Prophylactic Doses Of Low Molecular Weight Heparin Research Articles

Is early bilateral compression ultrasonography and D-dimer monitoring appropriately for prophylaxis and diagnosis of deep venous thrombosis after cesarean section women: a single-center observation study of Chinese Han population

BackgroundVenous thromboembolism (VTE) is most prevalent among parturients following a cesarean section (CS). The objective of this study was to assess the practical utility of bilateral compression ultrasonography (CUS) of the lower limbs, coupled with D-dimer monitoring, in the early diagnosis of VTE within the Han Chinese population.MethodsOur prospective observational study included 742 women who underwent CUS and D-dimer testing on the first day post-CS. Subsequently, telephone or outpatient follow-ups were conducted until 42 days postpartum. States of hypercoagulation and thrombosis, as indicated by CUS, were classified as CUS abnormal. A D-dimer level ≥ 3 mg/l was considered the D-dimer warning value. Early ambulation and mechanical prophylaxis were universally recommended for all parturients post-CS. A sequential diagnostic strategy, based on the 2015 RCOG VTE risk-assessment tool, was employed. Therapeutic doses of low-molecular-weight heparin (LMWH) were administered for the treatment of thromboembolic disease. Prophylactic doses of LMWH were given for VTE prophylaxis in parturients with hypercoagulative status accompanied by D-dimer levels ≥ 3 mg/l. All high-risk women (RCOG score ≥ 4 points) were additionally treated with preventive LMWH. Statistical analyses were conducted using the R statistical software, with a two-sided P value < 0.05 considered statistically significant.ResultsFifteen cases of VTE and 727 instances without VTE were observed. The overall VTE rate post-CS was 2.02% (15/742), with 66.7% (10/15) being asymptomatic. Eleven patients received a VTE diagnosis on the first postpartum day. Among the 41 parturients exhibiting hypercoagulation ultrasound findings and D-dimer levels ≥ 3 mg/l, despite receiving pharmacological VTE prophylaxis with LMWH, 4.88% (2/41) in the high-risk group were eventually diagnosed with VTE. A total of 30.86% (229/742) exhibited normal ultrasound findings and D-dimer levels < 3 mg/l on the first day post-CS, with no VTE occurrences in the postpartum follow-up. According to RCOG’s recommendation, 78.03% (579/742) of cesarean delivery women should receive prophylactic anticoagulation, while only 20.62% (153/742) met our criterion for prophylactic anticoagulation.ConclusionThe strategy of timely routine bilateral CUS and D-dimer monitoring is conducive to the early diagnosis and treatment of VTE, significantly reducing the use of LMWH in the Chinese Han population.

Bleeding and venous thromboembolism events in cancer patients taking direct oral anticoagulants vs. low molecular weight heparin

IntroductionPatients with cancer have an increased risk of developing venous thromboembolism (VTE), and subsequently a higher risk of bleeding secondary to anticoagulants. Low-molecular weight heparin (LMWH) has been the standard of care for these patients, with emerging data on the use of direct oral anticoagulants (DOACs). The primary objective of the study was to determine the prevalence of major bleeding events in cancer patients taking DOACs or LMWH for VTE. Secondary objectives included the rate of first VTE recurrence and the effect of concomitant antiplatelet agents and/or significant drug interactions on major bleeding or recurrent VTE. Materials and methodsUsing the electronic medical record at the University of Rochester Medical Center, we retrospectively identified adult patients with active malignancy who had a diagnosis of VTE requiring therapeutic anticoagulation within the study period of July 1st, 2015 to June 1st, 2019. Patients were excluded if they were receiving prophylactic doses of LMWH per the institution VTE guidelines. Data on anticoagulant medications were collected as well as information on major bleeding and recurrent VTE events. Results and conclusionsThere is insufficient evidence of difference in risk of major bleeding among patients who received a DOAC vs LMWH (cause-specific hazard ratio (HR) = 0.77, 95% CI 0.29–2.04, P = 0.60). There was also no evidence of a difference in risk of recurrent VTE between patients who received DOAC vs. LMWH (cause-specific HR = 0.98, 95% CI 0.15–6.26, P = 0.98). These results suggest that DOACs are not significantly less safe than LMWH for patients with cancer.

Systematic Review and Meta- Analysis of Randomized Controlled Trials on Primary Outpatient Thromboprophylaxis (POTP) in Patients with Gastric and Gastro-Esophageal Junction (GEJ) Cancers Receiving Chemotherapy

Introduction: Advanced gastric cancer is demonstrated as a highly thrombogenic cancer where the score of 2 is assigned per Khorana score (KS). POTP is currently suggested to patients with KS of 2 and above by recent clinical practice guidelines. We conducted an updated meta-analysis to evaluate the benefit of POTP with low-molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) in patients with gastric and gastro-esophageal junction (GEJ) cancers receiving chemotherapy. Methods: Comprehensive literature across MEDLINE and EMBASE databases were searched from inception through June 30, 2022, using search terms 'thromboprophylaxis’ OR 'anticoagulation’ OR 'low-molecular-weight heparin’ OR 'direct oral anticoagulants’ AND 'stomach cancer'/ 'gastro-esophageal junction cancer'. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). I2 statistic and Cochran's Q- statistic were used to assess heterogeneity among the studies. Results: A total of 631 patients with gastric and GEJ cancers from a subgroup of three RCTs were included. The prophylactic doses of LMWH and DOAC (rivaroxaban and apixaban) were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 1 to 1 in all studies. The I2 statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 5 (1.6%) in PATP group and 10 (5.1%) in control group with a RR of 0.31 (95% CI: 0.11 to 0.83, P = 0.02). The absolute RD was -0.05 (95% CI: -0.14 to 0.03, P= 0.23) with an estimate of the number needed to treat (NNT) of 29 to prevent one VTE event. Conclusions: POTP in gastric and GEJ cancers statistically significantly decreases VTE events, with relative risk reduction of 69% with a NNT of 29 to prevent one VTE event. Even though the ASCO and the International Thrombosis and Cancer Initiative suggested POTP in patients with gastric cancer by virtue of KS of 2, our meta-analysis findings do not support the routine use of POTP in patients with gastric and GEJ cancers receiving chemotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Presentation, Risk Factors and Outcome of Splanchnic Venous Thrombosis: A Report on 305 Cases

