Risk Factor For Thrombosis Research Articles

Nitrous oxide abuse leading to extreme homocysteine levels and thrombosis in young adults: a case series

BackgroundNeurologic complications from recreational use of nitrous oxide (N2O), which are attributed to vitamin B12 deficiency, have been well documented. With increasing dosages and frequency of N2O use, an additional association with thromboembolisms is becoming apparent. ObjectivesTo assess thrombotic complications of recreational N2O use. MethodsAll medical charts at the largest hospital in Amsterdam were searched for N2O use and subsequent neurologic and/or thrombotic events. For patients with thrombotic events, we extracted data on the risk factors for arterial and venous thrombosis as well as serum vitamin B12 and homocysteine concentrations. ResultsBetween January 2015 and May 2021, 326 patients who reported recreational use of N2O were identified; of these, 17 (5%) patients presented with severe thrombotic events associated with N2O (71% men; median age, 26 years [range, 18-53 years]), 5 patients presented with arterial thrombosis (3 with acute coronary syndrome, 1 with femoral artery thrombosis, and 1 with middle cerebral artery thrombus), and 12 patients presented with venous thromboembolisms (10 with pulmonary embolisms, 1 with portal vein thrombosis and 1 with cerebral vein thrombosis). Additionally, homocysteine were concentrations severely increased (median, 125 μmol/L [range, 22-253 μmol/L]; reference, <15 μmol/L). Patients reported use of 400 to 6000 g (ie, 50-750 balloons) of N2O in 1 day. Fifty percent of these patients had experienced neurologic symptoms before the thrombotic event. ConclusionWe describe an alarming incidence of serious thrombotic events among young adults after excessive recreational use of N2O, accompanied by extremely high homocysteine concentrations. The upward trend in the recreational use of N2O warrants more awareness of its dangers among both users and medical professionals. Furthermore, these findings could reopen the discussion on possible associations between hyperhomocysteinemia and thrombosis mediated through N2O.

Factor V Leiden-independent activated protein C resistance: Communication from the plasma coagulation inhibitors subcommittee of the International Society on Thrombosis and Haemostasis Scientific and Standardisation Committee

Activated protein C resistance (APC-R) due to the single-nucleotide polymorphism factor V Leiden (FVL) is the most common cause of hereditary thrombophilia. It is found predominantly in Caucasians and is uncommon or absent in other populations. Although FVL is responsible for >90% of cases of hereditary APC-R, a number of other F5 variants that also confer various degrees of APC-R and thrombotic risk have been described. Acquired APC-R due to increased levels of coagulation factors, reduced levels of inhibitors, or the presence of autoantibodies occurs in a variety of conditions and is an independent risk factor for thrombosis. It is common for thrombophilia screening protocols to restrict assessment for APC-R to demonstrating the presence or absence of FVL. The aim of this Scientific and Standardisation Committee communication is to detail the causes of FVL-independent APC-R to widen the diagnostic net, particularly in situations in which in vitro APC-R is encountered in the absence of FVL. Predilution clotting assays are not FVL specific and are used to detect clinically significant F5 variants conferring APC-R, whereas different forms of acquired APC-R are preferentially detected using the classical activated partial thromboplastin time-based APC-R assay without predilution and/or endogenous thrombin potential APC-R assays. Resource-specific recommendations are given to guide the detection of FVL-independent APC-R.

The risk factors for deep venous thrombosis in critically ill older adult patients: a subgroup analysis of a prospective, multicenter, observational study

BackgroundOlder adult patients mainly suffer from multiple comorbidities and are at a higher risk of deep venous thrombosis (DVT) during their stay in the intensive care unit (ICU) than younger adult patients. This study aimed to analyze the risk factors for DVT in critically ill older adult patients.MethodsThis was a subgroup analysis of a prospective, multicenter, observational study of patients who were admitted to the ICU of 54 hospitals in Zhejiang Province from September 2019 to January 2020 (ChiCTR1900024956). Patients aged > 60 years old on ICU admission were included. The primary outcome was DVT during the ICU stay. The secondary outcomes were the 28- and 60-day survival rates, duration of stay in ICU, length of hospitalization, pulmonary embolism, incidence of bleeding events, and 60-day coagulopathy.ResultsA total of 650 patients were finally included. DVT occurred in 44 (2.3%) patients. The multivariable logistic regression analysis showed that age (≥75 vs 60-74 years old, odds ratio (OR) = 2.091, 95% confidence interval (CI): 1.308-2.846, P = 0.001), the use of analgesic/sedative/muscarinic drugs (OR = 2.451, 95%CI: 1.814-7.385, P = 0.011), D-dimer level (OR = 1.937, 95%CI: 1.511-3.063, P = 0.006), high Caprini risk score (OR = 2.862, 95%CI: 1.321-2.318, P = 0.039), basic prophylaxis (OR = 0.111, 95%CI: 0.029-0.430, P = 0.001), and physical prophylaxis (OR = 0.322, 95%CI: 0.109-0.954, P = 0.041) were independently associated with DVT. There were no significant differences in 28- and 60-day survival rates, duration of stay in ICU, total length of hospitalization, 60-day pulmonary embolism, and coagulation dysfunction between the two groups, while the DVT group had a higher incidence of bleeding events (2.6% vs. 8.9%, P < 0.001).ConclusionIn critically ill older adult patients, basic prophylaxis and physical prophylaxis were found as independent protective factors for DVT. Age (≥75 years old), the use of analgesic/sedative/muscarinic drugs, D-dimer level, and high Caprini risk score were noted as independent risk factors for DVT.Trial registrationChinese Clinical Trial Registry (ChiCTR1900024956).URL: http://www.chictr.org.cn/listbycreater.aspx.

