COVID-19 and thrombosis: searching for evidence.

Early in the pandemic, COVID-19-related increases in rates of venous and arterial thromboembolism were seen. Many observational studies suggested a benefit of prophylactic anticoagulation for hospitalized patients using various dosing strategies. Randomized trials were initiated to compare the efficacy of these different options in acutely ill and critically ill inpatients as the concept of immune-mediated inflammatory microthrombosis emerged. We present a case-based review of how we approach thromboembolic prophylaxis in COVID-19 and briefly discuss the epidemiology, the pathophysiology, and the rare occurrence of vaccine-induced thrombotic thrombocytopenia.

Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: Patients hospitalised with COVID-19 are at risk for thrombotic events after discharge; the role of extended thromboprophylaxis in this population is unknown. METHODS: In this open-label, multicentre, randomised trial conducted at 14 centres in Brazil, patients hospitalised with COVID-19 at increased risk for venous thromboembolism (International Medical Prevention Registry on Venous Thromboembolism [IMPROVE] venous thromboembolism [VTE] score of ≥4 or 2-3 with a D-dimer >500 ng/mL) were randomly assigned (1:1) to receive, at hospital discharge, rivaroxaban 10 mg/day or no anticoagulation for 35 days. The primary efficacy outcome in an intention-to-treat analysis was a composite of symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Adjudication was blinded. The primary safety outcome was major bleeding. The primary and safety analyses were carried out in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04662684. FINDINGS: From Oct 8, 2020, to June 29, 2021, 997 patients were screened. Of these patients, 677 did not meet eligibility criteria; the remaining 320 patients were enrolled and randomly assigned to receive rivaroxaban (n=160 [50%]) or no anticoagulation (n=160 [50%]). All patients received thromboprophylaxis with standard doses of heparin during hospitalisation. 165 (52%) patients were in the intensive care unit while hospitalised. 197 (62%) patients had an IMPROVE score of 2-3 and elevated D-dimer levels and 121 (38%) had a score of 4 or more. Two patients (one in each group) were lost to follow-up due to withdrawal of consent and not included in the intention-to-treat primary analysis. The primary efficacy outcome occurred in five (3%) of 159 patients assigned to rivaroxaban and 15 (9%) of 159 patients assigned to no anticoagulation (relative risk 0·33, 95% CI 0·12-0·90; p=0·0293). No major bleeding occurred in either study group. Allergic reactions occurred in two (1%) patients in the rivaroxaban group. INTERPRETATION: In patients at high risk discharged after hospitalisation due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis. FUNDING: Bayer.

The Immediate Effect of COVID-19 Vaccination on Anticoagulation Control in Patients Using Vitamin K Antagonists.

BACKGROUND: In January 2021, the Dutch vaccination program against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was started. Clinical studies have shown that systemic reactions occur in up to 50% of vaccine recipients. Therefore, COVID-19 vaccination could affect anticoagulation control, potentially leading to an increased risk of thrombotic events and bleeding complications. AIMS: This article investigates whether the BNT162b2 vaccine affects anticoagulation control in outpatients using vitamin K antagonists (VKAs). METHODS: A case-crossover study was performed in a cohort of outpatient VKA users from four Dutch anticoagulation clinics who received a BNT162b2 vaccine. International normalized ratio (INR) results and VKA dosages before the first vaccination, the reference period, were compared with those after the first and second vaccination. RESULTS: A total of 3,148 outpatient VKA users were included, with a mean age (standard deviation) of 86.7 (8.7) years, of whom 43.8% were male, 67.0% used acenocoumarol, and 33.0% phenprocoumon. We observed a decrease of 8.9% of INRs within range in the standard intensity group (target INR 2.0-3.0). There was both an increased risk of supratherapeutic (odds ratio [OR] = 1.34 [95% confidence interval [CI] 1.08-1.67]) and subtherapeutic levels (OR = 1.40 [95% CI 1.08-1.83]) after first vaccination. In the high-intensity group (target INR 2.5-3.5), the risk of a supratherapeutic INR was 2.3 times higher after first vaccination (OR = 2.29 [95% CI 1.22-4.28]) and 3.3 times higher after second vaccination (OR = 3.25 [95% CI 1.06-9.97]). CONCLUSION: BNT162b2 was associated with an immediate negative effect on anticoagulation control in patients treated with VKAs, so it is advisable to monitor the INR shortly after vaccination, even in stable patients.