Background and Aims: Splanchnic vein thrombosis (SVT) is a manifestation of unusual site venous thromboembolism. Most common predisposing factors for SVT include liver cirrhosis, solid abdominal cancer, myeloproliferative neoplasms (MPN), and abdominal infection or inflammatory diseases. Complex balance between bleeding risk and the risk of thrombus extension or recurrence makes the management of SVT a clinical challenge. In this study, we reported clinical presentation and outcome data of patients with SVT followed in our center from January 2000 to December 2021, with a focus on MPN and cirrhotic patients. Methods: We performed a retrospective review of clinical reports of 305 SVT patients. According to PLT count in patients with no active bleeding, anticoagulation treatment was started as soon as possible with: no treatment for a platelet count <30.000/μl; prophylactic dose of LMWH or related drugs for a platelet count range 30.000 -50.000/μl and therapeutic dose low-molecular-weight heparin (LMWH) followed by early initiation of vitamin-K antagonist (VKA; INR range 1.8-2.5) for a platelet count >50.000/μl. Moreover, cytoreductive therapy was administered in MPN patients and prophylaxis with beta-blockers and endoscopic therapies were applied in cirrhotic SVT. Cox regression analysis was used to identify independent predictors of recanalization and overall survival. The Kaplan-Meier method was performed to estimate the overall survival and the time to reach vessel recanalization. Results: In a median follow up of 16.1 months (range, 1-346), 305 patients experienced a SVT (median age 59 years; 68.2% males). Isolated portal vein thrombosis was the most common site of thrombosis (55.1%), followed by multiple venous involvement (28.9%). Six patients developed a Budd-Chiari syndrome. SVT were associated to chronic liver disease, solid cancer and abdominal infections in 212 (69.5%), 100 (32.8%) and 34 (11.5%) patients, respectively. Ninety-seven patients had splenomegaly. MPN was identified in 38 (12.5%) patients. Among these patients, JAK2 and CALR mutation were detected in 81.6% and 13.2%, respectively, and abnormal karyotype in 10.5%. Ascites and esophageal varices were present in 47.5% and 48.8% of patients, respectively. Therapeutic decisions were taken as a multidisciplinary team, involving the use of VKA and LMWH in 70 and 163 patients, respectively. In addition, trans-jugular intrahepatic portosystemic (TIPS) or other surgical shunting was undertaken in 12% and variceal banding in 11%. In a median duration therapy of 9.6 months, bleeding complications and recanalization were reported in 9.5% and 35.4% of patients, respectively. At univariate analysis, VKA exposure was associated with a significantly lower risk of bleeding events compared to LMWH (p=0.039), while esophageal varices (p=0.049), leukocytosis at time of thrombosis (p=0.048), liver cirrhosis (p=0.010) and solid tumor (p=0.021) were associated with lack of recanalization. Only one death was attributed to fatal bleeding, whereas 76 patients died for causes not related to anticoagulation (cirrhosis, cancer, MPN evolution) with a median OS was not reached (range, 107,89-NR). Factors associated with poor survival included age (p<0.001), MPN (p=0.047), recurrent thrombosis (p=0.041), alkaline phosphatase (p=0.013), gamma-GT (p<0.001), albumin (p=0.021), MELD score (p=0.004), lack of recanalization (p<0.001), bleeding event (p=0.043), ascites (p=0.009), and antithrombotic therapy (p=0.006, Figure 1). Among MPN patients, poor survival outcome was also associated with driver mutations (p=0.034), hemoglobin level at thrombosis (p<0.001), splenomegaly (p=0.019), and cytoreductive therapy (p=0.019). Conclusions: Outcome in SVT patients mostly depends on the presence of an underlying MPN, liver failure, active bleeding, recurrence and recanalization rate. Moreover, the anticoagulant treatment was associated with a low bleeding incidence also in patients with major risk factors for bleeding (i.e. liver cirrhosis, cancer or esophageal varices). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P11.01.B Lower-extremity deep vein thrombosis and bleeding complications in primary brain tumor patients: A prospective study

