Anti-factor Xa vs aPTT for heparin monitoring in extracorporeal membrane oxygenation.

PURPOSE: The goal of this study was to evaluate the correlation of anti-factor Xa (anti-Xa) and activated partial thromboplastin time (aPTT) measures with heparin dosing in adult patients on extracorporeal membrane oxygenation (ECMO) support. METHODS: This was a retrospective cohort study evaluating adult patients managed on ECMO for at least 24 hours who received unfractionated heparin for systemic anticoagulation and were monitored per protocol using anti-Xa and/or aPTT coagulation assays. The primary outcome was the correlation between aPTT and anti-Xa measures. The secondary outcomes included, but were not limited to, the number of hemorrhagic and thrombotic events. RESULTS: Twenty-seven patients were included in this study. In the 227 events where both laboratory values were collected, a weak correlation was found between anti-Xa and aPTT (Spearman's correlation coefficient = 0.4, P = 0). In the 12 hemorrhagic events that occurred, aPTT was collected for only 10 events. Fifty percent of those events were associated with supratherapeutic aPTT, while none of the hemorrhagic events were associated with a supratherapeutic anti-Xa level. Two thrombotic events occurred, one of which had subtherapeutic anti-Xa and aPTT and the other of which had neither an anti-Xa nor aPTT measure on the day the event occurred. CONCLUSION: In a population of patients on ECMO, many of whom had coronavirus disease 2019 (COVID-19), there was a weak association between aPTT and anti-Xa measures. Hemorrhagic evens were more common than thrombotic events; however, a relationship between these events and aPTT or anti-Xa levels was not determined. The applicability of these findings to an ECMO population without COVID-19 is unknown and will require further study.

Unchanged Characteristics and Survival among Critically Ill COVID-19 Patients during First, Second, and Third Waves: A Prospective Observational Cohort.

BACKGROUND: This study was carried out to compare characteristics and outcomes in patients with acute respiratory failure related to COVID-19 during first, second, and third waves. METHODS: We included consecutive adults admitted to the intensive care unit between March 2020 and July 2021. We compared three groups defined by the epidemic intake phase: waves 1 (W1), 2 (W2), and 3 (W3). RESULTS: We included 289 patients. Two hundred and eight (72%) patients were men with a median age of 63 years (IQR: 54-72), of whom 68 (23.6%) died in hospital. High-flow nasal oxygen (HFNO) was inversely associated with the need for invasive mechanical ventilation (MV) in multivariate analysis (p = 0.003) but not dexamethasone (p = 0.25). The day-90 mortality rate did not vary from W1 (27.4%) to W2 (23.9%) and W3 (22%), p = 0.67. By multivariate analysis, older age (odds ratio [OR]: 0.94/year, p < 0.001), immunodeficiency (OR: 0.33, p = 0.04), acute kidney injury (OR: 0.26, p < 0.001), and invasive MV (OR: 0.13, p < 0.001) were inversely associated with higher day-90 survival as opposed to the use of intermediate heparin thromboprophylaxis dose (OR: 3.21, p = 0.006). HFNO use and dexamethasone were not associated with higher day-90 survival (p = 0.24 and p = 0.56, respectively). CONCLUSIONS: In patients with acute respiratory failure due to COVID-19, survival did not change between first, second, and third waves while the use of invasive MV decreased. HFNO or intravenous steroids were not associated with better outcomes, whereas the use of intermediate dose of heparin for thromboprophylaxis was associated with higher day-90 survival. Larger multicentric studies are needed to confirm our findings.

Significance of heparin induced thrombocytopenia (HIT) in COVID-19: a systematic review and meta-analysis.

Heparin-induced thrombocytopenia (HIT) occurs in approximately 3% of patients receiving heparinoids. About 30-75% of patients with type 2 of HIT develop thrombosis as a result of platelet activation. The most important clinical symptom is thrombocytopenia. Patients with severe COVID-19 are among those receiving heparinoids. This meta-analysis performed to picture the current knowledge and results of published studies in this field. Three search engines were searched and 575 papers were found. After evaluation, 37 articles were finally selected of which 13 studies were quantitatively analyzed. The pooled frequency rate of suspected cases with HIT in 13 studies with 11,241 patients was 1.7%. The frequency of HIT was 8.2% in the extracorporeal membrane oxygenation subgroup with 268 patients and 0.8% in the hospitalization subgroup with 10,887 patients. The coincidence of these two conditions may increase the risk of thrombosis. Of the 37 patients with COVID-19 and confirmed HIT, 30 patients (81%) were treated in the intensive care unit or had severe COVID-19. The most commonly used anticoagulants were UFH in 22 cases (59.4%). The median platelet count before treatment was 237 (176-290) x 103/µl and the median nadir platelet count was 52 (31-90.5) x 103/µl.