Generation of an anticoagulant aptamer that targets factor V/Va and disrupts the FVa-membrane interaction in normal and COVID-19 patient samples.

Coagulation cofactors profoundly regulate hemostasis and are appealing targets for anticoagulants. However, targeting such proteins has been challenging because they lack an active site. To address this, we isolate an RNA aptamer termed T18.3 that binds to both factor V (FV) and FVa with nanomolar affinity and demonstrates clinically relevant anticoagulant activity in both plasma and whole blood. The aptamer also shows synergy with low molecular weight heparin and delivers potent anticoagulation in plasma collected from patients with coronavirus disease 2019 (COVID-19). Moreover, the aptamer's anticoagulant activity can be rapidly and efficiently reversed using protamine sulfate, which potentially allows fine-tuning of aptamer's activity post-administration. We further show that the aptamer achieves its anticoagulant activity by abrogating FV/FVa interactions with phospholipid membranes. Our success in generating an anticoagulant aptamer targeting FV/Va demonstrates the feasibility of using cofactor-binding aptamers as therapeutic protein inhibitors and reveals an unconventional working mechanism of an aptamer by interrupting protein-membrane interactions.

COVID and venous thrombosis: systematic review of literature.

INTRODUCTION: We aimed to review the prevalence, the risk factors and the outcomes of venous thrombosis (VT) in patients hospitalized for COronaVirus Disease 19 (COVID-19). EVIDENCE ACQUISITION: Electronic bibliographic databases were searched using the words "COVID venous thrombosis". The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards. EVIDENCE SYNTHESIS: The search of the literature retrieved 877 results. After assessment of full texts, 69 papers were included in the qualitative analysis and 23 of them in the quantitative evaluation. The analyzed studies included a total of 106,838 patients hospitalized for COVID-19 from January to December 2020. The pooled reported prevalence rate of VT was in median 16.7% (IQR 5.8-30%), being higher in ICU patients (60.8-85.4%). VT events were reported in about 75% of cases in the popliteal and calf veins. Signs and symptoms were present in 6.1% of cases. At quantitative evaluation, older age, D-dimer and obesity increased the odds to experience a VT (OR=3.54, 95% CI 0.65-6.43, P=0.01; OR=956.86, 95% CI 225.67-1668.05, P=0.01; OR=1.42, 95% CI 1.01-1.99, P=0.03 respectively). Female sex seemed to be protective against the odds of VT (OR=0.77, 95% CI 0.63-0.93, P=0.007). CONCLUSIONS: Among patients hospitalized for COVID-19, VT is a relatively common finding, with higher prevalence rates in ICU patients. VT occurs mostly in the distal regions of the lower limb and is asymptomatic in most cases. Older age, obesity and higher D-dimer values on admission increased the odds of VT, while female sex was protective against the odds of VT.

Time-course analysis reveals that corticosteroids resuscitate diminished CD8+ T cells in COVID-19: a retrospective cohort study.

OBJECTIVE: To illustrate the effect of corticosteroids and heparin, respectively, on coronavirus disease 2019 (COVID-19) patients' CD8+ T cells and D-dimer. METHODS: In this retrospective cohort study involving 866 participants diagnosed with COVID-19, patients were grouped by severity. Generalized additive models were established to explore the time-course association of representative parameters of coagulation, inflammation and immunity. Segmented regression was performed to examine the influence of corticosteroids and heparin upon CD8+ T cell and D-dimer, respectively. RESULTS: There were 541 moderate, 169 severe and 156 critically ill patients involved in the study. Synchronous changes of levels of NLR, D-dimer and CD8+ T cell in critically ill patients were observed. Administration of methylprednisolone before 14 DFS compared with those after 14 DFS (ß = 0.154%, 95% CI=(0, 0.302), p=.048) or a dose lower than 40 mg per day compared with those equals to 40 mg per day (ß = 0.163%, 95% CI=(0.027, 0.295), p=.020) significantly increased the rising rate of CD8+ T cell in 14-56 DFS. CONCLUSIONS: The parameters of coagulation, inflammation and immunity were longitudinally correlated, and an early low-dose corticosteroid treatment accelerated the regaining of CD8+ T cell to help battle against SARS-Cov-2 in critical cases of COVID-19.

