Hematological changes as a consequence of COVID-19 and its vaccines / Alteraciones hematológicas como consecuencia de COVID-19 y sus vacunas

El virus SARS-CoV-2 continúa infectando a millones de individuos en el mundo. Aunque los síntomas más frecuentes observados en los pacientes con COVID-19 son fiebre, fatiga y tos, en los casos severos la hipercoagulabilidad y la inflamación son dos condiciones que pueden producir complicaciones y causar daño en órganos, poniendo en riesgo la vida del paciente. Con el fin de clasificar a los pacientes durante el triaje, se han explorado diferentes marcadores hematológicos, incluidos el recuento de plaquetas, linfocitos y eosinófilos, y la relación neutrófilos/ linfocitos, entre otros. Por su parte, para la evaluación de las coagulopatías, se vienen determinando marcadores como el dímero D y el fibrinógeno. En esta revisión se abordan las coagulopatías y los parámetros hematológicos en pacientes con COVID-19, al igual que las anormalidades en la coagulación como la trombocitopenia trombótica inmune inducida por las vacunas contra el SARS-CoV-2

The SARS-CoV-2 virus continues to infect millions of individuals around the world. Although the most frequent symptoms observed in patients with COVID-19 are fever, fatigue and cough, in severe cases hypercoagulability and inflammation are two conditions that can cause complications and organ failure, putting the patient's life at risk. In order to classify patients during triage, different hematological markers have been explored, including platelet, lymphocyte, and eosinophil counts, and the neutrophil/lymphocyte ratio, among others. Furthermore, for the evaluation of coagulopathies, markers such as D-dimer and fibrinogen are being evaluated. This review addresses the coagulopathies and hematological parameters in patients with COVID-19, as well as coagulation abnormalities such as immune thrombotic thrombocytopenia induced by SARS-CoV-2 vaccines

SARS-CoV-2 from a hematological perspective / SARS-CoV-2 desde una perspectiva hematológica

La infección viral respiratoria causada por el SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) produce la enfermedad por coronavirus 2019 o COVID-19. Hasta el 20% al 50% de los pacientes hospitalizados con COVID-19 tienen alteraciones de la coagulación (dímero D elevado, tiempo de protrombina prolongado, trombocitopenia y fibrinógeno bajo). Esta condición se caracteriza por eventos trombóticos más que hemorrágicos. De otro lado, se presenta disfunción endotelial, lo cual explica los niveles elevados de trombina, de dímero D y de otros productos de degradación de fibrina, la trombocitopenia y la prolongación de los tiempos de coagulación; estos cambios terminan por originar hipoxia, oclusión microvascular y congestión pulmonar mediada por trombosis [1]. Se ha demostrado que el tratamiento anticoagulante inicial con heparinas de bajo peso molecular reduce la mortalidad un 48% a los 7 días y un 37% a los 28 días, y logra una mejoría significativa del cociente presión arterial de oxígeno/fracción inspirada de O2 (PaO2/FiO2), al mitigar la formación de microtrombos y la coagulopatía pulmonar asociada, disminuyendo además la inflamación [2]. En el artículo titulado "Alteraciones hematológicas como consecuencia de COVID-19 y sus vacunas", se abordan las anormalidades en la coagulación como la trombocitopenia trombótica inmune inducida por las vacunas contra el SARS-CoV-2. Es importante anotar, que hoy en día la comunidad científica está de acuerdo en que sin la vacunación hubiera sido imposible lograr el control actual que se tiene de la pandemia, pero a la vez se debe tener en cuenta que cualquier inmunización tiene también efectos adversos que por lo general son leves, pero que en raras ocasiones se pueden presentar complicaciones de mayor magnitud

Acquired Factor VIII Inhibitors: A Case Study.