Abstract Background Primary brain tumor patients have a high risk of venous thromboembolism (VTE). Bleeding risk with prophylactic and therapeutic anticoagulation is an important concern in these patients, and data on the management of asymptomatic VTE events in this population are lacking. The aim of this prospective study is to investigate risk and risk factors for asymptomatic lower-extremity deep-vein thrombosis (LE-DVT) in patients with primary brain tumors, and to estimate the rate of bleeding complications on full, prophylactic or no anticoagulation. Material and Methods We included consecutive patients with primary brain tumours undergoing surgery. Screening for asymptomatic LE-DVT by compression ultrasound (CUS) was performed pre-operatively and postoperatively within 2 months after surgery. Telephone follow-up was done 6 and 12 months after surgery. The protocol pre-specified therapeutic doses of low-molecular-weight heparin (LMWH) in case of detection of an asymptomatic LE-DVT. Results Fifty patients were included (female: 34%, median age 58 years, WHO grade IV tumors: 78%, prophylactic-dose LMWH at baseline: 12%). During a median observation period of 9.1 months, LE-DVT was detected in 9 patients (18%). LE-DVTs included two asymptomatic events (4%) at pre-operative screening, five asymptomatic events (10%) at postoperative screening, and two symptomatic events (4%, both 4-level LE-DVT) at telephone follow-up. This corresponded to a 12-month cumulative incidence of LE-DVT of 14.9% (95%CI: 6.4-26.6). At postoperative screening, n=10 patients were on prophylactic-dose LMWH, and one of these patients had an LE-DVT event detected by screening. The two patients with symptomatic LE-DVT were not on thromboprophylaxis at the time of event. Among a variety of investigated potential risk factors, only higher age (Odds Ratio (OR) per 5 years increase=1.46, 95%CI: 1.01-2.13, p=0.05), higher neurologic assessment in neuro-oncology (NANO) scale (OR per 1 point increase=1.59, 1.00-2.54, p=0.05), higher serum Galectin-3 levels (OR per 1ng/ml increase=1.20, 1.01-1.42, p=0.041) but not D-Dimer (OR per 1mg/L increase=1.89, 0.75-4.77, p=0.178) emerged as significant predictors of any LE-DVT. Six patients (12%) developed bleeding events, including n=3 operative intracranial bleedings without LMWH, n=1 spontaneous ventricular hemorrhage without LMWH, n=1 minor subcutaneous bleeding without LMWH, and 1 intracerebral hematoma during therapeutic-dose LMWH initiated for asymptomatic distal LE-DVT. Conclusion In our study we detected a high-frequency of asymptomatic LE-DVT in patients with primary brain tumours. Conversely, symptomatic LE-DVT risk was low, which may be related to prior screening. Patients with primary brain tumors appear to have LE-DVT risk factors specific to this entity. Prophylactic-dose LMWH did not show any adverse safety signals regarding bleeding.

Effect of anticoagulant and platelet inhibition on the risk of bacteremia among patients with acute pyelonephritis: a retrospective cohort study

BackgroundAn increasing number of patients are being prescribed anticoagulants and platelet inhibitors (antithrombotic treatment). Basic research has suggested an association between antithrombotic treatment and bacteremia during kidney infection. Here, we investigated the association between antithrombotic treatment, bacteremia and acute kidney injury in patients with acute pyelonephritis.MethodsA retrospective cohort study was conducted in a large university hospital in Sweden. Data were retrieved from electronic medical records for adult patients with acute pyelonephritis in 2016. The main outcome was bacteremia and secondary outcome acute kidney injury. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated through multiple logistic regression. Treatment with different groups of antithrombotic agents were compared to no antithrombotic treatment.Results1814 patients with acute pyelonephritis were included, in whom bacteremia developed in 336 (18.5%). Low-molecular-weight heparin (LMWH) at prophylactic doses was associated with a lower risk of bacteremia, compared to no antithrombotic treatment (OR 0.5; 95% CI 0.3–0.7). Other antithrombotic treatments were not associated with a risk of bacteremia. Additionally, patients with prophylactic doses of LMWH had a lower risk of acute kidney injury (OR 0.5; 95% CI 0.3–0.8).ConclusionsWe found no association between antithrombotic treatment and an increased risk of bacteremia during acute pyelonephritis. Conversely, patients with prophylactic doses of LMWH had a slightly reduced risk of bacteremia. LMWH at prophylactic doses was also associated with a lower risk of acute kidney injury. Our results suggest that it is safe to continue antithrombotic treatment during acute pyelonephritis, in regards to bacteremia and acute kidney injury risk.

Thromboprophylaxis in COVID‐19: Weight and severity adjusted intensified dosing

BackgroundVenous thromboembolism (VTE) frequently occurs in hospitalized patients with coronavirus disease 2019 (COVID‐19). The optimal dose of anticoagulation for thromboprophylaxis in COVID‐19 is unknown. AimsTo report VTE incidence and bleeding before and after implementing a hospital‐wide intensified thromboprophylactic protocol in patients with COVID‐19. MethodsOn March 31, 2020, we implemented an intensified thromboprophylactic protocol consisting of 50 IU anti‐Xa low molecular weight heparin (LMWH)/kg once daily at the ward, twice daily at the intensive care unit (ICU). We included all patients hospitalized in a tertiary care hospital with symptomatic COVID‐19 between March 7 and July 1, 2020. The primary outcome was the incidence of symptomatic or subclinical VTE and major bleeding during admission. Routine ultrasound screening for VTE was performed whenever logistically possible. ResultsWe included 412 patients, of which 116 were admitted to the ICU. Of 219 patients with standard a prophylactic dose of LMWH, 16 (7.3%) had VTE, 10 of which were symptomatic (4.6%). Of 193 patients with intensified thromboprophylaxis, there were no symptomatic VTE cases, three incidental deep venous thrombosis cases (1.6%), and one incidental pulmonary embolism (0.5%). The major bleeding rate was 1.2% in patients with intensified thromboprophylaxis and 7.7% when therapeutic anticoagulation was needed. ConclusionIn hospitalized patients with COVID‐19, there were no additional symptomatic VTEs and a reduction in incidental deep vein thrombosis after implementing systematic thromboprophylaxis with weight‐adjusted prophylactic (ward) to intermediate (ICU), but not therapeutic dosed anticoagulation. This intensified thromboprophylaxis was associated with a lower risk of major bleeding compared with therapeutic dosed anticoagulation.