MPN and thrombosis was hard enough . . . now there's COVID-19 thrombosis too.

Both myeloproliferative neoplasms (MPNs) and coronavirus disease 2019 (COVID-19) are characterized by an intrinsic thrombotic risk. Little is known about the incidence and the outcome of thrombotic events in patients with MPN infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but common mechanisms of coagulation activation, typical of both disorders, suggest that these patients can be at particularly high risk. To define the best thromboprophylaxis and treatment regimens in both MPN and COVID-19, individual- and disease-specific thrombotic risk factors, bleeding risk, and concomitant specific treatments need to be considered. In this case-based review, an individualized approach is presented in a case of SARS-CoV-2 infection occurring in a man with polycythemia vera (PV). A primary anticoagulant thromboprophylaxis strategy and adjustment of his PV treatment were implemented. However, during the hospital stay, he experienced pulmonary embolism and therapeutic anticoagulation had to be set. Then his condition improved, and discharge was planned. Postdischarge decisions had to be made about the type and duration of venous thromboembolism treatment as well as the management of PV-specific drugs. The steps of our decisions and recommendations are presented.

How to recognize and manage COVID-19-associated coagulopathy.

COVID-19 is frequently associated with abnormalities on coagulation testing and a coagulopathy driven by inflammation, intravascular coagulation activation, and microvascular thrombosis. Elevated D-dimer is the most common finding and is a predictor of adverse outcomes including thrombosis, critical illness, and death. Although COVID-19-associated coagulopathy has some similarities to disseminated intravascular coagulation, the platelet count is usually preserved, coagulation times are usually normal or minimally prolonged, and thrombosis is more common than bleeding, at least in noncritically ill patients. Bleeding is uncommon but may be a significant problem in critically ill patients, including those who may develop a consumptive coagulopathy with frank disseminated intravascular coagulation and those on extracorporeal membrane oxygenation. Blood product support to correct coagulopathy is reserved for bleeding patients or those requiring invasive procedures. Current recommendations suggest that all hospitalized patients should receive at least a prophylactic dose of anticoagulation. Results from a multiplatform randomized clinical trial suggest that therapeutically dosed anticoagulation may improve outcomes, including the need for organ support and mortality in moderately ill patients but not in those requiring critical care. The results of ongoing trials evaluating the impact of different antithrombotic strategies (therapeutic agents and intensity) on COVID-19 outcomes are eagerly awaited and are expected to have important implications for patient management. We also discuss COVID-19 vaccine-associated cytopenias and bleeding as well as vaccine-induced thrombotic thrombocytopenia, in which thrombosis is associated with thrombocytopenia, elevated D-dimer, and, frequently, hypofibrinogenemia.

OpenSAFELY: impact of national guidance on switching anticoagulant therapy during COVID-19 pandemic.