The physiology of hemostasis is one of high complexity that involves the initiation, amplification, and propagation of the many moving parts of the hemostatic system and its regulatory mechanisms. It is imperative that clinical laboratory professionals have a strong understanding of the many intricacies of the physiology of coagulation and its in vitro testing. An elongated activated partial thromboplastin time can have several causes, and the correct cause must be elucidated in a timely manner for proper treatment. A mixing study with normal pooled plasma should be performed to evaluate for the presence of an inhibitor vs factor deficiency. Factor inhibitors, specifically factor VIII in this case study, should be titered so that the clinician can decide which treatment may work best for the patient. Continued monitoring of factor levels and inhibitor titers should be conducted to follow the resolution or progression of inhibitor presence.

Changes in haemostasis and inflammatory markers after mRNA BNT162b2 and vector Ad26.CoV2.S SARS-CoV-2 vaccination.

INTRODUCTION: Reported thromboembolic events after SARS-CoV-2 vaccinations are still raising concerns, predominantly in non-scientific population. The aim of our study was to investigate the differences between haemostasis and inflammatory markers in the subjects vaccinated with mRNA BNT162b2 and vector Ad26.CoV2.S vaccine. MATERIALS AND METHODS: The study included 87 subjects vaccinated with mRNA BNT162b2 and 84 with Ad26.CoV2.S vaccine. All the laboratory parameters (TAT, F 1 + 2, IL-6, CRP, big endothelin-1, platelets, fibrinogen, D-dimers, VWF activity) were investigated for the mRNA vaccine at five (before the first dose, 7 and 14 days after the first and second vaccine dose), and three time points (before the first dose, 7 and 14 days after) for the vector vaccine, respectively. All the markers were measured by well-established laboratory methods. RESULTS: Our results have shown statistically higher CRP levels in the vector group 7 days after vaccination (P = 0.014). Furthermore, study has revealed statistically significant rise in D-dimers (P = 0.004) between tested time points in both vaccine groups but without clinical repercussions. CONCLUSION: Although statistically significant changes in haemostasis markers have been obtained, they remained clinically irrelevant. Thus, our study implicates that there is no plausible scientific evidence of a significant disruption in the coagulation and inflammatory processes after vaccination with BNT162b2 mRNA and Ad26.CoV2.S vector SARS-CoV-2 vaccines.

Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19.

BACKGROUND: Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results. OBJECTIVES: We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19. METHODS: Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group. RESULTS: Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent. CONCLUSIONS: Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079).

BLOOD COAGULATION DISORDERS IN PATIENTS WITH LIVER CIRRHOSIS INFECTED COVID-19.

OBJECTIVE: The aim: To investigate the features of coagulation homeostasis in patients with liver cirrhosis (LC) in COVID-19 infection. PATIENTS AND METHODS: Materials and methods: At the clinical base of the Department of Propaedeutics of Internal Medicine, 32 patients with LC infected with COVID-19 were examined - 1 Group of patients. The study also included 30 patients with LC who were not infected with COVID-19 (2 Group of patients). RESULTS: Results: The analysis of the obtained data indicates disorders of the hemostasis system in patients with LC without the COVID-19 infection (Group 2), as well as in patients with LC at the time of being infected with COVID-19. The violation of the protein synthesis function of the liver is manifested through a decrease in the level of fibrinogen in blood serum (up to 2.0±0.5 gr/l in patients of Group 1 at the time of admission for inpatient care) and up to 21.9±0.5 gr/l in patients of group ІІ - р<0.05. This was accompanied by an acceleration of prothrombin time, thrombin time and activated partial thromboplastic time in patients with LC, as well as an increase in the level of antithrombin III. The level of D-dimer was reduced both in patients of group II and in patients of group I at the time of being infected with COVID-19. CONCLUSION: Conclusions: Changes in coagulation homeostasis characteristic of hypocoagulation syndrome have been established in patients with LC. COVID-19 infection in patients with LC leads to hypercoagulation, especially in patients with complicated stage of LC (ascites, encephalopathy, hepatorenal syndrome).

Recurrent floating common carotid artery thrombus related to COVID-19: A case report.