Post-Covid-19 Recurrent Lower Limb Ischemia in Healty Young Patient

Background: Although SARS-CoV-2 infection is primarily a respiratory illness, complications such as arterial and venous thromboembolism have been reported during acute infection and in the period after its resolution.Methods: We report the case of a 33-year-old male, previously healthy patient with acute recurrent unilateral arterial thrombosis of the leg occurring one month after a mild Covid-19 infection.Results: The patient has recently been diagnosed with essential hypertension and did not have other known risk factors for arterial thrombosis. He presented to the Emergency Department with a pale left foot and absent dorsal pedal pulse and after confirmed arterial occlusion by Doppler ultrasound, he underwent urgent thromboembolectomy. The following day a computed tomography angiogram showed recurrent thrombosis of the superficial femoral artery which was then resolved in an Angio-suite by balloon dilatation. Three months later he experienced another occlusion of the left superficial femoral artery based on pronounced neointimal hyperplasia and again underwent endarterectomy with patch plastic.Conclusion: SARS-Cov-2 infection should be considered a risk factor in the development of both arterial and venous thrombo-sis during the acute phase and in the post-infective period

Incidence and Risk Factors for Superficial and Deep Vein Thrombosis in Post-Craniotomy/Craniectomy Neurosurgical Patients.

Background Venous thromboembolism (VTE) is quite common among post-operative neurosurgical patients. This study aims to identify the incidence of deep vein thrombosis (DVT) and superficial vein thrombosis (SVT) among post-craniotomy/craniectomy patients and further evaluate established hypercoagulability risk factors such as trauma, tumors, and surgery. Methodology This single-center retrospective study investigated 197 patients who underwent a craniotomy/craniectomy. The incidences of DVT and SVT were compared, along with laterality and peripherally inserted central catheter (PICC) line involvement. A multivariate logistic regression analysis was conducted to identify risk factors for post-craniotomy/craniectomy VTE. This model included variables such as age, post-operative days before anticoagulant administration, female sex, indications for surgery such as tumor and trauma, presence of a PICC line, and anticoagulant administration. Results Among the 197 post-craniotomy/craniectomy patients (39.6% female; mean age 53.8±15.7 years), the incidences of DVT, SVT, and VTE were 4.6%, 9.6%, and 12.2%, respectively. The multivariate logistic regression analysis found that increasing the number of days between surgery and administration of anticoagulants significantly increased the risk of VTE incidence (odds ratio 1.183, 95% CI 1.068-1.311, p = 0.001). Conclusions Contrary to existing evidence, this study did not find trauma or the presence of tumors to be risk factors for VTE. Future prospective studies should assess VTE risk assessment models such as "3 Bucket" or "Caprini" to develop universal guidelines for administering anticoagulant therapy to post-craniotomy/craniectomy patients that consider the timing of post-operative therapy initiation.

Has Lockdown and COVID-19 Led to a Change in the Characteristics of Deep Vein Thrombosis and Patients Who Are Afflicted With It?

There is growing evidence identifying coronavirus disease 2019 (COVID-19) as a significant risk factor for thrombosis in inpatients. However, it remains uncertain if patients in the community have been influenced during the COVID-19 pandemic and national lockdown. This study, across four centres in the United Kingdom (UK), reviewed outpatients with deep vein thrombosis (DVT). This study aims to find out whether lockdown and COVID-19 led to a change in the characteristics of DVT and patients who are afflicted with it, alongside a review of DVT service. Data was collected retrospectively from electronic patient records system for the following periods: April 1 to June 30, 2019, and April 1 to June 30, 2020. These were the key months during the first national lockdown in UK. Data were analysed for patient demographics, risk factors, characteristics of DVT, management, and DVT reoccurrence. Statistical analyses were performed using GraphPad Prism 8 (Dotmatics, Boston, Massachusetts, United States). During the study periods, 227 outpatients from the community sustained DVT in 2019 and 211 in 2020. Of these patients, 13 in 2020 were COVID-19 positive. There was a difference in gender distribution with 128 males and 99 females in 2019, and 93 males and 118 females in 2020 (p= 0.0128). No significant difference was noted in the incidence of thrombophilia with nine in 2019 and three in 2020 (p=0.1437). Fewer long-haul journeys were made in 2020 (only two), compared to 16 in 2019 (p=0.012). Fewer patients had immobility as a risk factor in 2020 (n=55) compared to 2019 (n=79) (p=0.0494). However, there were more patients using oral contraceptive pills, with one in 2019 and nine in 2020 (p=0.0086) . There is no significant difference in the characteristics, extent, and management of DVT prior to and during the COVID-19 lockdown. National lockdowns do not affect DVT in the community; however, it is important to highlight the surrounding inpatient numbers.