Serotonin Release Assay: Functional Assay for Heparin- and Vaccine-Induced (Immune) Thrombotic Thrombocytopenia.

The serotonin release assay (SRA) has been the gold-standard assay for detection of heparin-dependent platelet-activating antibodies and integral for the diagnosis for heparin-induced thrombotic thrombocytopenia (HIT). In 2021, a thrombotic thrombocytopenic syndrome was reported after adenoviral vector COVID-19 vaccination. This vaccine-induced thrombotic thrombocytopenic syndrome (VITT) proved to be a severe immune platelet activation syndrome manifested by unusual thrombosis, thrombocytopenia, very elevated plasma D-dimer, and a high mortality even with aggressive therapy (anticoagulation and plasma exchange). While the platelet-activating antibodies in both HIT and VITT are directed toward platelet factor 4 (PF4), important differences have been found. These differences have required modifications to the SRA to improve detection of functional VITT antibodies. Functional platelet activation assays remain essential in the diagnostic workup of HIT and VITT. Here we detail the application of SRA for the assessment of HIT and VITT antibodies.

Heparin-Induced Thrombotic Thrombocytopenia (HITT) and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Similar but Different.

Heparin-induced thrombocytopenia (HIT) represents an autoimmune process whereby antibodies are formed against heparin in complex with platelet factor 4 (PF4) after heparin administration. These antibodies can be detected by a variety of immunological assays, including ELISA (enzyme-linked immunosorbent assay) and by chemiluminescence on the AcuStar instrument. However, pathological HIT antibodies are those that activate platelets in a platelet activation assay and cause thrombosis in vivo. We would tend to call this condition heparin-induced thrombotic thrombocytopenia (HITT), although some workers instead use the truncated abbreviation HIT. Vaccine-induced (immune) thrombotic thrombocytopenia (VITT) instead reflects an autoimmune process whereby antibodies are formed against PF4 after administration of a vaccine, most notably adenovirus-based vaccines directed against COVID-19 (coronavirus disease 2019). Although both VITT and HITT reflect similar pathological processes, they have different origins and are detected in different ways. Most notable is that anti-PF4 antibodies in VITT can only be detected immunologically by ELISA assays, tending to be negative in rapid assays such as that using the AcuStar. Moreover, functional platelet activation assays otherwise used for HITT may need to be modified to detect platelet activation in VITT.

Efficacy and Safety of Direct Oral Anticoagulants Compared With Heparin for Preventing Thromboembolism in Hospitalized Patients With COVID-19: A Systematic Review and Meta-Analysis.

A high rate of thromboembolism and a high risk of death have been reported regarding hospitalized patients with coronavirus disease 2019 (COVID-19). Recently, we noticed that clinicians in some comparative studies used direct oral anticoagulants (DOACs) to prevent thromboembolism in patients with COVID-19. However, it is uncertain whether DOACs are better than recommended heparin for hospitalized patients with COVID-19. Therefore, a direct comparison of the prophylactic effects and safety between DOACs and heparin is needed. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from 2019 to December 1, 2022. Randomized controlled trials or retrospective studies comparing the efficacy or safety of DOACs with that of heparin in preventing thromboembolism for hospitalized patients with COVID-19 were included. We assessed endpoints and publication bias using Stata 14.0. Five studies comprising 1360 hospitalized COVID-19 patients with mild to moderate cases were identified in the databases. Comparing the embolism incidence, we found that DOACs had a better effect than heparin, mainly low-molecular-weight heparin (LMWH), in preventing thromboembolism (risk ratio [RR] = 0.63, 95% confidence interval [CI] [0.43-0.91], P = 0.014). Considering safety, DOACs resulted in less bleeding than heparin during hospitalization (RR = 0.52, 95% CI [0.11-2.44], P = 0.411). Similar mortality was discovered in the 2 groups (RR = 0.94, 95% CI [0.59-1.51], P = 0.797). In noncritically hospitalized patients with COVID-19, DOACs are superior to heparin, even LMWH, in preventing thromboembolism. Compared with heparin, DOACs have a lower trend of bleeding and yield a similar mortality rate. Therefore, DOACs may be a better alternative for patients with mild to moderate COVID-19.

