The Interaction between IPSS Score and JAK2 Mutation Identifies Patients at Different Vascular Risk in Primary Myelofibrosis

BACKGROUND The rate of major arterial and venous thrombosis in primary myelofibrosis (PMF) and post-ET (PET) and post-PV (PPV) secondary myelofibrosis has been evaluated in a limited number of studies. In the present paper we describe the clinical epidemiology of thrombosis in a large series of patients with overt PMF and PPV/PET MF looking at the rate and risk factors. Moreover, we report findings on thrombosis rate in two cohorts of patients treated with Hydroxyurea (HU) or Ruxolitinib (Ruxo). METHODS Patients were registered in the European Registry for Myeloproliferative Neoplasms (ERNEST). This project, promoted by the European LeukemiaNet, is coordinated by FROM - Foundation for Research, Papa Giovanni XXIII Hospital, Bergamo (Italy) and supported by Novartis through a research collaboration . Patients were diagnosed in 6 Centers from Italy, Spain and Sweden, between Jan, 2001 and Dec, 2012, with the required follow-up information. Patients (n= 1010) with PMF (n=584, 59%), PET-MF (n=207, 20%) and PPV-MF (n=219, 21%) were evaluated for incident thrombosis as primary endpoint. Considering death as a competitive event, uni-and multivariate analyses were performed by applying Fine & Gray competing-risk regression models. RESULTS After a median follow-up of 3.8 years (IQR: 1.8-7.1) from diagnosis, 108 thromboses (10.7%) occurred, for an overall incidence rate of 2.0% pts-yr (95% CI: 1.7-2.5). Arterial thromboses were found in 50 patients (46.3%) including cerebral (n=21, 19.4%), myocardial infarction (n=13, 12.0%) and peripheral events (n=9, 8.3%). Venous thromboses were 58 (53.7%), of which 25 (23.0%) were DVT ± PE and 11 (10.2%) were splanchnic. Thrombosis rate was 1.91, 1.60 and 2.79% pts-yr in PMF, PET-MF and PPV-MF, respectively. In univariate analysis, factors significantly associated with an increased thrombotic risk in PMF were age (p=0.013) and the presence of the JAK2 mutation (p=0.003); in addition, a significant higher proportion of PMF patients at low and intermediate-1 vs intermediate-2 or high risk IPSS score, had thrombosis during the follow-up (p=0.008). In multivariate analysis, only JAK2 mutation retained statistical significance (SHR=3.12, 95% CI: 1.40-6.94, p=0.005). Conversely, neither in univariate nor in multivariable analysis, significant risk factors were not found.To investigate the possible interaction of IPSS score and JAK2 mutation we created a model whose results are presented in Fig. 1A: the cumulative incidence function (CIF) of thrombosis was significantly lower in patients with JAK2 wild-type and intermediate-2 or high IPSS score (CIF: 4% projected at 10 years; SHR=1 [reference category]), while patients at the highest risk for thrombosis harbored JAK2 mutation and were categorized at low or intermediate-1 by IPSS score (CIF: 20% projected at 10 years, SHR=7.13, p=0.008). Of note, thrombosis had a significant impact on mortality. After adjusting for sex, age, year of diagnosis, type of MF and IPPS, HR was 1.51, (95% CI. 1.15-1.98, p=0.003).The influence of drug exposure to incident thrombosis was investigated in two cohorts of 559 consecutive patients exposed to HU (n=470) or to Ruxo (n=89), median treatment 2.6 and 3.0 years, respectively. HU- compared to Ruxo-treated patients were older (median age 67 vs. 63 years, p=0.001), more frequently triple negatives (12% vs. 2%, p=0.036), less splenomegalic (spleen length >10 cm: 30% vs. 88%, p <.001) and less symptomatic (49% vs. 79%, p=0.031). Of note, median time from MF diagnosis to therapy start in Ruxo group was 4 years, whereas patients started HU at MF diagnosis. In 56 of 89 Ruxo-treated patients (62.9%), the drug was given after a prior HU therapy. The thrombosis rate from the time of initiation of therapy was 2.40% pts-yr (95% CI 1.78-3.24) under HU and 1.28% pts-yr (95% CI 0.48-3.41) under Ruxo (CIF curves in Fig. 1B). In multivariate analysis corrected for MF type, DIPPS at first drug administration, JAK2 mutation and time from MF diagnosis, exposure to Ruxo showed a non-significant trend towards a protection of approximately 70% compared to HU (SHR=0.33, 95% CI: 0.08-1.32, p=0.117). CONCLUSION IPSS score, in addition to the survival risk assessment, may be useful, if associated with the JAK2 mutation, to recognize patients at vascular risk and to suggest appropriate anti-thrombotic prophylaxis. The trend towards a benefit of Ruxo, compared to HU, warrants a study in larger case series. Figure 1 Figure 1. Disclosures Barbui: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Vannucchi: Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures.