The occurrence of arterial and venous thrombosis during coronavirus infection has been widely reported since the beginning of the epidemic. Floating carotid thrombus (FCT) in the common carotid artery is exceptional and its main known cause is atherosclerosis. We describe the case of a 54-year-old man who developed, one week after the onset symptomatology of related to COVID-19 infection, an ischemic stroke, complicating a large intraluminal floating thrombus in the left common carotid artery. Despite surgery and anticoagulation, a local recurrence with other thrombotic complications occurred and the patient died.

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.

Immature platelets in COVID-19.

Platelets play a critical role in immune response. Coronavirus disease 2019 (COVID-19) patients with a severe course often show pathological coagulation parameters including thrombocytopenia, and at the same time the proportion of immature platelets increases. In this study, the platelet count and the immature platelet fraction (IPF) of hospitalized patients with different oxygenation requirements was investigated daily over a course of 40 days. In addition, the platelet function of COVID-19 patients was analyzed. It was found that the number of platelets in patients with the most severe course (intubation and extracorporeal membrane oxygenation (ECMO)) was significantly lower (111.5 ∙ 106 /mL) than in the other groups (mild (no intubation, no ECMO): 203.5 ∙ 106 /mL, p < .0001, moderate (intubation, no ECMO): 208.0 ∙ 106 /mL, p < .0001). IPF tended to be elevated (10.9%). Platelet function was reduced. Differentiation by outcome revealed that the deceased patients had a highly significant lower platelet count and higher IPF (97.3 ∙ 106 /mL, p < .0001, 12.2%, p = .0003).

What is the context? Pathological coagulation is a feature of severe cases of COVID-19, with both bleeding complications and thrombosis. Patients with severe COVID-19 are frequently treated with extracorporeal membrane oxygenation (ECMO), which is often associated with bleeding complications. Platelets play an important role in blood clotting. The proportion of immature platelets has been characterized as hyperreactive and associated with high prothrombotic activity. In addition, they are discussed as predictors of COVID-19 disease severity.What is new? In grading the severity of disease in our patient cohort, we consider the required oxygenation measures. Thus, the focus is on severe cases requiring intubation and ECMO compared to moderate (intubation, no ECMO) and mild (no intubation, no ECMO) cases.What is the impact? This study focuses on severely ill patients who require ECMO treatment. Therefore, this study provides further evidence to use immature platelet fraction to predict the outcome of severe COVID-19 courses.

Pharmacology and Clinical Development of Factor XI Inhibitors.

Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.

The Long Term Residual Effects of COVID-Associated Coagulopathy.

During the acute phase of COVID-19, many patients experience a complex coagulopathy characterized by a procoagulant pattern. The present study investigates the persistence of hemostatic changes in post-COVID patients at a long-term follow up, and the link with the persistence of physical and neuropsychological symptoms. We completed a prospective cohort study on 102 post-COVID patients. Standard coagulation and viscoelastic tests were performed, along with an assessment of persistent symptoms and recording of acute phase details. A procoagulant state was adjudicated in the presence of fibrinogen > 400 mg/dL, or D-dimer > 500 ng/mL, or platelet count > 450,000 cells/µL, or a maxim clot lysis at viscoelastic test < 2%. A procoagulant state was identified in 75% of the patients at 3 months follow up, 50% at 6 months, and 30% at 12-18 months. Factors associated with the persistence of a procoagulant state were age, severity of the acute phase, and persistence of symptoms. Patients with major physical symptoms carry a procoagulant state relative risk of 2.8 (95% confidence interval 1.17-6.7, p = 0.019). The association between persistent symptoms and a procoagulant state raises the hypothesis that an ongoing process of thrombi formation and/or persistent microthrombosis may be responsible for the main physical symptoms in long-COVID patients.

Post-transcriptional control of haemostatic genes: mechanisms and emerging therapeutic concepts in thrombo-inflammatory disorders.