BACKGROUND: Early in the COVID-19 pandemic, the National Health Service (NHS) recommended that appropriate patients anticoagulated with warfarin should be switched to direct-acting oral anticoagulants (DOACs), requiring less frequent blood testing. Subsequently, a national safety alert was issued regarding patients being inappropriately coprescribed two anticoagulants following a medication change and associated monitoring. OBJECTIVE: To describe which people were switched from warfarin to DOACs; identify potentially unsafe coprescribing of anticoagulants; and assess whether abnormal clotting results have become more frequent during the pandemic. METHODS: With the approval of NHS England, we conducted a cohort study using routine clinical data from 24 million NHS patients in England. RESULTS: 20 000 of 164 000 warfarin patients (12.2%) switched to DOACs between March and May 2020, most commonly to edoxaban and apixaban. Factors associated with switching included: older age, recent renal function test, higher number of recent INR tests recorded, atrial fibrillation diagnosis and care home residency. There was a sharp rise in coprescribing of warfarin and DOACs from typically 50-100 per month to 246 in April 2020, 0.06% of all people receiving a DOAC or warfarin. International normalised ratio (INR) testing fell by 14% to 506.8 patients tested per 1000 warfarin patients each month. We observed a very small increase in elevated INRs (n=470) during April compared with January (n=420). CONCLUSIONS: Increased switching of anticoagulants from warfarin to DOACs was observed at the outset of the COVID-19 pandemic in England following national guidance. There was a small but substantial number of people coprescribed warfarin and DOACs during this period. Despite a national safety alert on the issue, a widespread rise in elevated INR test results was not found. Primary care has responded rapidly to changes in patient care during the COVID-19 pandemic.

Divergent impacts of tocilizumab and colchicine in COVID-19-associated coagulopathy: the role of alpha-defensins.

Patients who are severely affected by coronavirus disease 2019 (COVID-19) may develop a delayed onset 'cytokine storm', which includes an increase in interleukin-6 (IL-6). This may be followed by a pro-thrombotic state and increased D-dimers. It was anticipated that tocilizumab (TCZ), an anti-IL-6 receptor monoclonal antibody, would mitigate inflammation and coagulation in patients with COVID-19. However, clinical trials with TCZ have recorded an increase in D-dimer levels. In contrast to TCZ, colchicine reduced D-dimer levels in patients with COVID-19. To understand how the two anti-inflammatory agents have diverse effects on D-dimer levels, we present data from two clinical trials that we performed. In the first trial, TCZ was administered (8 mg/kg) to patients who had a positive polymerase chain reaction test for COVID-19. In the second trial, colchicine was given (0·5 mg twice a day). We found that TCZ significantly increased IL-6, α-Defensin (α-Def), a pro-thrombotic peptide, and D-dimers. In contrast, treatment with colchicine reduced α-Def and Di-dimer levels. In vitro studies show that IL-6 stimulated the release of α-Def from human neutrophils but in contrast to colchicine, TCZ did not inhibit the stimulatory effect of IL-6; raising the possibility that the increase in IL-6 in patients with COVID-19 treated with TCZ triggers the release of α-Def, which promotes pro-thrombotic events reflected in an increase in D-dimer levels.

State-of-the-art review - A review on snake venom-derived antithrombotics: Potential therapeutics for COVID-19-associated thrombosis?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent responsible for the Coronavirus Disease-2019 (COVID-19) pandemic, has infected over 185 million individuals across 200 countries since December 2019 resulting in 4.0 million deaths. While COVID-19 is primarily associated with respiratory illnesses, an increasing number of clinical reports indicate that severely ill patients often develop thrombotic complications that are associated with increased mortality. As a consequence, treatment strategies that target COVID-associated thrombosis are of utmost clinical importance. An array of pharmacologically active compounds from natural products exhibit effects on blood coagulation pathways, and have generated interest for their potential therapeutic applications towards thrombotic diseases. In particular, a number of snake venom compounds exhibit high specificity on different blood coagulation factors and represent excellent tools that could be utilized to treat thrombosis. The aim of this review is to provide a brief summary of the current understanding of COVID-19 associated thrombosis, and highlight several snake venom compounds that could be utilized as antithrombotic agents to target this disease.

Combined anticoagulant and antiplatelet therapy is associated with an improved outcome in hospitalised patients with COVID-19: a propensity matched cohort study.