Potential mechanisms of vaccine-induced thrombosis.

Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome characterized by high-titer anti-platelet factor 4 (PF4) antibodies, thrombocytopenia and arterial and venous thrombosis in unusual sites, as cerebral venous sinuses and splanchnic veins. VITT has been described to occur almost exclusively after administration of ChAdOx1 nCoV-19 and Ad26.COV2.S adenovirus vector- based COVID-19 vaccines. Clinical and laboratory features of VITT resemble those of heparin-induced thrombocytopenia (HIT). It has been hypothesized that negatively charged polyadenylated hexone proteins of the AdV vectors could act as heparin to induce the conformational changes of PF4 molecule that lead to the formation of anti-PF4/polyanion antibodies. The anti-PF4 immune response in VITT is fostered by the presence of a proinflammatory milieu, elicited by some impurities found in ChAdOx1 nCoV-19 vaccine, as well as by soluble spike protein resulting from alternative splice events. Anti-PF4 antibodies bind PF4, forming immune complexes which activate platelets, monocytes and granulocytes, resulting in the VITT's immunothrombosis. The reason why only a tiny minority of patents receiving AdV-based COVID-19 vaccines develop VITT is still unknown. It has been hypothesized that individual intrinsic factors, either acquired (i.e., pre-priming of B cells to produce anti-PF4 antibodies by previous contacts with bacteria or viruses) or inherited (i.e., differences in platelet T-cell ubiquitin ligand-2 [TULA-2] expression) can predispose a few subjects to develop VITT. A better knowledge of the mechanistic basis of VITT is essential to improve the safety and the effectiveness of future vaccines and gene therapies using adenovirus vectors.

Efficacy and safety of two heparin regimens for prevention of venous thromboembolism in hospitalized patients with COVID-19: a meta-analysis.

Venous thromboembolism (VTE) is common in patients with coronavirus disease-2019 (COVID-19). The optimal heparin regimen remains unknown and should balance thromboembolic and bleeding risks. The aim of this study was to evaluate the efficacy and safety of standard or higher heparin regimens for the prevention of VTE in patients hospitalized due to COVID-19. We performed a systematic literature search; studies reporting on hospitalized patients with COVID-19 who received standard heparin prophylaxis vs. high (intermediate or therapeutic) heparin regimens were included if outcome events were reported by treatment group and more than 10 patients were included. Primary study outcome was in-hospital VTE. Secondary study outcomes were major bleeding (MB), all-cause death, fatal bleeding and fatal pulmonary embolism. Overall, 33 studies (11,387 patients) were included. Venous thromboembolic events occurred in 5.2% and in 8.2% of patients who received heparin prophylaxis with at high-dose or standard-dose, respectively (RR 0.71, 95% CI 0.55-0.90, I2 48.8%). MB was significantly higher in patients who received high- compared to the standard-dose (4.2% vs 2.2%, RR 1.94, 95% CI 1.47-2.56, I2 18.1%). Sub-analyses showed a slight benefit associated with high-dose heparin in patients admitted to non-intensive care unit (ICU) but not in those to ICU. No significant differences were observed for mortality outcomes. Heparin prophylaxis at high-dose reduces the risk of VTE, but increased the risk of MB compared to the standard-dose. No clinical benefit for heparin high-dose was observed for ICU setting, but its role in the non-ICU deserves further evaluation. PROSPERO registration number: CRD42021252550.

Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19.

Importance: Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective: To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants: Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures: Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures: Organ support-free days, assigning a value of -1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results: Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support-free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support-free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance: Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration: ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589.

Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study.

There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in treating patients with COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted to two hospitals in Brazil. One hundred patients were planned to be randomised to either "standard of care" (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 h of randomisation. In the ITT population (n = 75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p = 0.24. However, in the mITT population, nebulised UFH reduced mortality (OR 0.2, p = 0.035). Length of hospital stay was similar between groups, but at day 29, there was a greater improvement in ordinal score following treatment with UFH in the ITT and mITT populations (p = 0.076 and p = 0.012 respectively), while mechanical ventilation rates were lower with UFH in the mITT population (OR 0.31; p = 0.08). Nebulised UFH did not cause any significant adverse events. In conclusion, nebulised UFH added to SOC in hospitalised patients with COVID-19 was well tolerated and showed clinical benefit, particularly in patients who received at least 6 doses of heparin. This trial was funded by The J.R. Moulton Charity Trust and registered under REBEC RBR-8r9hy8f (UTN code: U1111-1263-3136).