Risk of Recurrent Venous Thromboembolism and Hemorrhage Following Interruption of Anticoagulation at Delivery

Background: Current guidelines for regional anesthesia advise for the discontinuation of prophylactic and therapeutic low molecular weight heparin (LMWH) 12 hours and 24 hours, respectively prior to the use of neuraxial anesthesia (NA) for obstetric patients. Re initiating a prophylactic dose 12 hours following epidural catheter insertion/spinal anesthesia (SA) and at least 4 hours following epidural catheter removal is also recommended. There are limited data on the recurrent risk of venous thromboembolism (VTE) and bleeding using these standards. We conducted a retrospective single center study to assess the risk of VTE and/or bleeding in pregnant women using these criteria.Methods: Consecutive patients from 2013 to 2018 at Mount Sinai Hospital, a university affiliated tertiary care center in Toronto, Canada who were prescribed therapeutic or prophylactic LMWH antenatally and postpartum and who had NA were included. Hospital records were reviewed to determine the indication and dosage of LMWH, presence of thrombophilia, time of first LMWH injection postpartum, the mode of neuraxial anesthesia and delivery, the time of epidural catheter/spinal anesthesia, the time of epidural catheter removal, laboratory parameters and comorbid illnesses. Patients requiring therapeutic or prophylactic LMWH were assessed in the Hematology clinic and were advised to discontinue anticoagulation according to current recommendations. The primary outcomes were frequency of VTE, spinal hematoma and volume of postpartum blood loss. Statistical Analysis: Continuous variables were summarized as medians and interquartile ranges. Categorical variables were summarized as percentages. Characteristics associated with VTE and hemorrhage were analyzed using regression analysis.Results: Of 169 pregnancies, 158 fulfilled criteria, and 110 had complete data for the time of epidural catheter removal and initiation of LMWH. Median age was 34 (IQR 5) years and median weight 90 (IQR 70) kgs. Diagnoses included antiphospholipid syndrome, Budd Chiari, provoked and unprovoked VTE. Median platelet count at delivery was 185 (IQR 76) x 10(9)/L. Thirty-three percent were using concomitant ASA antenatally. Forty-four percent (n=48) had a vaginal delivery (VD). Sixty five (59%) had epidural anesthesia, 43 (39%) had SA and, two had combined spinal/epidural anesthesia. Median time to restarting LMWH was 7.8 (IQR 4.7) hours from epidural catheter removal/spinal insertion and 9 (IQR 3.9) hours from SA. There were no spinal hematomas. Median blood loss was 500 (IQR 400) ml. One patient, who received prophylactic dose LMWH antepartum, had a Caesarean delivery, spinal anesthesia and a prophylactic dose re-started 13.7 hours after SA, developed a delayed postpartum hemorrhage. One patient developed a VTE (1%). She developed a distal and superficial thrombus immediately after delivery. She was using antenatal prophylactic LMWH as she had an unprovoked VTE predating pregnancy, was heterozygous for the prothrombin gene mutation, had epidural anesthesia and VD. She received prophylactic LMWH three hours after catheter removal which was also 10 hours after catheter insertion.Limitations: Time of discontinuation of LMWH prior to induction could not be confirmed definitively as this was a retrospective review.Conclusion: Prospective studies are required to confirm these findings and to determine the safety of current recommendations of interrupting anticoagulation prior to regional anesthesia and delivery and to identify risk factors for hemorrhage and recurrent VTE to optimize anticoagulation regimens for these patients. DisclosuresMalinowski: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy.

Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation.

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann–Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13–0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Şiddetli COVİD-19 Hastalarında DMAH (Düşük Molekül Ağırlıklı Heparin) Doz Farklılıklarının Etkileri

Objective: The most prominent clinical finding in severe COVID-19 patients is endothelial damage. For these reasons, active administration of anticoagulants (such as heparin) is recommended to patients with severe COVID-19. The purpose of this study is to investigate the effects of different doses of low-molecular weight heparin (LMWH) on severe COVID-19 patients. Methods: This study was performed retrospectively in intensive care unit of a tertiary referral hospital. PCR (polymerase chain reaction) positive (+) patients were included in the study. Patients’ demographic data, length of stay in the hospital and intensive care unit, laboratory values (D-dimer, CRP, creatinine) on the last day of intensive care stay, mortality and invasive mechanical ventilator needs were recorded. Group O: consisted of patients not receiving anticoagulants, and Group 1 received a single daily dose of 40 mg enoxaparin sodium (equivalent to 4000 anti-Xa IU), and Group 2 received 2 daily doses of 1 mg/kg enoxaparin sodium. Results: A total of 191 patients were included in the study. 45% of the patients were female (n: 86), 55% were male. The mean age was found to be 67.6 ± 13.8. Patient numbers; group 0: 12, group 1: 90, group 2: 89. 7-day mortality was 50% in group 0, 22.2% in group 2, and 23.5% in group 3 (p value &lt;0.05). Conclusion: In a recent lung dissection report in critically ill patient with COVID-19; occlusion of pulmonary small vessels and formation of microthrombosis have been demonstrated. Prophylactic doses of LMWH are used more frequently. Some studies have suggested that septic patients may benefit from early diagnosis and specific treatment. As a result; in severe COVID-19 patients with limited mobilization, all doses of LMWH reduce morbidity and mortality.