Automated analysis of fibrous cap in intravascular optical coherence tomography images of coronary arteries

Thin-cap fibroatheroma (TCFA) and plaque rupture have been recognized as the most frequent risk factor for thrombosis and acute coronary syndrome. Intravascular optical coherence tomography (IVOCT) can identify TCFA and assess cap thickness, which provides an opportunity to assess plaque vulnerability. We developed an automated method that can detect lipidous plaque and assess fibrous cap thickness in IVOCT images. This study analyzed a total of 4360 IVOCT image frames of 77 lesions among 41 patients. Expert cardiologists manually labeled lipidous plaque based on established criteria. To improve segmentation performance, preprocessing included lumen segmentation, pixel-shifting, and noise filtering on the raw polar (r, θ) IVOCT images. We used the DeepLab-v3 plus deep learning model to classify lipidous plaque pixels. After lipid detection, we automatically detected the outer border of the fibrous cap using a special dynamic programming algorithm and assessed the cap thickness. Our method provided excellent discriminability of lipid plaque with a sensitivity of 85.8% and A-line Dice coefficient of 0.837. By comparing lipid angle measurements between two analysts following editing of our automated software, we found good agreement by Bland–Altman analysis (difference 6.7° ± 17°; mean ~ 196°). Our method accurately detected the fibrous cap from the detected lipid plaque. Automated analysis required a significant modification for only 5.5% frames. Furthermore, our method showed a good agreement of fibrous cap thickness between two analysts with Bland–Altman analysis (4.2 ± 14.6 µm; mean ~ 175 µm), indicating little bias between users and good reproducibility of the measurement. We developed a fully automated method for fibrous cap quantification in IVOCT images, resulting in good agreement with determinations by analysts. The method has great potential to enable highly automated, repeatable, and comprehensive evaluations of TCFAs.

Reevaluation of cardiovascular risk factors for thrombotic events in 580 Japanese patients with essential thrombocythemia.

Risk-adapted therapy is recommended to prevent thrombosis in essential thrombocythemia (ET) patients. An advanced age, a history of thrombosis, and the presence of the JAK2V617F mutation are well-defined risk factors for thrombosis in ET; however, the impact of cardiovascular risk (CVR) factors on thrombosis in ET remains elusive. Therefore, we herein investigated the impact of CVR factors on thrombosis in 580 ET patients who met the 2017 World Health Organization Classification diagnostic criteria. A univariate analysis identified hypertriglyceridemia and multiple CVR factors as strong risk factors for thrombosis (hazard ratio [HR] 3.530, 95% confidence interval [CI] 1.630-7.643, P = 0.001 and HR 3.368, 95% CI 1.284-8.833, P = 0.014, respectively) and hyper-LDL cholesterolemia as a potential risk factor (HR 2.191, 95% CI 0.966-4.971, P = 0.061). A multivariate analysis revealed that hypertriglyceridemia was an independent risk factor for thrombosis (HR 3.364, 95% CI 1.541-7.346, P = 0.002). Furthermore, poor thrombosis-free survival was observed in patients with a serum triglyceride level ≥ 1.2mmol/L (HR = 2.592, P = 0.026 vs. < 1.2mmol/L) or two or more CVR factors (P = 0.011 vs. no CVR factors and P = 0.005 vs. one CVR factor). These results revealed the impact of CVR factors on thrombosis in ET. Since CVR factors are manageable, lifestyle interventions, such as the control of serum triglyceride levels, may effectively prevent thrombosis in ET patients.

Comparison of reconstruction methods used during liver transplantation in case of a graft with replaced or accessory right hepatic artery: A retrospective study.

Variations in graft arterial anatomy can increase the risk of postoperative hepatic arterial thrombosis (HAT), especially in presence of a replaced or accessory right hepatic artery (RHA). We retrospectively analyzed 223 cases of liver transplantations with the presence of an RHA on the graft. Patient outcomes were compared according to the four different reconstruction methods used: (i) the re-implantation of the RHA into the splenic or gastroduodenal artery (n= 106); (ii) the interposition of the superior mesenteric artery (SMA) (n= 83); (iii) dual anastomosis (n= 24); (iv) use of an aortic patch including the origins of both the SMA and the coeliac trunk (n= 10). A competing risk analysis and Inverse Probability Weighting (IPW) were used. We found that the interposition of the SMA method was associated with a significantly lower incidence of HAT, at 4.8% compared to the re-implantation method at 17.9%, dual anastomosis at 12.5%, and aortic patch at 20%, p= .03. In the competing risk analysis with IPW, the only risk factor for RHA thrombosis was the type of reconstruction. Taking the SMA interposition group as the reference, the sub-hazard ratio (sHR) was 5.05 (CI 95 [1.72; 14.78], p< .01) for the re-implantation group, sHR=2.37 (CI 95 [0.51; 11.09], p= .27) for the dual anastomosis group and sHR=2.24 (CI 95 [0.35; 14.33], p= .40) for the aortic patch group. There were no differences for intraoperative transfusion, hospitalization duration (p= .37) or incidence of severe complications (p= .1). The long-term graft (p= .69) and patient (p= .52) survival was not different. In conclusion, the SMA interposition method was associated with a lower incidence of RHA thrombosis.

Clinical profile and risk factors of cerebral venous sinus thrombosis (CVST) in Sudan: A multicenter cross-sectional study.

Cerebral venous sinus thrombosis (CVST) is a relatively uncommon cause of stroke that mainly affects young ladies, with a wide spectrum of symptoms severity, and prognosis. In this study, we aim to study the clinical profile and Risk Factors of CVST among Sudanese patients in Khartoum state hospitals. This was a multi-center cross-sectional hospital-based study that covered 37 participants in three major hospitals in Khartoum, with radiologically confirmed Cerebral Venous Sinus Thrombosis (CVST). About 37 patients were included in this study. The median age was 35 years; the range was 52 years, with a minimum age of 23 years and a maximum of 75 years. The commonest presenting feature was headache (n=35; 94.6%), followed by blurring of vision (n=25; 67.6%), while seizures is a presenting symptom in nearly half of the patients (n=17; 45.9%), on examination papilledema was present in 83.8%. In this study 13.8% were pregnant, 31.0% were postpartum and OCPS users account for 27%. Regarding the involved sinus; Sagittal Venous Sinus and the transverse sinus were the most affected sinuses. Regarding treatment options: "low molecular weight heparin followed with warfarin" was found in 81.1%, followed by heparin in only 10.8%, while the new agents NOACs comprised only 8.1%. Cerebral Venous Sinus Thrombosis is mainly a disease of child-bearing women, although significant proportions of men were affected. Cerebral Venous Sinus Thrombosis presents in a wide variety of signs and symptoms.

