Upregulation of cAMP prevents antibody-mediated thrombus formation in COVID-19

Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2 virus. The exact mechanisms of COVID-19-associated hypercoagulopathy, however, remain elusive. Recently, we observed that platelets (PLTs) from patients with severe COVID-19 infection express high levels of procoagulant markers, which were found to be associated with increased risk for thrombosis. In the current study, we investigated the time course as well as the mechanisms leading to procoagulant PLTs in COVID-19. Our study demonstrates the presence of PLT-reactive IgG antibodies that induce marked changes in PLTs in terms of increased inner-mitochondrial transmembrane potential (Δψ) depolarization, phosphatidylserine (PS) externalization, and P-selectin expression. The IgG-induced procoagulant PLTs and increased thrombus formation were mediated by ligation of PLT Fc-γ RIIA (FcγRIIA). In addition, contents of calcium and cyclic-adenosine-monophosphate (cAMP) in PLTs were identified to play a central role in antibody-induced procoagulant PLT formation. Most importantly, antibody-induced procoagulant events, as well as increased thrombus formation in severe COVID-19, were inhibited by Iloprost, a clinically approved therapeutic agent that increases the intracellular cAMP levels in PLTs. Our data indicate that upregulation of cAMP could be a potential therapeutic target to prevent antibody-mediated coagulopathy in COVID-19 disease.

Real-World Use of Fostamatinib in Patients with Immune Thrombocytopenia and Thrombotic Risk

Patients with immune thrombocytopenia (ITP) are at increased risk for bleeding and are paradoxically at increased risk for thrombosis. Many patients with ITP have underlying cardiovascular (CV) disease and/or other thrombotic risk factors for which considerable attention to selecting a therapeutic agent to manage ITP is needed. Fostamatinib, a spleen tyrosine kinase inhibitor, may reduce the risk of thrombosis while not interfering with hemostasis. We present a case series of 5 patients with ITP who had significant CV histories; each had at least 2 thrombotic risk factors. After unsuccessful management of ITP with other treatments, fostamatinib was initiated, was observed to be tolerable, and provided a durable platelet response without associated thromboembolic events. Fostamatinib may be the treatment of choice for patients with ITP in whom use of prothrombotic treatments should be avoided and/or continued use of antiplatelet or anticoagulant medication is needed.

Contribution of the Elevated Thrombosis Risk of Males to the Excess Male Mortality Observed in COVID-19: An Observational Study

Background: The mortality rate of COVID-19 is elevated in males compared to females.Objective: Determine the extent that the elevated thrombotic risk in males relative to females contributes to excess COVID-19 mortality in males.Design: Observational study.Setting: Data sourced from electronic medical records from over 200 US hospital systems.Participants: 60,877 patients hospitalized with COVID-19.Exposure: Exposure variable: biological sex; key variable of interest: thrombosis.Main outcome measures: Primary outcome was COVID-19 mortality. We measured: 1) mortality rate of males relative to females, 2) rate of thrombotic diagnoses occurring during hospitalization for COVID-19 in both sexes, and 3) mortality rate when evidence of thrombosis was present.Results: The COVID-19 mortality rate of males was 29.9% higher than that of females. Males had a 35.8% higher rate of receiving a thrombotic diagnosis compared to females. The mortality rate of all patients with a thrombotic diagnosis was 40.0%— over twice that of COVID-19 patients without a thrombotic diagnosis (adjusted OR 2.50 [2.37 to 2.64], p-value < .001). When defining thrombosis as either a documented thrombotic diagnosis or a D-dimer level ≥ 3.0 μg/mL, 16.4% of the excess mortality in male patients could be explained by increased thrombotic risk. Conclusions and Relevance: Our findings suggest the higher COVID-19 mortality rate in males may be significantly accounted for by the elevated risk for thrombosis among males. Understanding the mechanisms that underlie increased male thrombotic risk may allow for the advancement of effective anticoagulation strategies that reduce COVID-19 mortality in males.