Comparison of standard prophylactic and preemptive therapeutic low molecular weight heparin treatments in hospitalized patients with COVID-19.

Anticoagulant treatment approach in patients with COVID-19 is not well studied and not standardized. We aimed to compare the effects of standard prophylactic and pre-emptive therapeutic Low-Molecular-weight Heparin (LMWH) treatment approaches on mortality in patients with COVID-19. This retrospective and single-centre study includes patients aged ≥ 18 years, who were diagnosed with COVID-19 and treated with LMWH during the hospital stay. Therapeutic dose of LMWH was defined as 1 mg/kg subcutaneously twice daily and prophylactic dose of LMWH was defined as 40 mg subcutaneously once daily. Among the 336 patients diagnosed with COVID-19 pneumonia, 115 patients, who received LMWH were included in the study. The mean age was 58.6 ± 13.3 and 58 (50.4 %) of the patients were male. Sixty-nine (60 %) of the patients were treated with prophylactic and 46 (40 %) therapeutic LMWH.In-hospital mortality was not different between patients treated therapeutic LMWH and prophylactic LMWH by the multivariate regression analysis (OR=2.187, 95% CI 0.484-9.880, p=0.309) and the propensity score modelling (OR=1.586, 95% CI 0.400-6.289, p=0.512.)CONCLUSION: Clinicians should consider the potential risks and benefits of standard prophylactic and pre-emptive therapeutic LMWH. Therefore, anticoagulant therapy should be individualized in patients with COVID-19 (Tab. 3, Ref. 28).

COVID-19-Associated Coagulopathy: Safety and Efficacy of Prophylactic Anticoagulation Therapy in Hospitalized Adults with COVID-19

Background:COVID-19-associated coagulopathy increases mortality in patients with COVID-19 infection. The International Society of Thrombosis and Hemostasis (ISTH) has published a guidance document recommending thromboprophylaxis with low-molecular weight heparin (LMWH) for all hospitalized patients with COVID-19. Despite standard dose LMWH thromboprophylaxis, arterial and venous thrombotic events occur in up to 30-40% of COVID-19 patients admitted to the intensive care unit (ICU). It is not known if patients with coagulopathy from COVID-19 benefit from higher levels of prophylactic anticoagulation therapy. No data exist regarding the comparative safety or efficacy of intermediate dose versus standard prophylactic dose LMWH.Study Design and Methods:This is a multi-center, randomized, open-label study (NCT04360824) comparing standard prophylactic dose enoxaparin (40 mg SC daily if BMI < 30 kg/m2; 30 mg SC twice daily or 40 mg SC twice daily if BMI ≥ 30 kg/m2) versus intermediate-weight adjusted dose enoxaparin (1 mg/kg SC daily if BMI < 30 kg/m2 or 0.5 mg/kg SC twice daily if BMI ≥ 30 kg/m2) in hospitalized patients with laboratory-confirmed SARS-CoV-2 infection who are either admitted to an intensive care unit or have a modified ISTH Overt DIC score ≥ 3.Objectives:The primary endpoint is to compare all-cause 30-day mortality of patients treated with standard prophylactic dose versus intermediate-dose enoxaparin. The secondary endpoints are to determine whether the use of standard prophylactic dose versus intermediate dose enoxaparin impacts major bleeding, arterial thrombosis, venous thrombosis, time to intubation or transfusion of blood products. The exploratory endpoints are to determine the effects of SARS-CoV-2 infection on laboratory coagulation parameters to better understand the mechanism of COVID-19 coagulopathy compared to healthy control subjects; parameters include citrullinated histone H3 (H3Cit), a component of neutrophil extracellular traps. The null hypothesis is that intermediate dose enoxaparin (intervention arm) will have a mortality rate that is not less than standard prophylactic dose enoxaparin (standard of care arm). Assuming a true margin of 20%, a sample size of 82 patients in each arm of the study is required to have 80% power when testing for a difference.Baseline Data:Three centers are currently enrolling patients. As of August 1, 2020, we have enrolled 52 patients (28 males and 24 females) with a median age of 61 years (range 24-80). 51% were Caucasian, 36% Hispanic, and 16% other ethnicities. Median BMI was 31 kg/m2 (range 20-52). Baseline D-Dimer was elevated in 95% of participants with a median of 2.23 mg/mL (range 0.39-40.32). The majority of participants had normal baseline PT, PTT, and platelet levels. All patients had fibrinogen levels over 100 mg/dL with a median of 607 mg/dL. Plasma H3Cit was elevated significantly in patients with COVID-19 (n = 21) vs healthy control subjects (n = 10) (6.48 vs 1.09 ng/mL, P = 0.001).Conclusion:Baseline data for the first 52 patients enrolled confirm the presence of multiple risk factors for thrombosis such as elevated BMI, D dimer, and plasma markers of neutrophil extracellular traps. In contrast to initial reports from China, the prevalence of thrombocytopenia and hypofibrinogenemia was very low in our cohort. Hispanics represented 36% of our study population, compared with 19% of overall COVID-19 infections in the region, suggesting a higher severity of illness in this subpopulation. The enrollment of this trial is ongoing with the addition of sites that have larger African American populations. As safety and efficacy data mature, this study will help clarify the optimum dose of prophylactic enoxaparin to prevent COVID-19 associated coagulopathy.DisclosuresNo relevant conflicts of interest to declare.