Diabetes mellitus is associated with a higher relative risk for venous thromboembolism in females than in males

AimsThe risk for developing venous thromboembolism (VTE) is about equal in both sexes. Research suggests diabetes mellitus (DM) is a risk factor for pulmonary embolism and deep vein thrombosis, both forms of VTE. We aimed at investigating the sex-specific impact of DM on VTE risk. Materials and methodsMedical claims data were analyzed in a retrospective, population-level cohort study in Austria between 1997 and 2014. 180,034 patients with DM were extracted and compared to 540,102 sex and age-matched controls without DM in terms of VTE risk and whether specific DM medications might modulate VTE risk. ResultsThe risk to develop VTE was 1.4 times higher amongst patients with DM than controls (95% CI 1.36–1.43, p < 0.001). The association of DM with newly diagnosed VTE was significantly greater in females (OR = 1.52, 95% CI 1.46–1.58, p < 0.001) resulting in a relative risk increase of 1.17 (95% CI 1.11–1.23) across all age groups with a peak of 1.65 (95% CI 1.43–1.89) between 50 and 59 years. Dipeptidyl peptidase 4 inhibitors were associated with a higher risk for VTE amongst female DM patients (OR = 2.3, 95% CI 1.3–4.3, p = 0.0096). ConclusionAmongst DM patients, females appear to be associated with a higher relative risk increase in VTE than males, especially during perimenopause.

Incidence and timing of coronary thrombosis in Kawasaki disease patients with giant coronary artery aneurysm

ObjectiveCoronary thrombosis is a common cardiovascular complication of Kawasaki disease (KD), which seriously affects the long-term therapeutic effect of KD. The purpose was to determine the incidence and timing of coronary thrombosis and to identify risk factors for coronary thrombosis in KD with giant coronary artery aneurysm (GCAA). Methods and resultsA total of 94 consecutive KD patients with GCAA from Children's Hospital Affiliated to Chongqing Medical University were enrolled retrospectively. The cumulative incidence of coronary thrombosis in KD patients with GCAA was 59 % (n = 54). Coronary thrombosis mainly occurred in the acute phase (n = 41/54, 76 %), with a median time of 16 days after onset. Cox regression analysis was used to identify risk factors for coronary thrombosis. Cox regression analysis indicated that male (hazard ratios, 1.87; 95 % CI, 1.01–3.44; P = 0.43), left anterior descending artery (LAD) involvement (hazard ratios, 3.75; 95 % CI, 1.85–7.39; P < 0.001), coronary absolute diameter ≥ 8 mm (hazard ratios, 2.93; 95 % CI, 1.36–6.29; P = 0.006) constituted a higher risk of coronary thrombosis after adjusting for confounders. Kaplan-Meier method showed the cumulative incidence for coronary thrombosis in KD patients with GCAA was 79 %, 92 %, and 88 % in male, LAD involvement, coronary absolute diameter > 8 mm, respectively. ConclusionsMale, LAD involvement, and coronary absolute diameter ≥ 8 mm were associated with a high incidence of coronary thrombosis. Based on the analysis of the incidence, time and risk factors of coronary thrombosis in different periods, this study may provide an essential reference for thromboprophylaxis management of KD with GCAA.

Rivaroxaban Prophylaxis in Noncirrhotic Portal Vein Thrombosis

BackgroundIn patients with noncirrhotic chronic portal vein thrombosis (PVT), the benefit of long-term anticoagulation is unknown. We assessed the effects of rivaroxaban on the risk of venous thromboembolism and portal hypertension-related bleeding in such patients.MethodsIn this multicenter, controlled trial, we randomly assigned patients with noncirrhotic chronic PVT without major risk factors for thrombosis to receive either rivaroxaban 15 mg/day or no anticoagulation. The primary end point was 2-year thrombosis-free survival. Secondary end points included the occurrence of site-specific thromboses and major bleeding events.ResultsA total of 111 participants were enrolled in the trial, with a mean age of 50.4±13.2 years; 58% of participants were men. An unplanned interim analysis was requested by the independent data safety monitoring board (DSMB) after 10 thrombotic events occurred. The thrombosis incidence rate was 0 per 100 person-years in the rivaroxaban group and 19.71 per 100 person-years (95% confidence interval, 7.49 to 31.92) in the no anticoagulation group (log-rank P=0.0008) after a median follow-up of 11.8 months. Based on the interim analysis, the DSMB recommended switching patients from the no anticoagulation group to anticoagulation. After a median follow-up of 30.3 months (intraquartile range, 24.3 to 47.8), major bleeding occurred in two patients receiving rivaroxaban and in one patient not receiving anticoagulation. No deaths occurred.ConclusionsAfter a median follow-up of 11.8 months, among patients with noncirrhotic chronic PVT without major risk factors for thrombosis, daily rivaroxaban reduced the incidence of venous thromboembolism and did not increase major bleeding events. (Funded by grants from the French Ministry of Health and the Association de Malades des Vaisseaux du foie; ClinicalTrials.gov number, NCT02555111.)