BACKGROUND: COVID-19 is a respiratory disease that results in a prothrombotic state manifesting as thrombotic, microthrombotic and thromboembolic events. As a result, several antithrombotic modalities have been implicated in the treatment of this disease. This study aimed to identify if therapeutic anticoagulation (TAC) or concurrent use of antiplatelet and anticoagulants was associated with an improved outcome in this patient population. METHODS: A retrospective observational cohort study of adult patients admitted to a single university hospital for COVID-19 infection was performed. The primary outcome was a composite of in-hospital mortality, intensive care unit (ICU) admission or the need for mechanical ventilation. The secondary outcomes were each of the components of the primary outcome, in-hospital mortality, ICU admission, or the need for mechanical ventilation. RESULTS: 242 patients were included in the study and divided into four subgroups: Therapeutic anticoagulation (TAC), prophylactic anticoagulation+antiplatelet (PACAP), TAC+antiplatelet (TACAP) and prophylactic anticoagulation (PAC) which was the reference for comparison. Multivariable Cox regression analysis and propensity matching were done and showed when compared with PAC, TACAP and TAC were associated with less in-hospital all-cause mortality with an adjusted HR (aHR) of 0.113 (95% CI 0.028 to 0.449) and 0.126 (95% CI 0.028 to 0.528), respectively. The number needed to treat in both subgroups was 11. Furthermore, PACAP was associated with a reduced risk of invasive mechanical ventilation with an aHR of 0.07 (95% CI 0.014 to 0.351). However, the was no statistically significant difference in the occurrence of major or minor bleeds, ICU admission or the composite outcome of in-hospital mortality, ICU admission or the need for mechanical ventilation. CONCLUSION: The use of combined anticoagulant and antiplatelet agents or TAC alone in hospitalised patients with COVID-19 was associated with a better outcome in comparison to PAC alone without an increase in the risk of major and minor bleeds. Sufficiently powered randomised controlled trials are needed to further evaluate the safety and efficacy of combining antiplatelet and anticoagulants agents or using TAC in the management of patients with COVID-19 infection.

COVID-19 and aortic disease: a practical systematic review of the literature on management and outcomes.

INTRODUCTION: Since the outbreak of the 2019 coronavirus (COVID-19), vascular specialists have faced dramatic changes in clinical and surgical practice. Although COVID-19 pulmonary signs and symptoms were the most pertinent problems initially, in the long term, cardiovascular complications became the most fearsome, with poor outcomes in terms of morbidity and mortality. Algorithms and decision-making procedures have been modified, not only to treat new clinical findings in COVID-19 positive patients, but also to avoid complications related to pulmonary and systemic infections. Additionally, COVID-19-negative patients experienced challenging management, due to hospital crowding, the risk of nosocomial COVID-19 transmission, and pandemic emergencies. In this context, aortic interventions were subject to several difficulties. First, in COVID-19-positive patients, there was the onset of new pathological scenarios including thrombotic manifestations and the subsequent complications. Second, in both COVID-19-negative and positive patients, there was a need to deliver optimal treatment with acceptable perioperative risks, forcing a rethinking of decision-making especially in terms of indications for treatments. The aim of this systematic review is to present evidence published on COVID-19 and aortic-related issues, highlighting some challenging aspects regarding management, treatment and outcomes. EVIDENCE ACQUISITION: Data search was performed on PubMed, Scopus and Web of Science, using as time range "January 1st, 2000 - May 1st, 2021." Only articles in English language were included. Key words used for the query were "Aorta" AND "COVID-19" OR "SARS-CoV-2." Furthermore, the NCBI database of "SARS-CoV-2 Resources" was interrogated to find further relevant studies. EVIDENCE SYNTHESIS: The search retrieved 416 papers; among these, 46 studies were eligible and reviewed in depth. The published literature suggests the existence of a hypercoagulable state in patients with COVID-19 disease occurring via direct and indirect mechanisms. COVID-19 infection seems to promote a prothrombotic status that aggravates vascular disease. Regardless of clinical laboratory or status, active COVID-19 infection is considered a risk factor for poor vascular surgery outcomes. Specifically, it is associated with a fourfold increased risk of death and a threefold increased risk of major adverse events. Prognosis of patients hospitalized with COVID-19 disease is often determined by the extent of pulmonary disease, although vascular complications also greatly affect outcomes. Nevertheless, although COVID­19 is highly morbid, in high­risk operations good outcomes can still be achieved even in elderly patients with COVID­19. CONCLUSIONS: In the case of aortic disease during active COVID-19 infection, poor outcomes are associated with COVID-19 vascular and non-vascular complications, while for COVID-19-negative patients not much changed in terms of outcomes, despite the difficulties in management. Endovascular repair, when possible, minimized the impact of treatment, reducing the risk of COVID-related postoperative complications or acquired infection in negative patients.

