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.

Whole Blood Procoagulant Platelet Flow Cytometry Protocol for Heparin-Induced Thrombocytopenia (HIT) and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT) Testing.

Heparin-induced thrombocytopenia (HIT) is a well-characterized, iatrogenic complication of heparin anticoagulation with significant morbidity. In contrast, vaccine-induced immune thrombotic thrombocytopenia (VITT) is a recently recognized severe prothrombotic complication of adenoviral vaccines, including the ChAdOx1 nCoV-19 (Vaxzevria, AstraZeneca) and Ad26.COV2.S (Janssen, Johnson & Johnson) vaccines against COVID-19. The diagnosis of HIT and VITT involve laboratory testing for antiplatelet antibodies by immunoassays followed by confirmation by functional assays to detect platelet-activating antibodies. Functional assays are critical to detect pathological antibodies due to the varying sensitivity and specificity of immunoassays. This chapter presents a protocol for a novel whole blood flow cytometry-based assay to detect procoagulant platelets in healthy donor blood in response to plasma from patients suspected of HIT or VITT. A method to identify suitable healthy donors for HIT and VITT testing is also described.

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.

An Unusual Case of Combined Thrombosis and Amegakaryocytopenia Resembling Thrombosis With Thrombocytopenia Syndrome Following COVID-19 Infection in an Unvaccinated Patient.

As a global community, we have learned that the manifestations of severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2), infection, or coronavirus disease 2019 (COVID-19), extends far beyond respiratory compromise. Thrombocytopenia is thought to occur secondary to increased platelet consumption. Platelet activation and platelet-mediated immune inflammation contribute towards the thromboembolic complications seen in COVID-19 patients. In this report, the authors present the unusual case of a 75-year-old female with a history of COVID-19 infection who presented with a transient ischemic attack, thrombocytopenia, and amegakaryocytopenia.

High-intensity exercise prescription guided by heart rate variability in breast cancer patients: a study protocol for a randomized controlled trial.

BACKGROUND: Breast cancer is a chronic disease with a large growth in its treatments, prognosis, improvements, side effects and rehabilitation therapies research. These advances have also highlighted the need to use physical exercise as a countermeasure to reduce the cardiotoxicity of pharmacological treatments, increase patients' strength and quality of life and improve body composition, physical condition and mental health. However, new investigations show the need for a closed exercise individualisation to produce higher physiological, physical and psychological benefits in remote exercise programs. To this end, the present study will use, in a novel way in this population, heart rate variability (HRV) as a measure for prescribing high-intensity training. Thus, the primary objective of this randomised clinical trial is to analyse the effects of a high-intensity exercise program daily guided by HRV, a preplanned moderate to high-intensity exercise intervention and a usual care group, in breast cancer patients after chemotherapy and radiotherapy treatments. METHODS: For this purpose, a 16-week intervention will be carried out with 90 breast cancer patients distributed in 3 groups (a control group, a moderate to high-intensity preplanned exercise group and a high-intensity exercise group guided by HRV). Both physical exercise interventions will be developed remotely and supervised including strength and cardiovascular exercises. Physiological variables, such as cardiotoxicity, biomarkers, lipid profile, glucose, heart rate and blood pressure; physical measures like cardiorespiratory capacity, strength, flexibility, agility, balance and body composition; and psychosocial variables, as health-related quality of life, fatigue, functionality, self-esteem, movement fear, physical exercise level, anxiety and depression will be measure before, after the intervention and 3 and 6 months follow up. DISCUSSION: Personalized high-intensity exercise could be a promising exercise intervention in contrast to moderate-intensity or usual care in breast cancer patients to reach higher clinical, physical and mental effects. In addition, the novelty of controlling HRV measures daily may reflect exercise effects and patients' adaptation in the preplanned exercise group and a new opportunity to adjust intensity. Moreover, findings may support the effectiveness and security of physical exercise remotely supervised, although with high-intensity exercise, to reach cardiotoxicity improvements and increase physical and psychosocial variables after breast cancer treatments. Trial registration ClinicalTrials.gov nº NCT05040867 ( https://clinicaltrials.gov/ct2/show/record/NCT05040867 ).