TET2 Mutation Is More Valuable in Predicting Thrombosis in Thrombocythemia Patients Compared to Polycythaemia Vera

Background Thrombosis is a common complication of myeloproliferative neoplasm (MPN) and its major cause of disability and death. With the development of next-generation gene sequencing technology, the relationship between non-driver mutations and thrombotic risk factors has also attracted close attention. Methods The clinical data of 125 MPN patients (75 ET and 50 PV) attending Xiyuan Hospital of the China Academy of Chinese Medical Sciences between January 2018 and March 2022 were retrospectively analyzed. A multivariate analysis of risk factors for thrombosis was performed using a Cox proportional hazards model. Results A total of 125 patients with MPN (75 ET and 50 PV) were evaluated, with a median age at diagnosis of 50 (18-78) years, 67 (53.6%) males and 58 (46.4%) females. The mutation rates of driver genes JAK2V617F, CALR, and MPL were 70.4%, 12.8%, and 0.8%, respectively. At least one non-driver mutation was detected in 36% of patients, with the highest rate of mutations in TET2 (12%), followed by ASXL1 (9.6%). Thrombotic events occurred in 35 of 125 patients (28.0%), and the incidence of thrombotic events was 21.3% (16/75) in ET patients and 38.0% (19/50) in PV patients, respectively. For 125 MPN patients, univariate analysis revealed significant associations between thrombosis and age at diagnosis, age >60 years at diagnosis, JAK2V617F mutation, TET2 mutation, WBC, NLR, cardiovascular risk factors and history of remote thrombosis. In the multivariate analysis that included the above 8 factors as covariates, age at diagnosis (HR: 1.03, 95％ CI: 1.00-1.06; P = 0.046), TET2 mutation (HR: 2.84, 95％ CI: 1.26-6.36; P = 0.011), NLR (HR: 1.18, 95％ CI: 1.06-1.32; P = 0.003), and history of remote thrombosis (HR: 5.33, 95％ CI: 1.93-14.70; P = 0.001) remained risk factors for thrombosis in MPN patients. In the subgroup analysis of ET and PV patients, univariate analysis was performed for the parameters, and factors with differences were used as covariates for further multivariate analysis. In ET patients, multivariate analysis showed that TET2 mutation and a history of remote thrombosis were independent risk factors for thrombosis in ET patients, with an HR of 4.1 (95% CI: 1.40-12.01; P = 0.01) for TET2 mutation and 6.89 (95% CI: 1.45-32.68; P = 0.015) for history of remote thrombosis (Table 1). In PV patients, multivariate analysis observed neutrophil-to-lymphocyte ratio (NLR) (HR: 4.77, 95% CI: 1.33-17.16; P = 0.017) and a history of remote thrombosis (HR: 1.67, 95% CI: 1.03-1.32; P = 0.014) as independent risk factors for thrombosis, however, no association of TET2 mutation with thrombosis was observed in PV (Table 1). Among 125 patients, TET2 mutations were detected in 15 patients (9 ET and 6 PV), with a mutation rate of 12%. Among them, 11 patients combined with JAK2V617F mutation (6 ET and 5 PV), 2 ET patients combined with CALR mutation and 1 ET patient combined with ASXL1 mutation. Two loci mutations of TET2 were detected in one patient with PV. The details of the 15 MPN patients with TET2 mutation are shown in Table 2. Our study above have shown that TET2 mutation is an independent risk factor for thrombosis in ET patients, and to understand their clinical characteristics and coagulation status, we compared the clinical characteristics and coagulation function of TET2 mutated and unmutated patients. We found that the age of ET patients with TET2 mutation was significantly higher than that of patients without TET2 mutation (P < 0.05) . In terms of coagulation function, compared with ET patients without TET2 mutation, patients with TET2 mutation were in a relatively hypercoagulable state, as evidenced by a significant increase in D-Dimer (P < 0.01) and a significant decrease in antithrombin Ⅲ (AT-III) (P < 0.05). Conclusion TET2 mutation is an independent risk factor for thrombosis in ET patients, but no such association was observed in PV. Therefore, TET2 mutation is more valuable in predicting thrombosis in ET patients compared to PV. ET patients with TET2 mutation were older and in a relatively hypercoagulable state of coagulation compared to TET2 unmutated patients. However, prospective studies with more patients are needed to validate our results and to fully elucidate the association. Our study reports risk factors for thrombosis in MPN patients in Asia and complements the data on the relationship between non-driver mutations and thrombotic events in Asian MPN patients, providing a reference for future larger studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Thrombotic and Infectious Complications in Patients with Autoimmune Hemolytic Anemia: A Multicenter Observational Study