Diagnostic Performance of a Particle Gel Immunoassay in Vaccine-Induced Immune Thrombotic Thrombocytopenia.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but serious complication of adenoviral vector-based COVID-19 vaccines. Similar to heparin-induced thrombocytopenia (HIT), antibodies reacting to platelet factor 4 (PF4) are responsible for platelet activation in VITT. The diagnosis of VITT includes the detection of anti-PF4 antibodies. Particle gel immunoassay (PaGIA) is one of the rapid immunoassays that is commonly used in the diagnosis of HIT to detect anti-PF4 antibodies. The aim of this study was to investigate the diagnostic performance of PaGIA in patients suspected of VITT. In this retrospective, single-center study, the correlation between PaGIA, enzyme immunoassay (EIA), and modified heparin-induced platelet aggregation assay (HIPA) in patients with findings suggestive of VITT was investigated. A commercially available PF4 rapid immunoassay (ID PaGIA H/PF4, Bio-Rad-DiaMed GmbH, Switzerland) and an anti-PF4/heparin EIA (ZYMUTEST HIA IgG, Hyphen Biomed) were used according to manufacturer's instructions. Modified HIPA was accepted as the gold standard test. Between March 8 and November 19, 2021, a total of 34 samples from clinically well-characterized patients (14 males, 20 females, mean age: 48.2 ± 18.2 years) were analyzed with PaGIA, EIA, and modified HIPA. VITT was diagnosed in 15 patients. Sensitivity and specificity of PaGIA were 54 and 67%, respectively. Anti-PF4/heparin optical density values were not significantly different between PaGIA positive and negative samples (p = 0.586). The sensitivity and specificity of EIA, on the other hand, were 87 and 100%, respectively. In conclusion, PaGIA is not reliable in the diagnosis of VITT because of its low sensitivity and specificity.

[Mechanism and clinical treatment strategy of heparin resistance].

Heparin resistance is becoming a hot issue of clinical concern. In critically ill patients, heparin resistance can lead to failure of anticoagulation therapy or increase the risk of major bleeding. Prompt recognition of heparin resistance can help to precisely adjust heparin dosage and avoid deterioration and adverse events. Heparin resistance can be mechanistically classified into the antithrombin-mediated and the non-antithrombin-mediated. Common etiologies include heparin-induced thrombocytopenia, severe infections such as severe COVID-19, treatment with extracorporeal circulation or extracorporeal membrane oxygenation (ECMO), and use of factor Xa reversal agents; heparin resistance is now often identified by the concordance of activated partial thromboplastin time (APTT) ratio with anti-FXa. Common clinical management strategies include antithrombin supplementation and replacement of anticoagulant drugs (e.g., direct thrombin inhibitors), but their safety and efficacy still need to be further validated.

Retroperitoneal Hematoma During Prophylactic Dose of Heparin Therapy for Coronavirus Disease 2019.

We report a case of retroperitoneal hematoma during prophylactic heparin therapy for coronavirus disease 2019 (COVID-19). A 79-year-old man was diagnosed with COVID-19 pneumonia with possible exacerbation of fibrotic hypersensitivity pneumonia. He received a prophylactic dose of subcutaneous heparin therapy, methylprednisolone pulse therapy and Intravenous remdesivir but developed a spontaneous iliopsoas muscle hematoma, and transcatheter arterial embolization was performed. Even with a prophylactic dose of subcutaneous heparin therapy, the course should be carefully monitored, especially in patients with preexisting risk factors for hemorrhagic complications. Once retroperitoneal hematoma develops, aggressive procedures, such as transcatheter arterial embolization, should be considered to avoid fatal outcomes.

Efficacy and safety of nafamostat mesilate anticoagulation in blood purification treatment of critically ill patients: a systematic review and meta-analysis.