High-Risk Pulmonary Embolism During Labor: JACC Patient Care Pathways.

While in labor, a 37-year-old woman developed acute dyspnea, hypoxemia, and tachycardia. Transthoracic echocardiography demonstrated severe right ventricular dilation and dysfunction, raising the suspicion of acute pulmonary embolism. The patient indeed had bilateral pulmonary embolism, necessitating percutaneous thrombectomy. Her course was complicated by another saddle pulmonary embolus, heparin-induced thrombocytopenia, and COVID-19 infection. This clinical case illustrates the importance of prompt diagnosis of acute pulmonary embolism in a peripartum female patient, the multidisciplinary approach of management, and how to approach clinical complications such as heparin-induced thrombocytopenia. Furthermore, long-term management in acute pulmonary embolism is presented.

Molecular docking-based virtual screening: Challenges in hits identification for Anti-SARS-Cov-2 activity

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) requires finding new drugs or repurposing drugs for clinical use. Molecular docking belongs to structure-based drug design providing a fast method for identifying the hit com-pounds with antiviral activity against SARS-Cov-2. However, the weakness of the docking method is compounded by the limited crystallographic information and comparison drugs due to the novelty of this virus can present challenges in identifying hits of anti-SARS-Cov-2. In the current review, we highlighted several aspects, especially those related to the target structure, docking validation, and virtual hit selection, that need to be considered to obtain reliable docking results. Here, we discussed several cases pertaining to the issue highlighted and approaches that could be used to solve them.

Comparison between unfractionated heparin (UFH) and fondaparinux on platelets and D-dimer level in COVID-19 patients with hypercoagulation

Introduction: This study aimed to compare the clinical effects between UFH and fondaparinux in COVID-19 patients with hypercoagulation. Material(s) and Method(s): This was a prospective cohort study. Samples were taken consecutively from hospitalized COVID-19 patients with hypercoagulation who received UFH or fondaparinux based on the standardized guidelines. A total of 71 patients met the inclusion criteria. Patients were evaluated for platelet and D-dimer values before and after administration of UFH or fondaparinux. Result(s): Although there was no difference in D-dimer reduction between the two groups (p = 0.44), fondaparinux showed a greater reduction, 26% against 22% for UFH. While on platelets, there was a significant difference (p = 0.04) between fondaparinux and UFH. Fondaparinux showed a reduced thrombocytopenia impact, as seen by an increase in pre-and post-therapy platelets of up to 50%, compared to 16% in UFH. In regard to the incidence of Heparin-Induced Thrombocytopenia (HIT), there was no significant difference between post-UFH therapy and post-fondaparinux therapy (p = 0.361). Conclusion(s): Fondaparinux did not reduce platelet levels as much as UFH, but there was no difference between the fondaparinux group compared to the UFH group in the effect of decreasing D-dimer levels and the sign of HIT. Copyright © 2022 Via Medica.

The Effect of (Hit) Training on Immune Globulins and White Blood Cells for Amateur Weightlifters after the Return of Activity from the Mandatory Quarantine for the Covid-19 Epidemic

The aim of the research is to identify an appropriate training method that raises the levels of immune globulins (IgA, IgM, IgG) and white blood cells and the effect of training by (HIT) method using resistance (weights) as a training curriculum that increases immunity and ensures the continuation of the pills after the return of activity from the stone The response to the Covid-19 epidemic among amateur weightlifters, the researchers relied on the method of trace analysis in an experimental way by conducting a pre-, medial and post-test with the same experimental one agroup on a sample of amateur weightlifters in the Fury private hall for weightlifting and body building in Adhamiya, the number of sample members reached (15 players) who interrupted training during the spread of the Covid 19 virus, and data treatment with (SPSS) system, and the conclusions were as follows, the effect of (HIT) training is effective in improving immune globulins (IgA, IgM, IgG) and white blood cells in light of the Corona pandemic And that the use of resistance (weights) according to the (HIT) method, which depends on the rest time equal to or slightly more than the training time had the effect of increasing the concentration of immune globulins and increasing the concentration of blood cells. White blood within the level.