The haemostatic system is pivotal to maintaining vascular integrity. Multiple components involved in blood coagulation have central functions in inflammation and immunity. A derailed haemostasis is common in prevalent pathologies such as sepsis, cardiovascular disorders, and lately, COVID-19. Physiological mechanisms limit the deleterious consequences of a hyperactivated haemostatic system through adaptive changes in gene expression. While this is mainly regulated at the level of transcription, co- and posttranscriptional mechanisms are increasingly perceived as central hubs governing multiple facets of the haemostatic system. This layer of regulation modulates the biogenesis of haemostatic components, for example in situations of increased turnover and demand. However, they can also be 'hijacked' in disease processes, thereby perpetuating and even causally entertaining associated pathologies. This review summarizes examples and emerging concepts that illustrate the importance of posttranscriptional mechanisms in haemostatic control and crosstalk with the immune system. It also discusses how such regulatory principles can be used to usher in new therapeutic concepts to combat global medical threats such as sepsis or cardiovascular disorders.

Effect of extracorporeal hemoadsorption in critically ill patients with COVID-19: A narrative review.

COVID-19 has been affecting the world unprecedentedly and will remain widely prevalent due to its elusive pathophysiological mechanism and the continuous emergence of new variants. Critically ill patients with COVID-19 are commonly associated with cytokine storm, multiple organ dysfunction, and high mortality. To date, growing evidence has shown that extracorporeal hemoadsorption can exert its adjuvant effect to standard of care by regulating immune homeostasis, reducing viremia, and decreasing endotoxin activity in critically ill COVID-19 cases. However, the selection of various hemofilters, timing of initiation and termination of hemoadsorption therapy, anticoagulation management of extracorporeal circuits, identification of target subgroups, and ultimate survival benefit remain controversial. The purpose of this narrative review is to comprehensively summarize the rationale for the use of hemoadsorption in critically ill patients with COVID-19 and to gather the latest clinical evidence in this field.

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC).

COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein-Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

The Effect of Heparin Full-Dose Anticoagulation on Survival of Hospitalized, Non-critically Ill COVID-19 Patients: A Meta-analysis of High Quality Studies.

BACKGROUND: International COVID-19 guidelines recommend thromboprophylaxis for non-critically ill inpatients to prevent thrombotic complications. It is still debated whether full-dose thromboprophylaxis reduces all-cause mortality. The main aim of this updated systematic review and meta-analysis is to evaluate the effect of full-dose heparin-based thromboprophylaxis on survival in hospitalized non-critically ill COVID-19 patients. METHODS: A systematic review was performed across Pubmed/Medline, EMBASE, Cochrane Central Register of clinical trials, Clinicaltrials.gov, and medRxiv.org from inception to November 2022. We conducted a meta-analysis of randomized clinical trials (RCTs) comparing full-dose heparin-based anticoagulation to prophylactic or intermediate dose anticoagulation or standard treatment in hospitalized non-critically ill COVID-19 patients. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials and Grading of Recommendations Assessment, Development and Evaluation was applied. The primary outcome was all-cause mortality at the longest follow-up available. RESULTS: We identified 6 multicenter RCTs involving 3297 patients from 13 countries across 4 continents. The rate of all-cause mortality was 6.2% (103/1662) in the full-dose group vs 7.7% (126/1635) in the prophylactic or intermediate dose group (Risk Ratio [RR] = 0.76; 95% confidence interval [CI] = 0.59-0.98; P = 0.037). The probabilities of any mortality difference and of NNT ≤ 100 were estimated at 98.2% and 84.5%, respectively. The risk of bias was low for all included RCTs and the strength of the evidence was "moderate." CONCLUSION: Our meta-analysis of high-quality multicenter RCTs suggests that full-dose anticoagulation with heparin or low molecular weight heparin reduces all-cause mortality in hospitalized non-critically ill COVID-19 patients. STUDY REGISTRATION: PROSPERO, review no. CRD42022348993.