), and 1.50 (95% CI, 1.00–2.24), respectively (Figure 1). Sensitivity analysis was conducted among 8 studies after excluding the medium and high risk of bias studies, which showed pooled odds ratio in CALR1 versus CALR2 and CALR1 versus JAK2 were 1.81 (95% CI of 1.04 to 3.13, p = .03) and 0.6 (95% CI of 0.44 to 0.82), respectively. Subgroup analysis based on the site of thrombosis did not show any statistically significant results except for a lower venous thrombotic risk with CALR2 compared to JAK2. This could be because our analysis was underpowered to detect the differential risk of arterial thrombosis between these patients. Our results suggest that ET patients with CALR1 or CALR2 mutations have a lower risk of thrombosis than those with JAK2 mutations. Moreover, ET patients with CALR1 were found to have a higher risk of thrombosis than those with CALR2. The pathophysiology for the difference is unknown, although it can be speculated that CALR2 mutation will lead to less activation of the thrombopoietin receptors and less ADP-induced platelet activation in light of its lower net positive charge.16 More recently, function of mutant CALR protein as rogue cytokine which functions in a way similar to thrombopoietin has been discovered. However, the association between CALR mutations and thrombotic risk requires further investigation, as the included studies varied in patient populations, study designs, and follow-up periods. In addition, we were unable to stratify the thrombotic events based on their severity or recurrence due to the lack of available data and we could not obtain adequate data on thrombosis-free survival. Our study highlights the need for personalized risk assessment and management strategies for ET patients based on their specific mutation status. The authors received no financial support for the research, authorship, and/or publication of this article. The authors have no conflicts of interest to declare. All the required information is in the manuscript itself.