COVID-19 Adenoviral Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT), COVID-19-Related Thrombosis, and the Thrombotic Thrombocytopenic Syndromes.

Adenoviral-based vaccines such as ChadoX1 CoV-19 (AstraZeneca) and Ad26.COV2.S (J&J) were developed to prevent infection and reduce hospitalization or death in Coronavirus Disease 2019 (COVID-19) patients. Although these vaccines passed safety and efficacy trials with excellent neutralizing capabilities against SARS-CoV-2, very rare reports of acute thrombotic thrombocytopenic events following administration emerged in certain populations, which triggered a series of clinical investigations that gave rise to a novel phenomenon called vaccine-induced immune thrombotic thrombocytopenia (VITT). Several converging pathways exist between VITT and other forms of thrombotic thrombocytopenic syndromes, specifically that of heparin-induced thrombocytopenia, which involves the formation of anti-PF4 antibodies and the activation of platelets leading to thrombocytopenia and thrombin-mediated clotting. Interestingly, certain differences in the presentation also exist in VITT, and guidelines have been published in recent months to assist clinicians in recognizing VITT to achieve desired outcomes. In this paper, we first discuss the clotting phenomenon in COVID-19 and delineate it from VITT, followed by a review of current knowledge on the clinical manifestations of VITT in lieu of other thrombotic thrombocytopenic syndromes. Likewise, emerging evidence on the role of adenoviral vectors and vaccine constituents is also discussed briefly.

Central retinal vein occlusion post ChAdOx1 nCoV-19 vaccination - can it be explained by the two-hit hypothesis?

PURPOSE: To report a case of central retinal vein occlusion (CRVO) seven days following the first dose of ChAdOx1 nCoV-19 vaccine and propose a hypothesis for the possible underlying pathogenesis. OBSERVATION: A 31-year-old male presented with CRVO with cystoid macular edema, one week after receiving his first ChAdOx1 nCoV-19 vaccine dose. Apart from mild hyperhomocysteinemia, no major thrombophilic or systemic risk factors were found. Anti-platelet factor 4 antibodies, specific for vaccine-induced immune thrombotic thrombocytopenia, were also negative. However, he tested strongly positive (> 250 U/mL) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG spike antibodies, 2 weeks post the first dose - suggestive of a prior subclinical infection. CONCLUSION: COVID-19 is known to be associated with an altered host one-carbon metabolism resulting in hyperhomocysteinemia. We hypothesize that a prior subclinical infection with COVID-19, the first hit, may have led to hyperhomocysteinemia in our patient and vaccination must have been the second hit that triggered the thrombotic event. Further studies, including correlation of thrombotic complications with IgG antibody titres post-vaccination, are essential in order to better understand the pathogenesis of such events.

[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.

Prevalence and clinical implication of thrombocytopenia and heparin-induced thrombocytopenia in patients who are critically ill with COVID-19.

As the COVID-19 pandemic continues to evolve, different clinical manifestations are better understood and studied. These include various haematologic disorders that have been shown to be associated with increased morbidity and mortality. We studied the prevalence of one unusual manifestation, heparin-induced thrombocytopenia (HIT) and its clinical implications in patients who are severely ill with COVID-19 in a single tertiary centre in Israel. The presence of thrombocytopenia, disseminated intravascular coagulation (DIC) and HIT, and their association with clinical course and outcomes were studied. One-hundred and seven patients with COVID-19 were included. Fifty-seven (53.2%) patients developed thrombocytopenia, which was associated with the worst outcomes (ventilation, DIC and increased mortality). Sixteen (28.0%) patients with thrombocytopenia were positive for HIT, all of which were supported by extracorporeal devices. HIT was independently associated with ventilation days, blood product transfusions, longer hospitalisation and mortality.Platelet abnormalities and HIT are common in patients who are critically ill with COVID-19 and are associated with the worst clinical outcomes. The mechanisms underlying HIT in COVID-19 are yet to be studied; HIT may contribute to the dysregulated immunologic response associated with COVID-19 critical illness and may play a significant part in the coagulopathy seen in these patients. As many patients with COVID-19 require aggressive thromboprophylaxis, further understanding of HIT and the implementation of appropriate protocols are important.