BACKGROUND: Nafamostat mesilate (NM), a broad-spectrum and potent serine protease inhibitor, can be used as an anticoagulant during extracorporeal circulation, as well as a promising drug effective against coronavirus disease 2019 (COVID-19). We conducted a systematic meta-analysis to evaluate the safety and efficacy of NM administration in critically ill patients who underwent blood purification therapy (BPT). METHODS: The Cochrane Library, Web of Science and PubMed were comprehensively searched from inception to August 20, 2021, for potential studies. RESULTS: Four randomized controlled trials (RCTs) and seven observational studies with 2723 patients met the inclusion criteria. The meta-analysis demonstrated that conventional therapy (CT) significantly increased hospital mortality compared with NM administration (RR = 1.25, p = 0.0007). In subgroup analyses, the in-hospital mortality of the NM group was significantly lower than that of the anticoagulant-free (NA) group (RR = 1.31, p = 0.002). The CT interventions markedly elevated the risk ratio of bleeding complications by 45% (RR = 1.45, p = 0.010) compared with NM interventions. In another subgroup analysis, NM used exhibited a significantly lower risk of bleeding complications than those of the low-molecular-weight heparin (LMWH) used (RR = 4.58, p = 0.020). The filter lifespan was decreased significantly (MD = -10.59, p < 0.0001) in the NA groups compared with the NM groups. Due to the poor quality of the included RCTs, these results should be interpreted with caution. CONCLUSION: Given the better survival outcomes, lower risk of bleeding, NM anticoagulation seems to be a safe and efficient approach for BPT patients and could yield a favorable filter lifespan. More multi-center RCTs with large samples are required for further validation of this study.

Use of nafamostat mesilate for anticoagulation during extracorporeal membrane oxygenation: A systematic review.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) represents an advanced option for supporting refractory respiratory and/or cardiac failure. Systemic anticoagulation with unfractionated heparin (UFH) is routinely used. However, patients with bleeding risk and/or heparin-related side effects may necessitate alternative strategies: among these, nafamostat mesilate (NM) has been reported. METHODS: We conducted a systematic literature search (PubMed and EMBASE, updated 12/08/2021), including all studies reporting NM anticoagulation for ECMO. We focused on reasons for starting NM, its dose and the anticoagulation monitoring approach, the incidence of bleeding/thrombosis complications, the NM-related side effects, ECMO weaning, and mortality. RESULTS: The search revealed 11 relevant findings, all with retrospective design. Of these, three large studies reported a control group receiving UFH, the other were case series (n = 3) or case reports (n = 5). The main reason reported for NM use was an ongoing or high risk of bleeding. The NM dose varied largely as did the anticoagulation monitoring approach. The average NM dose ranged from 0.46 to 0.67 mg/kg/h, but two groups of authors reported larger doses when monitoring anticoagulation with ACT. Conflicting findings were found on bleeding and thrombosis. The only NM-related side effect was hyperkalemia (n = 2 studies) with an incidence of 15%-18% in patients anticoagulated with NM. Weaning and survival varied across studies. CONCLUSION: Anticoagulation with NM in ECMO has not been prospectively studied. While several centers have experience with this approach in high-risk patients, prospective studies are warranted to establish the optimal space of this approach in ECMO.

ISTH guidelines for antithrombotic treatment in COVID-19.

Antithrombotic agents reduce risk of thromboembolism in severely ill patients. Patients with coronavirus disease 2019 (COVID-19) may realize additional benefits from heparins. Optimal dosing and timing of these treatments and benefits of other antithrombotic agents remain unclear. In October 2021, ISTH assembled an international panel of content experts, patient representatives, and a methodologist to develop recommendations on anticoagulants and antiplatelet agents for patients with COVID-19 in different clinical settings. We used the American College of Cardiology Foundation/American Heart Association methodology to assess level of evidence (LOE) and class of recommendation (COR). Only recommendations with LOE A or B were included. Panelists agreed on 12 recommendations: three for non-hospitalized, five for non-critically ill hospitalized, three for critically ill hospitalized, and one for post-discharge patients. Two recommendations were based on high-quality evidence, the remainder on moderate-quality evidence. Among non-critically ill patients hospitalized for COVID-19, the panel gave a strong recommendation (a) for use of prophylactic dose of low molecular weight heparin or unfractionated heparin (LMWH/UFH) (COR 1); (b) for select patients in this group, use of therapeutic dose LMWH/UFH in preference to prophylactic dose (COR 1); but (c) against the addition of an antiplatelet agent (COR 3). Weak recommendations favored (a) sulodexide in non-hospitalized patients, (b) adding an antiplatelet agent to prophylactic LMWH/UFH in select critically ill, and (c) prophylactic rivaroxaban for select patients after discharge (all COR 2b). Recommendations in this guideline are based on high-/moderate-quality evidence available through March 2022. Focused updates will incorporate future evidence supporting changes to these recommendations.