COVID-19 and acute limb ischemia: a systematic review.

INTRODUCTION: The main goal of this systematic review was to analyze the outcomes of acute limb ischemia (ALI) in patients suffering from the novel Coronavirus: COVID-19 (SARS-CoV-2). EVIDENCE ACQUISITION: A systematic review on Medline and Embase was conducted up to May 15, 2021. All papers were sorted by abstract and full text by two independent authors. Systematic reviews, commentaries, and studies that did not distinguish status of COVID-19 infection were excluded from review. Patient demographics were recorded along with modality of treatment (endovascular and/or surgical). We analyzed 30-day outcomes, including mortality. Primary outcome was to evaluate clinical characteristic of ALI in patients affected by SARS-CoV-2 in term of location of ischemia, treatment options and 30-day outcomes. EVINDENCE SYNTHESIS: We selected 36 articles with a total of 194 patients. Most patients were male (80%) with a median age of 60 years old. The treatment most used was thromboembolectomy (31% of all surgical interventions). A total of 32 patients (19%) were not submitted to revascularization due to critical status. The rate of technical success was low (68%), and mortality rate was high (35%). CONCLUSIONS: This review confirms that SARS-CoV-2 is associated with a high risk of ALI. Further studies are needed to investigate the association and elucidate potential mechanisms, which may include a hypercoagulable state and hyperactivation of the immune response. Furthermore, management of ALI is not standardized and depends on patient condition and extension of the thrombosed segment. ALI in COVID-19 patients is associated with high risk of failure of revascularization and perioperative mortality.

The Cross-Talk between Thrombosis and Inflammatory Storm in Acute and Long-COVID-19: Therapeutic Targets and Clinical Cases.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) commonly complicates with coagulopathy. A syndrome called Long-COVID-19 is emerging recently in COVID-19 survivors, characterized, in addition to the persistence of symptoms typical of the acute phase, by alterations in inflammatory and coagulation parameters due to endothelial damage. The related disseminated intravascular coagulation (DIC) can be associated with high death rates in COVID-19 patients. It is possible to find a prothrombotic state also in Long-COVID-19. Early administration of anticoagulants in COVID-19 was suggested in order to improve patient outcomes, although exact criteria for their application were not well-established. Low-molecular-weight heparin (LMWH) was commonly adopted for counteracting DIC and venous thromboembolism (VTE), due to its pharmacodynamics and anti-inflammatory properties. However, the efficacy of anticoagulant therapy for COVID-19-associated DIC is still a matter of debate. Thrombin and Factor Xa (FXa) are well-known components of the coagulation cascade. The FXa is known to strongly promote inflammation as the consequence of increased cytokine expression. Endothelial cells and mononuclear leucocytes release cytokines, growth factors, and adhesion molecules due to thrombin activation. On the other hand, cytokines can activate coagulation. The cross-talk between coagulation and inflammation is mediated via protease-activated receptors (PARs). These receptors might become potential targets to be considered for counteracting the clinical expressions of COVID-19. SARS-CoV-2 is effectively able to activate local and circulating coagulation factors, thus inducing the generation of disseminated coagula. LMWH may be considered as the new frontier in the treatment of COVID-19 and Long-COVID-19. Indeed, direct oral anticoagulants (DOACs) may be an alternative option for both early and later treatment of COVID-19 patients due to their ability to inhibit PARs. The aim of this report was to evaluate the role of anticoagulants-and DOACs in particular in COVID-19 and Long-COVID-19 patients. We report the case of a COVID-19 patient who, after administration of enoxaparin developed DIC secondary to virosis and positivity for platelet factor 4 (PF4) and a case of Long-COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state.