Screening, molecular simulation & in silico kinetics of virtually designed covid-19 main protease inhibitors.

Coronavirus (covid-19) infection is considered to be deadliest ever pandemic experienced by the human being. It has very badly affected the socio-economic health of human and stuck the scientific community to think and rethink about its complete eradication. But due to no effective treatment or unavailability of vaccine the health professional could not show any significant improvement to control the pandemic. The situation needs newer molecule, vaccine or effective treatment to control covid-19 infection. Different target in viruses has been explored and proteases enzymes were found to be therapeutically effective target for the design of potential anti-covid-19 molecule as it plays the vital role in viral replication and assembly. Structure-based drug design was employed to discover the small molecule of anti-covid-19. Here we considered the small library of naturally occurring polyphenolic compounds and molecular docking, Molecular dynamics (MD) simulations, free binding energy calculation and in-silico ADME calculations to identify the newer HITs. Based upon their score the two molecules were identified as promising candidate. The docking scores were found to be -7.643 and -7.065 for the HIT1 and HIT-2 respectively. In MD simulations study the RMSD values were found to be 4.3 Å & 4.9 Å respectively. To validate these results MM-GBSA was performed and their binding free energies were computationally determined. The prime energy values of identified HITs (-13412.45 & -13441.8 kJ/mole) were found to be very close proximity to reference molecule (-13493.05 kJ/mole). Then in-silico ADME calculations were performed to calculate the drug likeliness identified HITs. BY considering all the values comparative to reference molecule and obtained in-silico pharmacokinetic properties of identified HITs we can suggest that HIT-1 and HIT-2 would be the most promising molecules that can inhibit the main protease enzyme of covid-19. These two molecules would become the potential drug candidate for the treatment of covid-19 infections.

A Case of COVID-19 Vaccine-Induced Thrombotic Thrombocytopenia.

This report discusses a case of a 37-year-old female who developed vaccine-induced thrombotic thrombocytopenia (VITT) after receiving the Johnson and Johnson COVID-19 vaccination. The patient first presented to the ED with complaints of a worsening headache. Labs were significant for thrombocytopenia with a platelet count of 22,000, and the patient was admitted to the inpatient unit for monitoring. The day after admission, the patient was found to have a right common femoral artery embolus, left distal popliteal trifurcation embolism, a small pulmonary embolism in the right lower lobe, and a mural thrombus of the infrarenal abdominal aorta. Following these findings, the patient underwent emergent thrombectomy of the common and superficial femoral arteries. Over the hospital course of six days, the patient received steroids and IV immunoglobulin (IVIG), which led to the resolution of the thrombocytopenia. The patient was given argatroban followed by apixaban for anticoagulation. She was instructed to follow up with hematology within one to two weeks post-discharge for monitoring of anticoagulation and thrombus surveillance. This case report outlines the clinical course, diagnosis, and treatment of a case of VITT, which will assist physicians in early recognition and adequate treatment of this condition as the COVID-19 pandemic continues.

A case of severe COVID-19 with pulmonary thromboembolism related to heparin-induced thrombocytopenia during prophylactic anticoagulation therapy.