Autoimmune hemolytic anemia (AIHA) is a rare disease due to autoantibodies directed against erythrocyte epitopes. The clinical course is greatly heterogeneous with different anemia severity at onset, occurrence of relapses and AIHA-related complications. The latter include thrombosis and infections that represent major causes of morbidity and mortality in this patient population. Predictors of such complications and preventive measures are object of active investigation. In this observational retrospective study the occurrence of infections and thrombosis was evaluated among 180 AIHA patients from 9 Italian hematologic centers. Events' severity was graded according to CTCAE and association with AIHA type, hematologic parameters and therapies was analyzed. Anti-thrombotic and anti-infectious prophylaxis were also collected. As shown in table 1, patients were mainly middle aged females, AIHA type was consistent with known epidemiology (53% warm, wAIHA; 35% cold, cAIHA; 8% mixed and atypical cases), and 10 patients suffered from Evans syndrome (ES, association of AIHA with immune thrombocytopenia/neutropenia). Thrombotic events occurred in 35 cases (19%), mainly in wAIHA and mixed/atypical cases (25 versus 11%, p=0.02), and more often interested the venous district (83%) and were grade 3 pulmonary embolism in 62% of cases. Arterial episodes were rare but mainly grade 4 and included 4 myocardial infractions, 1 stroke, and 1 retinal artery occlusion. All arterial episodes occurred in wAIHA patients (p=0.02). Notably, nearly all patients were on active steroid treatment at the time of thrombosis, likely related to active hemolysis. Among the 4 previously splenectomized patients 3 experienced thrombosis. No relationship were noted with baseline hematologic values. Interestingly, only 15% of cases had received primary thromboprophylaxis mainly with low molecular weight heparin, and none of them experienced thrombosis. Regarding infections, 49 grade >2 events (27%) were registered mainly bacterial or viral, and rarely fungal. Five grade 4 and 1 fatal SARS-CoV-2 pneumonia. At the time of infection, 2/3 of patients were on active AIHA treatment either with steroids (33%) or rituximab (17%), and 40% with more than 1 agent. No statistically significant associations were noted among infections and AIHA type, baseline hematologic values, ongoing therapy, nor previous splenectomy, but for a higher trend of events among ES patients. Cotrimoxazole and acyclovir prophylaxis had been administered in one fourth of cases, mainly upon rituximab treatment or use of cytotoxic immunosuppressors. In conclusion, these data confirm a remarkable prevalence of thrombotic and infectious complications in AIHA patients and suggest that current prophylactic measures, performed in a small fraction of cases only, should be implemented. Interestingly, thrombotic episodes were mainly high grade and more frequent in patients with wAIHA and mixed/atypical cases, usually showing more severe anemia at onset; the association with active steroid treatment suggests a link to active hemolysis as a risk factor for thrombosis. Although no predictors of infections emerged, the association with previous therapy lines more than with actual AIHA treatment deserves further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ASXL1 Is a Risk Factor for Thrombosis in Polycythemia Vera

Objective To explore the risk factors of thrombosis in PV patients and establish the prognostic model of thrombosis in PV patients. Methods The clinical data of 1004 PV patients who were treated in the Second Hospital of Tianjin Medical University from September 2017 to May 2022 were retrospectively analyzed. Kaplan-Meier survival analysis and Cox multivariate analysis were used to analyze the risk factors of thrombosis in PV patients and the thrombosis prognosis model. Results Among the 1004 PV patients, 473 patients (47.1%) developed thrombosis, and 54.8% of the patients developed thrombosis after PV was diagnosed. Thrombosis occurred in 68.4% of patients with ASXL1-mutant PV. Cox multivariate analysis showed that: age≥60 years (P=0.004, HR=1.608, 95%CI[1.168,2.213]), JAK2V617F allele burden (V617F%)≥50% (P=0.04, HR=1.396, 95%)CI[1.015, 1.920]), history of thrombosis (P<0.0001, HR=2.115, 95%CI[1.501,2.980]), at least one cardiovascular risk factor (P<0.0001, HR=1.851, 95%CI[1.310],2.615]) is a risk factor for thrombosis in PV patients. According to the results of Cox multivariate analysis, each risk factor was assigned 1 point, and a prognostic model of PV thrombosis was established. The incidence of thrombosis in the low-risk group (0 points), intermediate-risk group (1 point) and high-risk group (≥2 points) were 70.3%, 34.9%, and 19.7%, respectively. Conclusion Patients with ASXL1-mutated PV are at increased risk of thrombosis. The prognostic model of thrombosis in PV patients established by age≥60 years, V617F% ≥50%, history of thrombosis, and at least one cardiovascular risk factor can effectively predict thrombosis in PV patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk Factors for Thrombosis in Patients Aged > 60 Years with Essential Thrombocythemia without Previous Thrombotic Events

Risk Factors for Thrombosis in Patients Aged > 60 Years with Essential Thrombocythemia without Previous Thrombotic Events

Clinical Features and Outcomes of Pre-Fibrotic Primary Myelofibrosis Patients with Triple-Negative, JAK2V617F and Calr Mutations