Anticoagulants for people hospitalised with COVID-19.

BACKGROUND: The primary manifestation of coronavirus disease 2019 (COVID-19) is respiratory insufficiency that can also be related to diffuse pulmonary microthrombosis and thromboembolic events, such as pulmonary embolism, deep vein thrombosis, or arterial thrombosis. People with COVID-19 who develop thromboembolism have a worse prognosis. Anticoagulants such as heparinoids (heparins or pentasaccharides), vitamin K antagonists and direct anticoagulants are used for the prevention and treatment of venous or arterial thromboembolism. Besides their anticoagulant properties, heparinoids have an additional anti-inflammatory potential. However, the benefit of anticoagulants for people with COVID-19 is still under debate. OBJECTIVES: To assess the benefits and harms of anticoagulants versus active comparator, placebo or no intervention in people hospitalised with COVID-19. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase, LILACS and IBECS databases, the Cochrane COVID-19 Study Register and medRxiv preprint database from their inception to 14 April 2021. We also checked the reference lists of any relevant systematic reviews identified, and contacted specialists in the field for additional references to trials. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs), quasi-RCTs, cluster-RCTs and cohort studies that compared prophylactic anticoagulants versus active comparator, placebo or no intervention for the management of people hospitalised with COVID-19. We excluded studies without a comparator group and with a retrospective design (all previously included studies) as we were able to include better study designs. Primary outcomes were all-cause mortality and necessity for additional respiratory support. Secondary outcomes were mortality related to COVID-19, deep vein thrombosis, pulmonary embolism, major bleeding, adverse events, length of hospital stay and quality of life. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We used Cochrane RoB 1 to assess the risk of bias for RCTs, ROBINS-I to assess risk of bias for non-randomised studies (NRS) and GRADE to assess the certainty of evidence. We meta-analysed data when appropriate. MAIN RESULTS: We included seven studies (16,185 participants) with participants hospitalised with COVID-19, in either intensive care units, hospital wards or emergency departments. Studies were from Brazil (2), Iran (1), Italy (1), and the USA (1), and two involved more than country. The mean age of participants was 55 to 68 years and the follow-up period ranged from 15 to 90 days. The studies assessed the effects of heparinoids, direct anticoagulants or vitamin K antagonists, and reported sparse data or did not report some of our outcomes of interest: necessity for additional respiratory support, mortality related to COVID-19, and quality of life. Higher-dose versus lower-dose anticoagulants (4 RCTs, 4647 participants) Higher-dose anticoagulants result in little or no difference in all-cause mortality (risk ratio (RR) 1.03, 95% CI 0.92 to 1.16, 4489 participants; 4 RCTs) and increase minor bleeding (RR 3.28, 95% CI 1.75 to 6.14, 1196 participants; 3 RCTs) compared to lower-dose anticoagulants up to 30 days (high-certainty evidence). Higher-dose anticoagulants probably reduce pulmonary embolism (RR 0.46, 95% CI 0.31 to 0.70, 4360 participants; 4 RCTs), and slightly increase major bleeding (RR 1.78, 95% CI 1.13 to 2.80, 4400 participants; 4 RCTs) compared to lower-dose anticoagulants up to 30 days (moderate-certainty evidence). Higher-dose anticoagulants may result in little or no difference in deep vein thrombosis (RR 1.08, 95% CI 0.57 to 2.03, 3422 participants; 4 RCTs), stroke (RR 0.91, 95% CI 0.40 to 2.03, 4349 participants; 3 RCTs), major adverse limb events (RR 0.33, 95% CI 0.01 to 7.99, 1176 participants; 2 RCTs), myocardial infarction (RR 0.86, 95% CI 0.48 to 1.55, 4349 participants; 3 RCTs), atrial fibrillation (RR 0.35, 95% CI 0.07 to 1.70, 562 participants; 1 study), or thrombocytopenia (RR 0.94, 95% CI 0.71 to 1.24, 2789 participants; 2 RCTs) compared to lower-dose anticoagulants up to 30 days (low-certainty evidence). It is unclear whether higher-dose anticoagulants have any effect on necessity for additional respiratory support, mortality related to COVID-19, and quality of life (very low-certainty evidence or no data). Anticoagulants versus no treatment (3 prospective NRS, 11,538 participants) Anticoagulants may reduce all-cause mortality but the evidence is very uncertain due to two study results being at critical and serious risk of bias (RR 0.64, 95% CI 0.55 to 0.74, 8395 participants; 3 NRS; very low-certainty evidence). It is uncertain if anticoagulants have any effect on necessity for additional respiratory support, mortality related to COVID-19, deep vein thrombosis, pulmonary embolism, major bleeding, stroke, myocardial infarction and quality of life (very low-certainty evidence or no data). Ongoing studies We found 62 ongoing studies in hospital settings (60 RCTs, 35,470 participants; 2 prospective NRS, 120 participants) in 20 different countries. Thirty-five ongoing studies plan to report mortality and 26 plan to report necessity for additional respiratory support. We expect 58 studies to be completed in December 2021, and four in July 2022. From 60 RCTs, 28 are comparing different doses of anticoagulants, 24 are comparing anticoagulants versus no anticoagulants, seven are comparing different types of anticoagulants, and one did not report detail of the comparator group. AUTHORS' CONCLUSIONS: When compared to a lower-dose regimen, higher-dose anticoagulants result in little to no difference in all-cause mortality and increase minor bleeding in people hospitalised with COVID-19 up to 30 days. Higher-dose anticoagulants possibly reduce pulmonary embolism, slightly increase major bleeding, may result in little to no difference in hospitalisation time, and may result in little to no difference in deep vein thrombosis, stroke, major adverse limb events, myocardial infarction, atrial fibrillation, or thrombocytopenia.  Compared with no treatment, anticoagulants may reduce all-cause mortality but the evidence comes from non-randomised studies and is very uncertain. It is unclear whether anticoagulants have any effect on the remaining outcomes compared to no anticoagulants (very low-certainty evidence or no data). Although we are very confident that new RCTs will not change the effects of different doses of anticoagulants on mortality and minor bleeding, high-quality RCTs are still needed, mainly for the other primary outcome (necessity for additional respiratory support), the comparison with no anticoagulation, when comparing the types of anticoagulants and giving anticoagulants for a prolonged period of time.