302. Using Antiphospholipid Antibody Presence as an Additional Biomarker to Identify COVID-19 Positive Patients with High Risk for Thrombosis

Background Patients who are hospitalized with Coronavirus 2019 (COVID-19) are known to have increased risk for thrombosis. Several mechanisms have been proposed for increased thrombogenesis, including antiphospholipid antibodies (APLs). We sought to better understand the relationship between a commonly used marker of thrombosis, D-dimer, and antiphospholipid antibodies in relation to thrombosis in COVID-19. Methods This was a single-center prospective cohort study. Participants were adults admitted to the hospital with COVID-19 between March and December of 2020. Included patients required a positive COVID-19 nasopharyngeal nucleic acid amplification testing (NAAT), coagulation studies, and regular assessment of D-dimer levels. Patients who were excluded were pregnant adults, use of oral anticoagulants prior to admission, and absence of a positive COVID-19 nasopharyngeal NAAT. We tested 52 patients for antiphospholipid antibodies (APLs), including lupus anticoagulant (LA), anti-beta-2 glycoprotein antibodies (B2GP), and anti-cardiolipin antibodies (aCL). The endpoint for analysis was hospital discharge or development of a confirmed thrombosis. Results Twenty-nine of fifty-two patients (55.7%) with COVID-19 had non-negative APLs. Of these patients, twenty-seven (93.1%) had non-negative aCLs, the majority of which were IgM antibodies. There was a total of 7 thrombotic events in our cohort. The sensitivity of D-dimer alone was 85% and the sensitivity of APLs alone was 71%. In patients with an intermediate D-dimer level (i.e., greater than 2 milligrams per liter (mg/L) but less than 5 mg/L), the addition of non-negative APLs increased the sensitivity of D-dimer to 100%. In patients with a high D-dimer (i.e., greater than 5), the combined sensitivity of D-dimer and APLs was 60%. Out of the 7 thrombotic events in our cohort, two patients had negative APLs, however both patients had a D-dimer of greater than 5 mg/L. Conclusion The use of APLs can assist in risk-stratifying patients in an intermediate-risk D-dimer group to consider prophylactic anticoagulation if APLs are negative and to consider therapeutic anticoagulation if APLs are non-negative. In the high-risk group (i.e., a D-dimer greater than 5 mg/dL), a therapeutic anticoagulation approach may be more appropriate. Disclosures All Authors: No reported disclosures

Thromboprophylaxis in active cancer patients: Is it a controversial clinical issue or not? Preliminary results of ACT4CAT study.

e18803 Background: Cancer Associated Thrombosis (CAT) is an increasing challenge for oncology patients since oncologists sometimes are reluctant to mitigate the risk with thromboprophylaxis. Active cancer patients while receiving chemotherapy have a 7fold risk of thrombosis compared with no cancer patients. Anticoagulation holds a prominent place in prevention of CAT usually with Low Molecular Weight Heparins (LMWHs). Methods: ACT4CAT is prospective observational study conducted by HeSMO across Greece, aiming to record the clinical practice of CAT prophylaxis in patients with solid tumors. Ambulatory, high thrombotic risk, active cancer patients who received thromboprophylaxis enrolled after signing informed consent. Results: Preliminary results collected from 18 oncology departments. From 431 enrolled patients 322 (65.4%) had completed the study. Tumor types included: lung 28.8%, gastrointestinal 39.8%, gynecological 7.0%, breast 4.4%, urological 7.0% and others 20%. Majority of patients (88.2%) received High-Risk for Thrombosis Chemotherapy Agents (HRTCAs) such as platinum agents (55.9%), antimetabolites (44.7%) and immunotherapy (12.6%). In 1st line were 62.1%, 2nd line 18.4%, adjuvant 8.9% and neoadjuvant 2.4%. The following table depicts: age, gender, metastatic disease, Khorana score ≥2 and HRTCAs. All patients received thromboprophylaxis for 5.3±3.6 months with: tinzaparin 90.8%, fondaparinux 5.5%, bemiparin 1.5%, enoxaparin 1.2%, apixaban 0.5% and rivaroxaban 0.5%. Intermediate doses received 70.9% of patients regardless clinical setting (1st, 2nd, adjuvant & neoadjuvant: 70.2%, 79.2%, 51.3% and 70.0% respectively, p = 0.0254), although intermediate doses were used more in metastatic stages (OR:2.4 95%CI: 1.4-4.2, p = 0.0028). Nine thrombotic events reported (2.1%, 95%CI: 1.1-3.9%), irrespective of clinical setting but with a trend towards prophylactic doses. Eleven grade 1 bleedings reported (2.6%, 95%CI: 1.4-4.5%), despite clinical setting or dose used. Conclusions: Thromboprophylaxis in ambulatory active cancer patients with high thrombotic risk is safe and effective. Oncologists are alerted about CAT negative influences in cancer patients’ prognosis. Apart from Khorana score, factors such as metastases, use of HRTCAs and drug-drug interactions influence the clinical decision of thromboprophylaxis in active cancer patients mainly with LMWHs and quite often with intermediate doses regardless clinical setting. Clinical trial information: NCT03909399. [Table: see text]