Efficacy of repeated intravenous tranexamic acid in reducing perioperative bleeding of acetabular fractures

BACKGROUND: Application of tranexamic acid (TXA) in the treatment of acetabular fractures could reduce intraoperative and postoperative blood loss. OBJECTIVE: To investigate the effect of single and repeated intravenous infusion of TXA on blood loss of acetabular fractures. METHODS: 120 patients with acetabular fractures admitted to our hospital from January 2017 to September 2020 were retrospectively divided into three groups: Patients accepted 1g TXA at preoperative 30 minutes were defined as single TXA group (n = 40); Patients accepted 1g TXA at preoperative 30 minutes and 1g TXA at 3 hours after the start of surgery were defined as repeated TXA group (n = 40); Patients accepted normal saline at preoperative 30 minutes were defined as control group (n = 40). RESULTS: The total blood loss in single TXA group and repeated TXA group were significantly lower than control group, and the total blood loss in the repeated TXA group was significantly lower than single TXA group (P < 0.05). The hidden blood loss from surgery to postoperative 1 day in repeated TXA group was significantly lower than single TXA group and the control group(P < 0.05). No significant differences were observed in the operative time, postoperative transfusion rate and thrombosis rate among the three groups (P > 0.05). CONCLUSION: Repeated TXA is more recommended during acetabular fracture surgery since it can reduce the total blood loss without increasing the operative time, postoperative transfusion rate and thrombosis rate compared with single TXA.

Platelet count rose while D-dimer levels dropped as deaths and thrombosis declined, an observational study on anticoagulation shift in COVID-19

Background: High levels of D-dimer and low platelet counts are associated with poor outcome in COVID-19. As anticoagulation appeared to improve survival, hospital-wide recommendations regarding higher doses of anticoagulation was implemented 4/9/2020. Objectives: To investigate if trends in D-dimer levels and platelet counts associated with death, thrombosis, and the shift in anticoagulation. Methods: Retrospective cohort study of 429 patients with COVID-19 at Karolinska University Hospital. Information on D-dimer levels and platelet counts was obtained from laboratory databases and clinical data from medical records. Results: Thirty-day mortality and thrombosis rate was 19% and 18%, respectively. Pulmonary embolism was common; 65/83 (78%). Increased D-dimer levels the first week in hospital were significantly associated with death and thrombosis (OR 6.06; 95% Cl 2.10–17.5, and 3.11; 95% CI 1.20–8.10, respectively). If platelet count increased more than 35×109/L per day, the mortality and thrombotic risk decreased (OR 0.16; 95% CI 0.06–0.41, and OR 0.36; 95% CI 0.17–0.80). After implementation of updated hospital-wide recommendations, the daily mean significantly decreased regarding D-dimer levels while platelet counts rose; -1.93; 95% CI -1.00–2.87 mg/L FEU and 65; 95% CI 54–76 ×109/L and significant risk reductions for death and thrombosis were observed; OR 0.48; 95% CI 0.25–0.92 and 0.35; 95% CI 0.17–0.72. Conclusions: In contrast to D-dimer levels, increase of platelet count over the first week in-hospital was associated with improved survival and reduced thrombotic risk. The daily mean levels of D-dimer dropped while the platelet counts rose, coinciding with increased anticoagulation and a decline in thrombotic burden and mortality.