Bleeding and thrombosis outcomes in hospitalised COVID-19 patients on low-molecular-weight heparin and antiplatelet therapy.

BACKGROUND: An increased incidence of thromboembolic events in hospitalised COVID­19 patients has been demonstrated despite the use of low-molecular-weight heparin (LMWH). Antiplatelet therapy prior to admission and early in the disease course has been hypothesised to be protective against thrombosis. OBJECTIVES: To describe the bleeding and thrombosis outcomes in hospitalised patients with confirmed COVID­19 receiving LMWH, with and without concomitant antiplatelet therapy. Secondary objectives were to explore predictors of bleeding and thrombosis outcomes, and dosing practices of antiplatelet therapy and LMWH. METHODS: We conducted a descriptive, cross-sectional study of bleeding and thrombosis outcomes at Tygerberg Academic Hospital, Cape Town, South Africa, during the first COVID­19 wave, in 808 hospitalised patients with confirmed COVID­19 receiving LMWH with and without concomitant antiplatelet therapy. Multivariate logistic regression analysis was performed if predictors were deemed statistically and clinically significant. RESULTS: Patients receiving both LMWH and antiplatelet therapy had similar bleeding outcomes compared with patients only receiving LMWH (odds ratio (OR) 1.5; 95% confidence interval (CI) 0.6 - 4.0). Patients receiving both LMWH and antiplatelet therapy had increased odds of developing thrombosis compared with patients only receiving LMWH (OR 4.8; 95% CI 2.1 - 10.7). CONCLUSION: The bleeding risk in COVID­19 patients receiving both LMWH and antiplatelet therapy was not significantly increased. A potentially higher risk of thrombosis in patients receiving LMWH and antiplatelet therapy was observed. However, this could reflect confounding by indication. Randomised studies are required to further evaluate the use of antiplatelet therapy to treat hospitalised patients with COVID­19.

Fatal intracerebral haemorrhage associated with thrombosis with thrombocytopenia syndrome after ChAdOx1-S vaccine. / Hemorragia intracerebral fatal asociada al síndrome de trombosis con trombocitopenia tras la vacuna ChAdOx1-S.

