American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis for patients with COVID-19: March 2022 update on the use of anticoagulation in critically ill patients.

BACKGROUND: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for patients with COVID-19. METHODS: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing systematic evidence reviews (up to January 2022). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 and May 2021 as part of the living phase of these guidelines. RESULTS: The panel made 1 additional recommendation: a conditional recommendation for the use of prophylactic-intensity over therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of thrombotic and bleeding risk. CONCLUSIONS: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation for patients with COVID-19-related critical illness.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: January 2022 update on the use of therapeutic-intensity anticoagulation in acutely ill patients.

BACKGROUND: COVID-19-related acute illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation in patients with COVID-19. METHODS: ASH formed a multidisciplinary guideline panel that included patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process and performed systematic evidence reviews (through November 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 as part of the living phase of these guidelines. RESULTS: The panel made one additional recommendation. The panel issued a conditional recommendation in favor of therapeutic-intensity over prophylactic-intensity anticoagulation in patients with COVID-19-related acute illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of risk of thrombosis and bleeding. The panel also noted that heparin (unfractionated or low molecular weight) may be preferred because of a preponderance of evidence with this class of anticoagulants. CONCLUSION: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation in patients with COVID-19-related acute illness.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: July 2021 update on postdischarge thromboprophylaxis.

BACKGROUND: COVID-19-related acute illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development, and evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 who are discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation. CONCLUSIONS: This recommendation was based on very low certainty in the evidence, underscoring the need for high-quality randomized controlled trials assessing the role of postdischarge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.

American Society of Hematology living guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19: May 2021 update on the use of intermediate-intensity anticoagulation in critically ill patients.

BACKGROUND: COVID-19-related critical illness is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by performing systematic evidence reviews (up to 5 March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021. RESULTS: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19-related critical illness who do not have confirmed or suspected VTE. CONCLUSIONS: This recommendation was based on low certainty in the evidence, which underscores the need for additional high-quality, randomized, controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence regarding predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of nonanticoagulant therapies (eg, antiviral agents, corticosteroids) on thrombotic risk.

American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-related critical illness and acute illness are associated with a risk of venous thromboembolism (VTE). OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis for patients with COVID-19-related critical illness and acute illness who do not have confirmed or suspected VTE. METHODS: ASH formed a multidisciplinary guideline panel and applied strict management strategies to minimize potential bias from conflicts of interest. The panel included 3 patient representatives. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic evidence reviews (up to 19 August 2020). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 2 recommendations. The panel issued conditional recommendations in favor of prophylactic-intensity anticoagulation over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness or acute illness who do not have confirmed or suspected VTE. CONCLUSIONS: These recommendations were based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials comparing different intensities of anticoagulation. They will be updated using a living recommendation approach as new evidence becomes available.

A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease.

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).

Abciximab/Heparin Therapy for Left Ventricular Assist Device Implantation in Patients With Heparin-Induced Thrombocytopenia.

BACKGROUND: Optimal anticoagulation strategy remains uncertain in patients with heparin-induced thrombocytopenia (HIT) and undergoing left ventricular assist device (LVAD) implantation. We describe our protocol of abciximab and heparin in these patients. METHODS: Our protocol is to administer abciximab, 0.25 mg/kg loading dose, followed by continuous infusion of 0.125 µg · kg-1 · min-1 throughout cardiopulmonary bypass. Full-dose heparin is then given with subsequent additional doses to maintain an activated clotting time of 400 seconds or longer. The abciximab infusion is stopped 15 minutes after heparin reversal with protamine, and platelets are transfused. RESULTS: Six patients underwent LVAD implantation with this protocol in our program. HIT was confirmed in 4 patients was suspected in 2, which was negative after the operation. One patient received a HeartMate XVE (Thoratec Corp, Pleasanton, CA) and the others received HeartMate II (Thoratec Corp). There were no thromboembolic complications. One patient required chest reexploration for bleeding and temporary right VAD support. Postoperative anticoagulation with argatroban was restarted on median postoperative day 3 (range, days 1 to 6) and warfarin was started on day 5 (range, days 3 to 12). Median postoperative intensive care unit stay was 9 days (range, 5 to 76 days), and hospital stay was 22 days (range, 18 to 132 days). After the initial LVAD implantation, 1 patient required HeartMate XVE LVAD exchange to HeartMate II and subsequent heart transplant, both of which were performed with the abciximab/heparin protocol. A HeartMate II device was explanted in another patient after myocardial recovery. The remaining 4 patients are alive on device support. CONCLUSIONS: This is the first report of a novel abciximab/heparin protocol for LVAD implantation in patients with HIT. The preliminary results suggest the feasibility and safety of this protocol.

Clinically suspected heparin-induced thrombocytopenia during extracorporeal membrane oxygenation.

PURPOSE: Patients receiving extracorporeal membrane oxygenation (ECMO) are at risk for thrombocytopenia including heparin-induced thrombocytopenia (HIT). The purpose of this study was to determine the frequency of suspected HIT in patients receiving ECMO and unfractionated heparin (UFH). MATERIALS AND METHODS: We conducted a retrospective review in adult patients on ECMO. Patients were included if they received ECMO for at least 5 days and concomitant UFH. RESULTS: There were 119 patients who met inclusion criteria. Twenty-three patients (19%) had a heparin-platelet factor 4 immunoassay performed. Patients with suspected HIT had a significantly lower platelet count within the first 3 days of ECMO, 69×10(9)/L (22-126×10(9)/L) vs 87.5×10(9)/L (63-149×10(9)/L); P=.04. The lowest platelet count on the day of HIT testing was 43×10(9)/L (26-73), representing a 71% reduction from baseline. Twenty patients (87%) had an optical density score less than 0.4, and all patients had a score less than 1.0. A functional assay was performed in 7 patients (30%), with only 1 patient having laboratory-confirmed HIT. CONCLUSIONS: The evaluation of HIT occurred in a small percentage of patients, with HIT rarely being detected. Patients who had heparin-platelet factor 4 immunoassay testing exhibited lower platelet counts with a similar duration of ECMO and UFH exposure.