Therapeutic dosing of low-molecular-weight heparin may decrease mortality in patients with severe COVID-19 infection.

ABSTRACTBACKGROUND: Venous thromboembolism or extensive thrombosis is relatively common in patients with severe COVID-19 infection and has been associated with increased mortality. During the current COVID-19 pandemic, several prophylactic doses and types of low-molecular-weight heparin (LMWH) are being used worldwide; however, there are no high-quality studies or recommendations for an optimal prophylactic LMWH dose.OBJECTIVES: Investigate the relationship between coagulation parameters and the LMWH dose, and mortality and ICU admission in hospitalized patients with severe COVID-19 pneumonia.DESIGN: Retrospective.SETTING: Tertiary care hospital.PATIENTS AND METHODS: Data on clinical features, coagulation parameters and anticoagulant medications of inpatients with severe COVID-19 were collected for the period between 11 March 2020 and 31 April 2020.MAIN OUTCOME MEASURES: Mortality and ICU admission for prophylactic dose LMWH (0.5 mg/kg twice daily) and therapeutic dose LMWH (1 mg/kg twice daily).SAMPLE SIZE: 154 cases.RESULTS: Ninety-eight (63.6%) patients were treated with the LMWH prophylactic dose and 56 (36.4%) patients were treated with the therapeutic dose. Forty-four (44.9%) of 98 patients using the prophylactic dose LMWH died, while 10 (17.9%) of 56 patients using the therapeutic dose LMWH died (P=.001). Mortality was 6.4-fold higher in the prophylactic dose LMWH users than in the therapeutic dose LMWH users (OR=6.5, 95% CI: 2.4–17.6, P<.001).CONCLUSIONS: Therapeutic dosing of LMWH may decrease mortality in patients with severe COVID-19 infected pneumonia. More aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.LIMITATIONS: Lack of information about bleeding complications. LMWH was not compared with other anticoagulant therapies. There was no comparison between our two groups on the APACHE score. Used different doses of LMWH in different clinics in our hospital. Single-center, retrospective study.CONFLICT OF INTEREST: None.

Inadequate prophylactic effect of low-molecular weight heparin in critically ill COVID-19 patients.

PurposeThe aim of this study was to investigate potential markers of coagulopathy and the effects of thromboprophylaxis with low-molecular-weight heparin (LMWH) on thromboelastography (TEG) and anti-factor Xa in critically ill COVID-19 patients.Material and MethodsWe conducted a prospective study in 31 consecutive adult intensive care unit (ICU) patients. TEG with and without heparinase and anti-factor Xa analysis were performed. Standard thromboprophylaxis was given with dalteparin (75–100 IU/kg subcutaneously).ResultsFive patients (16%) had symptomatic thromboembolic events. All patients had a maximum amplitude (MA) > 65 mm and 13 (42%) had MA > 72 mm at some point during ICU stay. Anti-factor Xa activity were below the target range in 23% of the patients and above target range in 46% of patients. There was no significant correlation between dalteparin dose and anti-factor Xa activity.ConclusionsPatients with COVID-19 have hypercoagulability with high MA on TEG. The effect of LMWH on thromboembolic disease, anti-factor Xa activity and TEG was variable and could not be reliably predicted. This indicates that standard prophylactic doses of LMWH may be insufficient. Monitoring coagulation and the LMWH effect is important in patients with COVID-19 but interpreting the results in relation to risk of thromboembolic disease poses difficulties.

A Systematic Review and Meta- Analysis of Randomized Controlled Trials on Primary Ambulatory Thromboprophylaxis (PATP) in Patients with Gastrointestinal Cancers Receiving Chemotherapy

Introduction: PATP in solid cancer patients remains uncertain and is not routinely recommended although thrombosis is shown to be the second leading cause of death in cancer patients. Many studies failed to demonstrate in solid cancer outpatients improvement in overall survival despite decreasing venous thromboembolism (VTE) rates by PATP. We conducted a systematic review and meta-analysis of RCTs to determine the benefit and risk of PATP with low-molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in patients with gastrointestinal cancers receiving chemotherapy. Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2019. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Results: A total of 1,932 patients with gastric, gastroesophageal junctional (GEJ) and colorectal cancers from a subgroup of three RCTs were included in our meta-analysis. The prophylactic doses of LMWHs and DOAC (rivaroxaban) were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2 statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 13 (1.26%) in PATP group and 23 (2.55%) in control group with a RR of 0.49 (95% CI: 0.25 to 0.96, P = 0.04). The absolute RD in VTE was -0.01 (95% CI: -0.03 to -0.00, P 0.04) with an estimate of the number needed to treat (NNT) of 78 to prevent one VTE event. In a subset of patients with gastric and GEJ cancers (n=587), the VTE incidence was 4 (1.37%) in PATP group and 10 (3.40%) in control group with a RR of 0.40 (95% CI: 0.13 to 1.24, P = 0.11). Conclusions: In our study, the relative risk reduction is 48% with a NNT of 78 to prevent one VTE in ambulatory patients with gastrointestinal cancers. Nevertheless, there is no statistically significant reduction in VTE events in a subset of gastric and GEJ cancers which are considered high risk in Khorana score. Based on the findings, PATP is not recommended in patients with gastrointestinal cancers on chemotherapy at this time. Further studies are necessary to define high risk subsets of gastrointestinal cancer patients receiving chemotherapy who may benefit from PATP. Disclosures Oo: Medical Education Speakers Network: Honoraria; Janssen and Janssen: Other: site co-investigator.