INTRODUCTION: The COVID-19 pandemic has had a devastating impact on health, society and economics worldwide. Therefore, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have recently emerged as an important measure to fight the pandemic. ChAdOx1-S (Oxford-AstraZeneca) is an adenovirus-vectored vaccine that expresses the SARS-CoV-2 spike protein. It shows an acceptable safety profile. Nevertheless, several cases of unusual thrombosis and thrombocytopenia have been reported after initial vaccination with ChAdOx1-S mimicking autoimmune heparin-induced thrombocytopenia. This condition has been called thrombosis with thrombocytopenia syndrome (TTS) and complications such as intracerebral haemorrhage have been described. CASE REPORT: We present a case of intracerebral haemorrhage after ChAdOx1-S vaccination. Middle-aged patient with no prior medical history was seen in the emergency room 16 days after the first dose of ChAdOx1-S vaccine with sudden onset left hemiplegia and severe holocranial oppressive headache. She did not receive heparin treatment in the previous 100 days. Blood test showed moderate thrombocytopenia and a right frontal lobar haemorrhage was seen on computed tomography scan, computed tomography venography was negative for thrombosis. The presence of antibodies against platelet factor 4 was confirmed. The patient's neurological condition progressively worsened. She developed a treatment resistant intracranial hypertension syndrome and she died three weeks later. CONCLUSIONS: TTS is a rare adverse effect of ChAdOx1-S vaccine, defined by the presence of thrombosis in uncommon locations. In our case we report an spontaneous intracerebral haemorrhage probable due to the thrombocytopenia related to probable TTS. It represents a rare clinical presentation of TTS.

TITLE: Hemorragia intracerebral fatal asociada al síndrome de trombosis con trombocitopenia tras la vacuna ChAdOx1-S.Introducción. La pandemia por COVID-19 ha tenido un impacto devastador en la salud, la sociedad y la economía en el mundo. Por ello, las vacunas contra el coronavirus del síndrome respiratorio agudo grave 2 (SARS-CoV-2) han surgido como medida importante para combatir la pandemia. ChAdOx1-S (Oxford-AstraZeneca) es una vacuna vectorizada por adenovirus que expresa la proteína de espiga del SARS-CoV-2. Se han notificado varios casos de trombosis y trombocitopenia inusuales tras la ChAdOx1-S que imitan la trombocitopenia autoinmune inducida por heparina. Esta situación se denomina síndrome de trombosis con trombocitopenia (STT), y se han descrito casos de hemorragia intracerebral secundaria. Caso clínico. Presentamos un caso de hemorragia intracerebral tras la vacunación con ChAdOx1-S. Una paciente de mediana edad sin antecedentes médicos de interés fue atendida en urgencias 16 días después de la primera dosis de ChAdOx1-S con una hemiplejía izquierda de inicio repentino y una cefalea opresiva holocraneal grave. No recibió heparina los 100 días anteriores. El análisis de sangre mostró trombocitopenia moderada y en la tomografía computarizada se observó una hemorragia lobar frontal derecha sin trombosis en la venografía por tomografía computarizada. Se confirmó la presencia de anticuerpos contra el factor 4 de las plaquetas en la sangre. La paciente presentó un síndrome de hipertensión intracraneal resistente al tratamiento y falleció tres semanas después. Conclusiones. El STT es un efecto adverso infrecuente de la vacuna ChAdOx1-S que se define por la presencia de trombosis en localizaciones infrecuentes. En nuestro caso, describimos una hemorragia intracerebral espontánea secundaria a la trombocitopenia desencadenada por el STT. Representa una presentación clínica poco frecuente del STT.

[Heparin-induced thrombocytopenia and vaccine-induced immune thrombotic thrombocytopenia: novel insights on anti-platelet factor 4 antibodies].

The levels of anti-platelet factor 4 (PF4) antibodies, also known as anti-PF4 or heparin complex antibodies, are used to diagnose heparin-induced thrombocytopenia (HIT). In HIT, anti-PF4 antibodies induced by heparin exposure cause thrombocytopenia and thrombosis. However, anti-PF4 antibodies were recently reported to be associated with the development of fatal vaccine-induced immune thrombotic thrombocytopenia (VITT) after adenoviral vector vaccination for coronavirus disease 2019. HIT and VITT are caused by anti-PF4 antibodies and have similar pathological conditions. However, the severity of these conditions differs and the detection sensitivity of their antibodies varies depending on the assays used. Herein, we review HIT and VITT associated with anti-PF4 antibodies.