A 53-year-old male Japanese patient with COVID-19 was admitted to our hospital after his respiratory condition worsened on day 9 of the disease. With the diagnosis of severe COVID-19, treatment with remdesivir, dexamethasone, and unfractionated heparin was started for the prevention of thrombosis. Although the patient's respiratory status data improved after treatment, severe respiratory failure persisted. Thrombocytopenia and D-dimer elevation were observed on day 8 after heparin therapy initiation. Heparin-induced thrombocytopenia (HIT) antibody measured by immunological assay was positive, and contrast computed tomography showed pulmonary artery thrombus. The patient was diagnosed with HIT because the pre-test probability score (4Ts score) for HIT was 7 points. Heparin was changed to apixaban, a direct oral anticoagulant, which resulted in a reduction of the pulmonary thrombus and improvement of the respiratory failure. In patients with COVID-19, anticoagulant therapy with heparin requires careful monitoring of thrombocytopenia and elevated D-dimer as possible complications related to HIT. (151/250 words).

Vaccine-Induced Thrombotic Thrombocytopenia: A Case of Splanchnic Veins Thrombosis.

Vaccines have been vital in preventing and curbing the spread of SARS-CoV-2 infection. Adenoviral vector-based vaccines, namely the ChAdOx1-S vaccine (AstraZeneca, Cambridge, UK) and Ad26.COV2.S (Janssen; Johnson & Johnson, New Brunswick, NJ, USA), have been associated with a possibly fatal adverse event known as vaccine-induced thrombotic thrombocytopenia (VITT), wherein thrombi form in unusual sites, mainly the cerebral and splanchnic veins. With the female gender predominantly affected, patients present with headache, abdominal pain, neurological symptoms and fever. It is hypothesized that certain components of the vaccine, including the adenovirus vector, may trigger the formation of antibodies against platelet factor 4 (PF4). The antigen-antibody complexes that form thereafter then activate a cascade of reactions eventually leading to the consumptive coagulopathy. This pathogenesis closely resembles a well-understood complication of heparin, known as heparin-induced thrombocytopenia. The lab results in VITT are reflective of its proposed pathophysiology: low platelets, low fibrinogen and high D-dimer, in addition to elevated anti-PF4 titers are classic findings. Treatment mainly includes non-heparin anticoagulants, intravenous immune globulin (IVIG) and plasma exchange. There is some role for surgical intervention, such as mechanical thrombectomy. Mortality due to VITT is usually caused by cerebral hemorrhage. We describe a case of a 36-year-old female who presented with epigastric pain two weeks after receiving her first dose of the AstraZeneca vaccine, and upon workup, was subsequently found to have thrombosis of her right portal and right common iliac vein.

Towards the discovery of potential RdRp inhibitors for the treatment of COVID-19: structure guided virtual screening, computational ADME and molecular dynamics study.

Coronavirus disease 2019 (COVID-19) has become a major challenge affecting almost every corner of the world, with more than five million deaths worldwide. Despite several efforts, no drug or vaccine has shown the potential to check the ever-mutating SARS-COV-2. The emergence of novel variants is a major concern increasing the need for the discovery of novel therapeutics for the management of this pandemic. Out of several potential drug targets such as S protein, human ACE2, TMPRSS2 (transmembrane protease serine 2), 3CLpro, RdRp, and PLpro (papain-like protease), RNA-dependent RNA polymerase (RdRP) is a vital enzyme for viral RNA replication in the mammalian host cell and is one of the legitimate targets for the development of therapeutics against this disease. In this study, we have performed structure-based virtual screening to identify potential hit compounds against RdRp using molecular docking of a commercially available small molecule library of structurally diverse and drug-like molecules. Since non-optimal ADME properties create hurdles in the clinical development of drugs, we performed detailed in silico ADMET prediction to facilitate the selection of compounds for further studies. The results from the ADMET study indicated that most of the hit compounds had optimal properties. Moreover, to explore the conformational dynamics of protein-ligand interaction, we have performed an atomistic molecular dynamics simulation which indicated a stable interaction throughout the simulation period. We believe that the current findings may assist in the discovery of drug candidates against SARS-CoV-2.