Apixaban Versus Dalteparin for Thromboprophylaxis in Patients with Acute Spinal Cord Injury: A Pilot Study

Background: Patients with acute spinal cord injury (SCI) have a high risk of venous thromboembolism despite thromboprophylaxis. Low molecular weight heparin (LMWH), the current standard of care, is inconvenient for long term thromboprophylaxis, costly, and partially effective. Direct oral anticoagulants (DOACs) have been shown to be at least as effective and as safe as LMWH in other thromboprophylaxis settings but there is no randomized evaluation of DOACs in this population. Aim: By conducting a feasibility randomized trial, we aimed to determine the likely recruitment rate of eligible patients into an RCT in which patients with acute SCI were randomized to a prophylactic dose of LMWH or apixaban. Methods: A pilot study was performed at Hamilton General Hospital (HGH). Adult patients with an acute traumatic SCI presenting to the hospital within 1 week of SCI and at least 36 h after the injury were included. Exclusion criteria were the need for therapeutic oral anticoagulation prior to enrolment; active bleeding, intracranial or peri-spinal hematoma, or a bleeding disorder; pregnancy or breastfeeding; severe renal failure (creatinine clearance ≤30 ml/min); severe cirrhosis (Child-Pugh class C); severe thrombocytopenia (platelets &lt;50), unsuitability as determined by the attending physician; geographic inaccessibility; failure to obtain written consent; previous hypersensitivity to study drugs; or expected short hospital admission (≤7 days) due to a minor injury. Eligible patients were randomized to apixaban 2.5 mg twice daily or dalteparin 5000 units once daily for 90 days or until fully mobilized, whatever came first. The primary feasibility outcome was recruitment rate per year. We expected a recruitment rate of 20 patients per year based on an estimated admission rate in a retrospective study at HGH. The primary efficacy outcome was a composite of symptomatic, objectively verified, venous thromboembolism (upper or lower limb deep vein thrombosis (DVT) and/or pulmonary embolism (PE)) or sudden death where PE cannot be excluded. This outcome did not include a catheter-associated DVT. The primary safety end-point was major bleeding. Results: A total of 26 eligible patients were screened and 8 patients were enrolled per year resulting in a recruitment yield of 30.8% (95% confidence interval: 16-50%). The reasons for exclusion included: presence of an epidural hemorrhage (n=8), failure to obtain consent (n=2), not suitable for the study (n=2), &gt;1 week from SCI (n=2), indication for therapeutic anticoagulation (n=2), active bleeding (n=1), and minor injury with an expected short hospital admission (n=1). Four patients were randomized to each drug. Median age was 61 (range 51 to 70) and 7 (87.5%) were males. There were no symptomatic VTE or sudden deaths. One patient randomized to apixaban had major bleeding. There were no serious adverse events. Conclusions: Our pilot study is the first randomized trial to examine the role of a DOAC compared with LMWH for thromboprophylaxis in this high-risk group. The primary feasibility outcome was not met, and therefore a multicenter RCT is unlikely to be feasible. The efficacy and safety of DOACs on this indication should be evaluated in registry- or health care database studies. Disclosures Eikelboom: Heart and Stroke Foundation: Research Funding; Sanofi Aventis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Eli Lilly: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.

Early low-molecular-weight heparin administration is associated with shorter time to SARS-CoV-2 swab negativity.

Antiviral and immune-modulating properties of low-molecular-weight heparin (LMWH) against Coronaviridae have been reported by in vitro studies, but no in vivo evidence is yet available. We sought to know whether the timing of prophylactic doses of LMWH during the course of COVID-19 may affect the time to SARS-CoV-2 nasal-oropharyngeal swab negativization. Retrospective monocentric cross-sectional study on patients requiring sub-intensive ward admission due to first SARS-CoV-2 infection and undergoing early (EH; within 7 days from COVID-19 signs and symptoms onset) versus delayed prophylactic LMWH (DH; after 7 days). SARS-CoV-2 RNA was measured by reverse transcription real-time PCR according to scheduled time points: first swab after 2 weeks from COVID-19 onset, then at 1-week intervals until negativity. Time to SARS-CoV-2 swab negativity was shorter in EH (38 patients) compared with DH (55 patients): 22 versus 37 days (P=0.004). The number of confirmative negative swabs in EH was significantly higher compared with DH at week 2 (21.1% versus 3.6%; P=0.017) and 4 (60.0% versus 19.6%; P<0.001). At univariate, EH differed from DH for several disease severity and clinical management parameters. Nevertheless, after accounting for the differences, Cox regression showed early LMWH administration (hazard ratio [HR] 2.91 [1.51, 5.63]; P=0.002) and higher lymphocytes nadir (HR 1.04 [1.01, 1.08]; P=0.020) as predictors of shorter time to swab negativity. This potential antiviral and/or immune-modulating activity of LMWH needs further in vivo confirmations by randomized controlled trials.