WoundClot® Hemostatic Gauze Reduces Bleeding Time after Arterial Venous Fistula Decannulation

<b><i>Introduction:</i></b> Decannulation of the arteriovenous fistula (AVF) after each hemodialysis session requires a precise compression on the needle puncture site. The objective of our study was to evaluate the bleeding time (BT) needed to achieve hemostasis using WoundClot, an innovative hemostatic gauze, and to assess whether its long-term use can improve AVF preservation. <b><i>Methods:</i></b> This is a prospective single center study. Initially, the time to hemostasis after AVF decannulation was compared between WoundClot and cotton gauze in 24 prevalent hemodialysis patients. Thereafter, the patients continued to use WoundClot for 12 months and were compared to a control group consisting of 25 patients using regular cotton gauze. Follow-up data included parameters of dialysis adequacy, AVF interventions, and thrombotic events. <b><i>Results:</i></b> WoundClot use shortened significantly the time needed for hemostasis. Mean venous BT decreased by 3.99 (±4.6) min and mean arterial BT by 6.38 (±4.8) min when using WoundClot compared to cotton gauze (<i>p</i> &#x3c; 0.001). At the end of the study, dialysis adequacy expressed by spKt/V was higher in the WoundClot group compared to control (1.73 vs. 1.53, respectively, <i>p</i> = 0.047). Although patients in WoundClot group had a higher baseline BT, arterial and venous pressures did not differ between the groups after a median follow up of 10.8 months. AVF thrombosis rate was similar between the groups. <b><i>Conclusions:</i></b> WoundClot hemostatic gauze significantly reduced the time required for hemostasis after AVF decannulation and may be associated with better AVF preservation. We suggest using WoundClot for arterial BT longer than 15 min and for venous BT longer than 12.5 min.

Effect of Pre-Procedure Clopidogrel With Iliac Vein Stenting in Non-Thrombotic Vein Lesions

Objectives: Iliac vein stenting is a relatively new procedure in the treatment of chronic venous insufficiency. Research has shown that it is a safe and effective form of treatment, however, one of the well-known risks is in-stent thrombosis. We hypothesize that a single 75 mg dose of Clopidogrel the night prior to the procedures along with a 3-month regimen post-op would decrease the 30-day thrombosis rate. Methods: A retrospective study was performed on 3,518 patients from September 2012 to August 2018 who received an iliofemoral stent. Patients were broken down into 2 main groups: those given Clopidogrel post-stent and those given Clopidogrel both pre- and post-stent. In our practice, we prescribe a 3-month course of Clopidogrel after iliac vein stenting. Patients were also checked for any anticoagulant medications pre- and/or post-stent. The 30-day thrombosis rates were recorded for each patient. Results: 1,205 patients received Clopidogrel pre-procedurally and post-procedurally, 1,941 patients received Clopidogrel only post-procedurally. 372 patients were excluded from the study because they were on other anti-coagulant medications. Mean follow-up for this cohort was 17 months. 112 total patients developed some degree of 30 day in-stent thrombosis (3.6%). 74 patients developed a complete thrombosis of the stent and 38 developed a partial (≤60% occlusion) thrombosis. Of the 1,205 patients who were on clopidogrel pre-stenting, 28 had a complete thrombosis and 10 had a partial in-stent thrombosis. Of the 1,941 patients on Clopidogrel only post-stenting, 46 had a complete thrombosis and 28 had a partial in-stent thrombosis. Using the Chi-squared test, there were no statistically significant differences between the group of patients receiving Clopidogrel pre- and post-stent vs. just post-stent with respect to 30-day any degree of thrombosis rates (complete and partial thrombosis) (p = .33). Using the Chi-squared test, there were no statistically significant differences between the group of patients receiving Clopidogrel pre- and post-stent vs. just post-stent with respect to 30-day complete thrombosis rates (p = .93). Conclusions: There appears to be no statistical difference in 30-day thrombosis rates between those receiving Clopidogrel the night prior vs. those who do not receive Clopidogrel the night prior. Therefore, we conclude that it is not necessary to give this single dose the night prior to iliac vein stenting procedures.

Proximal Trauma Increases Risk of Venous Thrombosis in Soft Tissue Reconstruction of Open Lower Limb Fractures