VWF, Platelets and the Antiphospholipid Syndrome

The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPLs). Laboratory criteria for the classification of APS include the detection of lupus anticoagulant (LAC), anti-cardiolipin (aCL) antibodies and anti-β2glycoprotein I (aβ2GPI) antibodies. Clinical criteria for the classification of thrombotic APS include venous and arterial thrombosis, along with microvascular thrombosis. Several aPLs, including LAC, aβ2GPI and anti-phosphatidylserine/prothrombin antibodies (aPS/PT) have been associated with arterial thrombosis. The Von Willebrand Factor (VWF) plays an important role in arterial thrombosis by mediating platelet adhesion and aggregation. Studies have shown that aPLs antibodies present in APS patients are able to increase the risk of arterial thrombosis by upregulating the plasma levels of active VWF and by promoting platelet activation. Inflammatory reactions induced by APS may also provide a suitable condition for arterial thrombosis, mostly ischemic stroke and myocardial infarction. The presence of other cardiovascular risk factors can enhance the effect of aPLs and increase the risk for thrombosis even more. These factors should therefore be taken into account when investigating APS-related arterial thrombosis. Nevertheless, the exact mechanism by which aPLs can cause thrombosis remains to be elucidated.

How we approach thrombosis risk in children with COVID-19 infection

Thrombosis within the microvasculature and medium to large vessels is a serious and common complication among critically ill individuals with COVID-19. While children are markedly less likely to develop severe disease than adults, they remain at risk for thrombosis during acute infection and with the post-acute inflammatory illness termed multisystem inflammatory syndrome in children. Significant knowledge deficits in understanding COVID-19 associated coagulopathy and thrombotic risk pose clinical challenges for pediatric providers who must incorporate expert opinion and personal experience to manage individual patients. We discuss clinical scenarios to provide framework for characterizing thrombosis risk and thromboprophylaxis in children with COVID-19.

Thrombocytopenia and thrombosis in hospitalized patients with COVID-19

As our understanding on coronavirus disease 2019 (COVID-19) deepens, it is increasingly recognized that COVID-19 is more than a respiratory condition. Thrombocytopenia and thromboembolic complications are a composite factor associated with critical COVID-19 and increased mortality. Immune-inflammation-mediated destruction, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection per se and increased consumption are proposed to be responsible for thrombocytopenia. Multiple concomitant conditions or results caused by SARS-CoV-2 infection are high risk factors for thrombosis. Recently, platelet activation and platelet-mediated immune inflammation induced by SARS-CoV-2 infection were also found to be the contributors to the thrombosis in COVID-19 patients. In addition to thrombus scoring system, D-dimer is an excellent indicator for monitoring thrombosis. COVID-19 patients with high risk for thrombosis should be subjected to early thromboprophylaxis, and prolonged activated partial-thromboplastin time should not be a barrier to the use of anticoagulation therapies in the control of thrombosis in COVID-19 patients.