PF802 ANTICOAGULANT THERAPY IN THROMBOCYTOPENIC PATIENTS WITH BLOOD CANCER AND CATHETER‐RELATED VTE: RESULTS FROM A DELPHI CONSENSUS ON PLATELETS COUNT BELOW 50 X 109L

Background:Management of venous thromboembolism (VTE) in patients with haematological malignancies (HM) and thrombocytopenia challenges clinicians because this scenario is encumbered with several risks. Our panel, composed by elected members of the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) Working Party on Thrombosis and Haemostasis (WPHT). has recently published a consensus,reached by RAND method, focused on the platelet cut‐off for safely administering Low Molecular Weight Heparin (LMWH) in adult patients with hematological malignancies, acute (no later than 1 month) or non‐acute VTE and thrombocytopenia (PLT&lt; 100 × 109/L).Aims:Aim of the current study was to produce a formal consensus, not achieved by the previous method, focused on anticoagulant treatment with LMWH in adult patients with HM affected by acute or non‐acute catheter‐related VTE and severe thrombocytopeniaMethods:Delphi methodology was adopted to allow members of the GIMEMA‐WPHT to achieve consensus on the above reported issue, starting from available scientific data. For each indication, the panel members (N = 21, 3 validators and 18 participants) rated the benefit‐to‐harm ratio of the indication on a scale of 1 to 5, where 1 means that the expected harms greatly outweigh the expected benefits, and 5 means that the expected benefits greatly outweigh the expected harms. The first survey consisted of 7 different statement; after analysis of the first results, it was decided to discuss and re‐formulate 3 items, panel members were then asked to rate again items for which no consensus had been achieved. The interventions considered were the administration of different doses of LMWH (therapeutic, reduced dose at 50% of full therapeutic dose, prophylactic dose) and PLT transfusions, according to platelet counts &gt;30 &lt;50 × 109/L, in patients with catheter‐related VTE. LMWH doses were defined according to the datasheet for each LMWH molecule.Results:After the first round, an agreement &gt;80%was reached for 4 out of the initial 7 items. Three items were thus reformulated nd partecipants were asked to reasses them After the second round, an agreement was reached for all items. The panel of experts expressed the following consensus: for the management of acute‐catether related VTE with platelet counts &gt;30 &lt;50 × 109/L in patients with HM, anticoagulant treatment with reduced dose to 50% of LMWH is appropriate (90%agreement); for the management of non‐acute catheter‐related VTE, treatment with reduced dose to 50% of LMWH is also appropiate. PLTs transfusions were deemed inappropriate in both,acute (90% agreement) and non‐acute (100% agreement) catheter‐related VTE. The administration of prophylactic dose of LMWH was deemed inappropriate with an agreement of 90% in patients with acute catheter‐related VTE and 80% in subjects with non‐acute catheter‐related VTE.Summary/Conclusion:Delphi method has allowed to reach consensus on a still debated issue, where scientific evidences are lacking.GIMEMA‐WPHT suggests anticoagulant treatment with reduced dose to 50% of LMWH for platelet counts &gt;30 &lt;50 × 109/L in patients with haematological malignancies and either acute or non‐acute catheter‐related VTE.

Safety and Outcome of Intravenous Thrombolysis in Stroke Patients on Prophylactic Doses of Low Molecular Weight Heparins at Stroke Onset.

Background and Purpose- There are limited data on intravenous thrombolysis treatment in patients with ischemic stroke who have received prophylactic doses of low molecular weight heparins (LMWHs). We aimed to evaluate the safety and outcomes of intravenous thrombolysis treatment in stroke patients taking thromboprophylactic doses of LMWH. Methods- We analyzed 109 291patients treated with intravenous thrombolysis, recorded in the Safe Implementation of Treatments in Stroke International Thrombolysis Register between 2003 and 2017 not taking oral anticoagulants or therapeutic doses of heparin at stroke onset. One thousand four hundred eleven patients (1.3%) were on prophylactic LMWH for deep venous thrombosis prevention. Outcome measures were symptomatic intracerebral hemorrhage, parenchymal hematoma, death within 7 days and 3 months, and functional dependency at 3 months. Results- Patients on LMWH were older, had more severe strokes, more prestroke disability, and comorbidities than patients without LMWH. There was no significant increase in adjusted odds ratios (aOR) for symptomatic intracerebral hemorrhage (aOR, 1.02 [95% CI, 0.48-2.17] as per Safe Implementation of Treatments in Stroke -MOST, aOR, 0.95 [0.59-1.53] per ECASS II]), nor for 7-day mortality (aOR, 1.14 [0.82-1.59]), in the prophylactic LMWH group. The LMWH group had a higher aOR for 3-month mortality (aOR, 1.94 [1.49-2.53]) and functional dependency, aOR, 1.44 (1.10-1.90). Propensity score analysis matching patients on baseline characteristics removed differences between groups on all outcomes except 3-month mortality. Conclusions- Intravenous thrombolysis in patients with acute ischemic stroke on treatment with prophylactic doses of LMWH at stroke onset is not associated with an increased risk of symptomatic intracerebral hemorrhage or early death.

A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: A British Society for Haematology Guideline.

The previous BSH guideline for the management of erythrocytosis was published in 2005 (McMullin et al, 2005) and amended in 2007 (McMullin et al, 2007). Here, we re‐evaluate the literature formulate guidance on the management of specific situations encountered in polycythaemia vera (PV) and the management of the other types of secondary erythrocytosis. Recommendations for the diagnostic pathway of investigation of an erythrocytosis, risk stratification and management of PV are in the accompanying guideline (McMullin et al, 2018). We review evidence and outline guidance on management of acute thrombotic events and secondary prevention of thrombosis in PV. The unusual thrombotic events, splanchnic vein and cerebral vein thromboses are discussed and haemorrhage. The specific situations of surgery and pregnancy and guidance on management of pruritus are included. The evidence for the management of other causes of erythrocytosis, including idiopathic erythrocytosis, congenital erythrocytosis, hypoxic pulmonary disease and post‐transplant erythrocytosis, is reviewed and recommendations made.