Lower limb salvage after major trauma is a complex undertaking. For patients who have suffered multi-level trauma to their lower limb we postulated that pelvic injury or ipsilateral lower limb injury proximal to the site of a free flap may increase the rate of post-operative complications. All patients who underwent lower limb free flap reconstruction as a result of acute trauma between January 2010 and December 2017 were included. The patients were divided into the study group (50 patients), who sustained a lower limb or pelvic injury proximal to the free flap site, and control group (91 patients) who did not sustain proximal lower limb or pelvic trauma. Complication rates were compared between the two groups. Overall, the proximal trauma group anastomotic thrombosis rate of 18.0% was significantly higher than the control group thrombosis rate of 2.2%. There was no statically significant difference in rates of hematoma, swelling or infection. Flap loss rate in the proximal trauma group was 4.0%, compared to the control group at 2.2%. All patients with a failed flap went onto have a successful reconstruction with a subsequent flap in the acute admission and there were no amputations. In the proximal injury study group despite the significantly increased rate of microvascular thrombosis requiring revision, the ultimate primary free flap survival rate was still 96%. Overall, severe coexisting proximal trauma predicted a higher venous microvascular complication rate but was not a contraindication to limb salvage.

Clinical Characteristics Associated With Higher Enoxaparin Dosing Requirements for Venous Thromboembolism Prophylaxis in Trauma Patients

Introduction Enoxaparin dosed by an anti-Xa trough level is effective at reducing venous thromboembolism (VTE) in trauma patients. We identified the patient characteristics associated with higher enoxaparin dosing based on anti-Xa trough levels. Methods A retrospective review was conducted on trauma patients admitted between August 2014 and February 2018 who received enoxaparin dosed by the anti-Xa trough level. Patients who received enoxaparin < 50 mg every 12 hours were compared to those who required ≥ 50 mg every 12 hours. Results Of the 246 patients included, 32 (13.0%) required enoxaparin ≥ 50 mg every 12 hours to achieve the prophylactic trough level. Factors associated with a higher dose of enoxaparin were male (96.8% vs. 3.2%, P < .01), younger age (39.5 vs. 52.7 years, P < .01), higher creatinine clearance (CrCl) (125.9 vs. 93.7 mL/min, P < .01), higher body surface area (2 m2 vs. 1.8 m2, P < .01), and higher injury severity score (18.4 vs. 10.8, P < .01). Height, weight, and body mass index were not significant factors. On regression analysis, CrCl was the only independent predictor for higher enoxaparin dose. There was an increased deep venous thrombosis rate in the higher dose cohort (12.5% vs. 0, P < .01) but no significant differences in transfusion rates. Conclusion Trauma patients who require higher enoxaparin doses to achieve prophylactic anti-Xa trough levels have a higher CrCl. Patients with high CrCl may benefit from an initial higher dose of enoxaparin to achieve a target anti-Xa level in a shorter time interval to decrease VTE risk.

Clinical Thrombosis Rate was not Increased in a Cohort of Cancer Patients with COVID-19

Increased rates of thromboembolic events (TE) have been reported in patients with coronavirus disease (COVID-19), even without prior predisposition to thrombosis. D-dimer levels have been shown to positively correlate with disease severity and mortality, leading to adoption of new empiric anticoagulation protocols by many centers. We aimed to assess whether COVID-19 further increased the risk of TE events in a cancer population who tested positive for COVID-19 at Montefiore Medical Center, Bronx, NY. The electronic medical records of 218 cancer patients were retrospectively reviewed up to April 10th, 2020. Work-up of thrombosis was done by the primary team upon clinical or laboratory suspicion. All imaging studies' reports, within 20 days of COVID-19 positive test, were reviewed for presence of new arterial or venous thrombosis. Mortality was assessed up to one month since positive COVID-19 test result. Twelve patients (5.5%) were found to have new arterial (N=6, 50%) or venous (N=6, 50%) thrombosis. Five patients (41.7%) had history of prior TE events. Incidence of deep venous thrombosis and pulmonary embolism was 1.8% and 0.5%, respectively. Arterial events occurred in the brain (66.7%), aorta (16.7%) and coronary arteries (16.7%). Median time from COVID test was 8 days (IQR, 1.5 - 11.3). Five patients (41.7%) had received either prophylactic or therapeutic anticoagulation for a median 2 days (IQR, 1 - 5). Median peak D-dimer within 36 hours of the TE event was 9.8 mcg/mL (N=4 patients, IQR, 1.7 - 18.3). Mortality did not differ significantly between the patients with new TE events vs those without; mortality 41.7% vs 37.4%, respectively, p=0.77. Empiric anticoagulation did not improve mortality. Fifty percent of all TE events were arterial. The overall TE rate of 5.5% in the cancer population was not higher than the risk of general population. Our findings support the need for larger studies in the COVID-19+ cancer population.