The 2016 WHO classification recognized pre-fibrotic primary myelofibrosis (pre-PMF) as a distinct entity. However, little is known about the clinical characteristics and prognosis of pre-PMF patients with JAK2V617F mutations, CALR exon 9 mutations, and triple-negative (TN) mutations. Thrombotic prognostic model specific for pre-PMF is still lacking and the applicability of International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET-thrombosis) needs further validation in pre-PMF patients. We conducted a retrospective study of 168 pre-PMF patients defined by 2016 WHO diagnostic criteria in the First Affiliated Hospital of Zhejiang University School of Medicine and the Fourth Affiliated Hospital of Zhejiang University School of Medicine (ChiCTR2200061208). We retrospectively evaluated the clinical characteristics, prognosis of hemorrhage and thrombosis, and the evolution risk to overt-PMF and acute leukemia in 168 pre-PMF patients. We also assessed the risk factors for thrombosis events and validated the availability of IPSET-thrombosis scoring system in pre-PMF patients. Among 168 pre-PMF patients, 98 (58.3%) harbored JAK2V617F, 22 (13.1%) CALR and 2 (1.2%) MPL mutations; 46 (27.4%) patients were negative for all three mutations. Compared to JAK2V617F-mutated cases, TN pre-PMF patients were younger (P<0.001), had fewer constitutional symptoms (P=0.003), lower white blood cell count (WBC) (P=0.01), hemoglobin level (HB) (P=0.007), mean platelet volume (MPV) (P=0.03), hematocrit value (HCT) (P=0.045), red blood cell distribution width (RDW) (P<0.001) and lactic dehydrogenase (LDH) (P=0.021). They also had fewer thrombotic events (1, 2.2%) compared to JAK2V617F group (25, 26.3%) and CALR group (5, 22.7%) during the follow-up and at diagnosis (P<0.001) (Figure A). A proportion of 7.1% and 18.2% progressed to overt-PMF in JAK2V617F and CALR group, respectively, while no TN pre-PMF patients developed overt-PMF progression (0, 0.0%) (P=0.015) (Figure B). We also found, although not statistically significant, a lower incidence of hemorrhagic events (2% vs. 12%) and acute leukemia (2% vs. 5%) in TN pre-PMF groups compared with JAK2V617F pre-PMF groups (Figure C, Figure D). As for risk factors for thrombosis, univariable analysis found thrombosis was associated with constitutional symptoms (P=0.003), thrombosis history (P<0.001), smoking status (P=0.007) and JAK2V617F mutations (P=0.008). Patients with higher HB (P=0.013), MPV (P=0.042) and HCT (P=0.040) were also more likely to develop thrombotic events. In multivariable analysis, smoking history (P=0.036; HR 0.902, 95% CI 0.05-0.212), higher HB value (P=0.048; HR 1.336, 95% CI 1.001-1.156) and thrombosis history (P=0.001; HR 0.313, 95% CI 0.009-0.053) had negative impact on the development of thrombosis events (Figure E). When divided by HB value with cut-off point of 144.5, subjects with HB value <144.5 g/L were less likely to develop thrombosis events compared to ≥144.5 g/L (P=0.003) (Figure F). And subjects with no history of smoking were less likely to develop thrombosis events compared to subjects with a history of smoking (P=0.004) (Figure G). We also validated IPSET-thrombosis scoring system in pre-PMF patients, results showed significant statistical difference among very low-, low-, intermediate- and high-risk groups (P<0.001) (Figure H). In conclusion, TN pre-PMF patients were younger, had fewer constitutional symptoms, lower WBC, HB, MPV, HCT, RDW and LDH, and less likely to develop thrombotic events and overt-PMF compared to JAK2V617F and CALR groups. TN pre-PMF patients with smoking history, higher HB and thrombosis history had higher risks of thrombosis events. And IPSET-thrombosis scoring system was applicable in stratifying thrombosis risks of pre-PMF patients. Acknowledgment: The research was supported by the Key R&D Program of Zhejiang, No. 2022C03137; Public Technology Application Research Program of Zhejiang, China, No. LGF21H080003; the Key Project of Jinhua Science and Technology Plan, China, No. 2020-3-011; the 2019-2022 Key Medical Discipline (Hematology) Fund of Jinhua, China. Correspondence to: Dr Jian Huang, Department of Hematology, The First Affiliated Hospital of Zhejiang University School of Medicine. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prevalence of the JAK2V617F Mutation in Patients with Ischemic Stroke

Introduction: Patients with the Philadelphia negative myeloproliferative neoplasms (MPN) have an increased risk of thromboembolic events, ischemic cerebrovascular events in particular. The somatic mutation JAK2V617F is associated with MPN with a prevalence of 96% in polycythemia vera (PV), 55% in essential thrombocythemia (ET), and 65% in primary myelofibrosis (PMF). The JAK2V617F mutation is found to be an independent risk factor for thrombosis in patients with MPN. However, whether the JAK2V617F mutation is a risk factor for arterial thrombosis in the absence of an MPN diagnosis is still uncertain. The sensitivity of the assay used for detection is crucial when assessing the presence of the JAK2V617F mutation. A higher sensitivity enables detection of lower allele burdens. This is illustrated by the varying prevalences (0.1-3.1%) in background population studies. In the Danish population study GESUS of approximately 20.000 individuals, the JAK2V617F mutation was detected by droplet digital PCR (ddPCR) with an assay sensitivity of 0.009%. The GESUS study found a JAK2V617F prevalence of 3.1%. Similarly, prevalence studies of JAK2V617F mutation in stroke have varying detection limits from 0.01-5% mutant alleles. The vast majority of these studies are retrospective studies in younger subpopulations of stroke patients. We aimed to investigate the prevalence of the JAK2V617F mutation in a prospective design of consecutively enrolled unselected patients with ischemic stroke or transient ischemic attack by the highly sensitive ddPCR. Method: We recruited 90 consecutive patients with ischemic stroke or transient ischemic attack during admission at the Department of Neurology, Zealand University Hospital, Denmark. A blood sample was taken within 7 days of the onset of symptoms and screened for the JAK2V617F mutation by ddPCR. Patients unable to give informed consent were excluded from the study. Results: Out of 90 patients (mean age 71, range 46-92; female 37%) with ischemic stroke or transient ischemic attack, the JAK2V617F mutation was found in 11 patients (12.2%). Allele burdens ranged from 0.0021 to 24. All 11 patients suffered an ischemic stroke. Six out of 11 patients with the JAK2V617F mutation had elevated blood cell levels i.e. erythrocytosis, thrombocytosis, and/or leukocytosis at the time of recruitment. Only three patients had continuously elevated blood cell levels after 1 month. Patient no. 6 with a JAK2V617F mutation allele burden of 34% had blood cell levels meeting the diagnostic criteria for MPN and was diagnosed with ET. Patient no. 2 had a JAK2V617F allele burden of 14% and increased levels of hemoglobin and platelet count, which both normalized spontaneously after 1 month. The patient was referred for a hematological workup and was found to have mild splenomegaly and a bone marrow biopsy showing myeloproliferative features. In light of the normal blood cell parameters, patient no. 2 was diagnosed with MPN-U. The patients with a JAK2V617F mutation are presented in table 1. Additional data will be presented at ASH. Conclusion and implications: The present study reveals a JAK2V617F mutation prevalence (12.2%) in a stroke population that is substantially higher compared to the background population (GESUS) in the same region of Denmark, using the same assay. The GESUS study showed a JAK2V617F mutationprevalence of 3.1% and for individuals above age 60 a prevalence of 4.1%. Given the fact that the JAK2V617F mutation is present in patients with and without cytosis, our results highly suggest that the JAK2V617F mutation per se is a thrombogenic factor in ischemic stroke. This calls for an exploration of the pathophysiological mechanisms and potential treatments to prevent future thrombotic events in individuals with and without cytosis. Table legend: Clinical and paraclinical characteristics of ischemic stroke patients with the JAK2V617F mutation. IS, ischemic stroke; TIA, transient ischemic attack; HTN, hypertension; HLP, hyperlipidemia; AF, atrial fibrillation; IHD, ischemic heart disease; DM2, diabetes mellitus type 2; Hb, hemoglobin; PLT, platelet count; WBC, white blood cells. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Unbiased Identification of Thrombosis Risk Factors in Polycythemia Vera (PV) Using Machine Learning and Rich Data from Automated Extraction of Medical Records Generates Dynamic Models Highly Predictive for Thrombosis in PV