Impact of Blood Group Type on Severity of Disease in COVID-19 Patients

Background The virus SARS-CoV-2, which causes COVID-19 has rapidly spread into a global pandemic. In critically ill patients with the disease, common symptoms include sepsis, severe pneumonia with acute respiratory distress syndrome (ARDS), and complications such as coagulopathy and thrombosis. Many patients with COVID-19 have sequelae such as venous thromboembolism (VTE) including pulmonary embolism (PE) and deep vein thrombosis (DVT) as well as arterial thromboembolism (ATE) including stroke. COVID-19 induced inflammation can induce a prothrombotic state by activating the coagulation cascade; coupled with the immobility of severe and critically ill patients in ICU, making thrombosis common in this patient population. Different blood types in patients include A, B, AB, and O. ABO carbohydrate moieties are genetically inherited and have been linked to predisposing patients to cardiovascular diseases, cancers, and even susceptibility of COVID-19. Blood type positivity and negativity are determined by the Rhesus (Rh) factor, which is a protein found on the surface of red blood cells and is also genetically inherited and linked to higher incidence of certain diseases such as diabetes. Studies have shown a relationship between blood types and increased severity of infection from COVID-19 including increased risk of thrombosis. Blood type A has been shown to have higher severity of disease with O blood type having a lower risk of infection or mortality. This study was done to evaluate if patients with different blood types have increased risk for thrombosis or higher mortality rates with COVID-19 infection. Methods A retrospective analysis was performed on COVID-19 positive hospitalized patients between March 1, 2020 and June 26, 2020 at our institution with reported blood typing. Patients who had a thromboembolism (VTE, DVT, PE, ATE, or stroke) verified by imaging were extracted from this cohort and included in the analysis. The prevalence of different blood types in COVID-19 patients was compared to the general population without COVID-19. The incidence of thrombosis and mortality rate based on blood type was analyzed to understand severity of COVID-19 disease. Statistical analysis was performed using chi-squared testing. Results Among 1265 COVID-19 positive patients during our time frame, 138 patients were identified to have a thrombosis. Of those, 102 patients with thrombosis and 402 without thrombosis had reported blood types that were used for analysis. There was no significant difference in prevalence of blood types in COVID-19 patients (A 34.3%, AB 2.9%, B 16.7%, O 46.1%) to the general nonCOVID-19 population (A32.7%, AB 4.2%, B 14.9%, O 48.1%) (p=0.8572). There was no significant difference in incidence of thrombosis between blood types: A (23.3%), AB (15%), B (20.7%), and O (18.7%) (p=0.6513). When stratifying by Rh factor, there was also no significant difference in incidence of thrombosis by blood types: A- (11.1%), A+ (24.1%), AB- (0%), AB+ (15.8%), B- (25%), B+ (20.3%), O- (18.2%), O+ (18.7%) (p=0.9054). There was also no significant difference in mortality rate between COVID-19 patients based on blood types in our cohort: A (20.7%), AB (15%), B (13.4%), and O (21.8%) (p=0.3747). Conclusion Our study demonstrates that there is no increased prevalence of one blood type over another between COVID-19 patients compared to the general population, showing that patients are not at higher risk for COVID-19 infection based on blood type. There was also no difference between blood types based on incidence of thrombosis. When further stratifying with Rh factor, there was also no difference in incidence of thrombosis based on blood types. This shows that regardless of Rh positivity or negativity, there is no increased risk for thrombosis in COVID-19 patients based on blood type. There is also no difference in mortality in COVID-19 patients based on blood type. Since COVID-19 patients who are critically ill and have more severe disease have higher incidence of thrombosis and higher mortality rates, our study suggests that patients are not at higher risk for severe COVID-19 disease based on blood type. However, this study is also limited due to small sample size, and prospective studies are needed to better understand the relationship between blood type and severity of disease in COVID-19+ patients. Disclosures No relevant conflicts of interest to declare.