Prior hematologic conditions carry a high morbidity and mortality in patients supported with continuous-flow left ventricular assist devices.

BACKGROUND: Mechanical support leads to an increased risk of both bleeding and thrombotic events, but little is known about the risk of device support in patients with a baseline predisposition to these events. The aim of this study was to examine outcomes among patients with baseline hematologic conditions who underwent continuous-flow LVAD implantation (CF-LVAD). METHODS: We retrospectively reviewed records of 286 patients who underwent CF-LVAD implantation at the Columbia University Medical Center between April 2008 and December 2013. Patients diagnosed with the following hematologic conditions were enrolled: idiopathic thrombocytopenic purpura (ITP); Factor V Leiden; elevated Factor VIII; heparin-induced thrombocytopenia (HIT); or undefined hypercoagulable state. RESULTS: Of the 286 CF-LVAD patients implanted during the study period, 12 were considered to have a significant hematologic condition predisposing them to either bleeding or thrombotic events. The study included 5 patients with ITP, 1 with Factor V Leiden, 1 with elevated Factor VIII, 2 with HIT and 3 patients with undefined hypercoagulable state. Patients were supported for a total of 168.46 months, with a median of 10.76 months (IQR 4.78 to 21.36 months). There was a high frequency of thrombotic (0.57 event per patient-year), neurologic (0.36 event per patient-year) and bleeding (0.64 event per patient-year). Actuarial survival rates at 6 and 12 months were 81.8%, but fell to 49% at 2 years. CONCLUSIONS: Patients with a history of prior hematologic conditions are at high risk for bleeding, thrombotic and neurologic events during device support, leading to early mortality. This case series questions the benefit of CF-LVAD in these patients and the appropriate management with regard to anti-coagulation. Further studies on the outcomes of these patients are warranted.

A severe case of cefoxitin-induced immune hemolytic anemia.

Drug-induced immune hemolytic anemia is a rare but underdiagnosed and potentially fatal condition. We report a case of severe hemolytic anemia induced by cefoxitin in a 45-year-old woman admitted with menometrorrhagia. Hemoglobin levels reached a nadir of 4.7 g/dl approximately 72 h after cefoxitin initiation, and hemolysis resolved when cefoxitin was discontinued and prednisone 1 mg/kg was initiated. A transfusion reaction workup revealed no abnormalities. Direct antiglobulin testing was weakly positive with anti-C3. The patient's plasma and RBC eluate reacted with cefoxitin-treated RBCs but not with untreated RBCs in the presence or absence of cefoxitin.

Cost utility of substituting enoxaparin for unfractionated heparin for prophylaxis of venous thrombosis in the hospitalized medical patient.

BACKGROUND: Both heparin and enoxaparin are effective for the prevention of venous thromboembolism (VTE) in medical patients. On the basis of price, heparin appears preferable because it is less expensive. However, choosing enoxaparin may have greater cost utility when the outcomes of heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) are considered. OBJECTIVE: To determine the cost utility of substituting enoxaparin for heparin from payer and institutional perspectives. DESIGN: A decision analysis model was used. Cost data were based on Medicare reimbursement and the medication and laboratory costs for a multi-institutional healthcare system. Quality-adjusted life years (QALYs) saved by preventing HIT/HITT through the use of enoxaparin were based on published data. Costs are expressed on a per-day basis, and the incremental cost of enoxaparin over that of heparin was used in the calculation of cost/QALY. A sensitivity analysis also was performed. SETTING: Inpatient medicine. PATIENTS: All medical patients for whom VTE prophylaxis was appropriate. INTERVENTIONS: Substitution of enoxaparin for heparin. MEASUREMENT: Cost/QALY. RESULTS: From a payer perspective, using enoxaparin resulted in a decrease in cost of 28.61 dollars over that of heparin and saved 0.00629 QALYs in the base case, resulting in a savings of 4550.17 dollars/QALY. The sensitivity analysis showed this finding of decreased cost and increased effectiveness to be consistent. From an institutional perspective, the use of heparin generally appeared less costly but was dependent on medication price, length of stay required, and bed utilization. CONCLUSIONS: From a payer and, by extrapolation, a societal perspective, cost-utility analysis supports the use of enoxaparin in place of heparin for the prevention of VTE in medical inpatients. From an institutional perspective, the decision is more complicated, but in most cases, the use of enoxaparin also is supported.

Off-pump right atrial thrombectomy for heparin-induced thrombocytopenia with thrombosis.

This report describes a 72-year-old woman with atrial fibrillation who presented with lower extremity ischemia secondary to thromboembolism. After lower extremity thrombectomy, the patient developed heparin-induced thrombocytopenia with thrombosis (HITT). Her postoperative course was complicated by recurrent supraventricular and ventricular tachycardia, secondary to a mobile thrombus in the right atrium extending into the right ventricle. Because administration of heparin was contraindicated, the patient underwent off-pump right atrial thrombectomy during a brief period of inflow occlusion. Postoperatively, she was placed on lepirudin. Her platelet count normalized without any further thrombotic episodes, and she was discharged on warfarin.