Background: Thrombosis is a leading cause of early morbidity and mortality in patients (pts) with polycythemia vera (PV)1. Thrombosis risk informs treatment decisions in PV but current risk stratification relies upon two non-modifiable factors - Age(</≥ 60) and thrombosis history (hx)2 - thereby offering no potential to monitor changes in risk. We used a rich dataset and machine learning (ML) methods to identify clinically available data useful for dynamic prediction of individualized thrombosis risk in PV. Methods: Under Weill Cornell Medicine (WCM) institutional board approval, we identified in our research repository (RDR) 470 eligible pts with PV diagnosis (Dx) and annotated thrombosis outcomes, as previously described3. We queried electronic medical records using our RDR, Observational Medical Outcomes Partnership, Structured Query Language, and novel workflows implemented in R and Python, to automate extraction of all available clinical data for pts at every clinical visit. Over 2100 clinical parameters were available for ~8400 hematology clinic visits yielding ~1.4 million data elements. These data included all laboratory measures, molecular studies, pathology reports, vitals, medications and clinical hx. Data completeness varied across data types with 283 parameters available in >90% of visits for all pts. In total, 292 parameters with over 50% availability were assessed while others were excluded from analysis. Multivariate imputation by chained equations (MICE) was used to impute missing data. To address potential artifacts from imputation, all analyses were performed on 10 separately imputed datasets and results were aggregated. AutoGluon infrastructure was used to identify the best performing ML algorithms. We then used our dataset to train random forest (RF) ML models that classify, at each clinic visit, the likelihood of thrombosis within a year. Parameters were ranked by Gini feature importance to identify a practical clinical model comprised of a few core parameters (eg 3-7) and interrogated the performance of >2x105 of these models (every combination of top 20 parameters in groups of 3-7) compared to the full model. Model performance was evaluated using the F1 score, which is considered highly predictive when >0.8. Results: Of 470 PV pts, Dx at median age of 54 (range 20-94), 64 (14%) had a thrombosis hx at Dx (8.1% venous, 6.6% arterial). Over a median follow-up of 10 years (yr), 159 thromboses occurred in 115 pts (88 venous, 71 arterial). Cumulative incidence of thrombosis was non-linear, as previously appreciated1. Annual incidence rate (IR) of thrombosis was higher shortly after diagnosis (IR of 4.4% vs 1%, 2yr cutoff), and following a thrombotic event (IR of 9.7% vs 1.8%, 2 yr cutoff). Consistent with this observation, ML models identified time from Dx, and time from prior thrombosis among the top 20 most predictive parameters as assessed by Gini feature importance (Figure 1). Most predictive parameters also included risk factors previously implicated in PV thrombosis (age, blood counts, JAK2 allele burden) as well as known thrombosis risk factors under-recognized in PV (blood type4, BMI, creatinine), and parameters not previously thought to contribute to thrombosis risk (MCV, uric acid, LDH). The full ML model was highly predictive of thrombosis with an F1 of 0.82 (Figure 2). We then identified simplified models (combinations of 4-5 variables) that performed similarly to the full model with an F1 > 0.8. One example combines age, time since Dx, time since prior thrombosis, and BMI. These models are being validated against external datasets and an online risk calculator will be developed. Discussion: We used ML and deep datasets for unbiased identification of the clinical parameters most predictive of near-term thrombosis risk in PV pts. These models address dynamic changes to patient risk due to intrinsic factors (e.g. age, blood type), life events (e.g. time since Dx/thrombosis) and clinical changes (e.g. ANC, BMI) that can be used to tailor risk mitigation strategies. Validation of models with at least core variables of age, time since Dx, time since prior thrombosis, and BMI against external datasets would likely establish a universal model to dynamically predict individualized risk of thrombosis in PV pts. References 1 Hultcrantz. et al. Ann Intern Med. 2018 2 Barbui T, et al.Leukemia 2018 3 Abu-Zeinah G, et al. Leukemia 2021 4 Groot H, et al. Arterioscler Thromb Vasc Biol 2020 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal