Protein C and S activities in COVID-19: A systematic review and meta-analysis.

COVID-19 has been associated with alterations in coagulation. Recent reports have shown that protein C and S activities are altered in COVID-19. This may affect the complications and outcome of the disease. However, their exact role in COVID-19 remains uncertain. The aim of the current study was therefore to analyze all papers in the literature on protein C and S activities in COVID-19. We searched three medical electronic databases. Of the 2442 papers, 28 studies were selected for the present meta-analysis. For the meta-analysis, means ± standard deviations with 95% confidence intervals (CI) for protein C and S activities were extracted. Pooled p values were calculated using STATA software. Protein C and S activities were significantly lower in COVID-19 patients than in healthy controls (pooled p values: 0.04 and 0.02, respectively). Similarly, protein C activities were considerably lower in nonsurviving patients (pooled p value = 0.00). There was no association between proteins C or S and thrombosis risk or ICU admission in COVID-19 patients (p value > 0.05). COVID-19 patients may exhibit lower activities of the C and S proteins, which might affect disease outcome; however, additional attention should be given when considering therapeutic strategies for these patients.

Pharmacokinetic-Pharmacodynamic Modelling in Hemophilia A: Relating Thrombin and Plasmin Generation to Factor VIII Activity After Administration of a VWF/FVIII Concentrate.

BACKGROUND: Hemophilia A patients are treated with factor (F) VIII prophylactically to prevent bleeding. In general, dosage and frequency are based on pharmacokinetic measurements. Ideally, an alternative dose adjustment can be based on the hemostatic potential, measured with a thrombin generation assay (TGA), like the Nijmegen hemostasis assay. OBJECTIVE: The objective of this study was to investigate the predicted performance of a previously developed pharmacokinetic-pharmacodynamic model for FVIII replacement therapy, relating FVIII dose and FVIII activity levels with thrombin and plasmin generation parameters. METHODS: Pharmacokinetic and pharmacodynamic measurements were obtained from 29 severe hemophilia A patients treated with pdVWF/FVIII concentrate (Haemate P®). The predictive performance of the previously developed pharmacokinetic-pharmacodynamic model was evaluated using nonlinear mixed-effects modeling (NONMEM). When predictions of FVIII activity or TGA parameters were inadequate [median prediction error (MPE) > 20%], a new model was developed. RESULTS: The original pharmacokinetic model underestimated clearance and was refined based on a two-compartment model. The pharmacodynamic model displays no bias in the observed normalized thrombin peak height and normalized thrombin potential (MPE of 6.83% and 7.46%). After re-estimating pharmacodynamic parameters, EC50 and Emax values were relatively comparable between the original model and this group. Prediction of normalized plasmin peak height was inaccurate (MPE 58.9%). CONCLUSION: Our predictive performance displayed adequate thrombin pharmacodynamic predictions of the original model, but a new pharmacokinetic model was required. The pharmacodynamic model is not factor specific and applicable to multiple factor concentrates. A prospective study is needed to validate the impact of the FVIII dosing pharmacodynamic model on bleeding reduction in patients.

The Nijmegen ultra-sensitive Bethesda Assay detects very low-titer factor VIII inhibitors in patients with congenital and acquired hemophilia A.

BACKGROUND: An inhibitor can develop in congenital hemophilia A (HA) patients against exogenous infused factor (F)VIII, whereas in acquired HA (AHA) inhibitors initially develop against endogenous FVIII. Inhibitors can be detected with the Nijmegen Bethesda Assay (NBA), which has an international cut-off level of 0.60 Nijmegen Bethesda Units/mL (NBU/mL). Thereby, very low-titer inhibitors may remain undetected. AIM: To describe the design and validation of the Nijmegen ultra-sensitive Bethesda Assay (NusBA) for the detection of very low-titer inhibitors. METHODS: The NusBA is a modification of the NBA in which the ratio of patient plasma to normal pooled plasma is changed from 1:1 to 9:1. Analytical validation was performed according to the CLSI EP10 guideline in order to determine trueness and reproducibility. Clinical validation was performed in two cohorts of congenital HA patients (82 adults) with pharmacokinetic data and four AHA patients. The limit of quantitation (LOQ) was determined by measuring plasma samples spiked with inhibitor levels in the low range (0.05-0.80 NBU/mL). RESULTS: The LOQ for the NusBA was 0.10 NusBU/mL, with a coefficient of variation of 24.2 %. Seven (8.5 %) congenital HA patients had a positive NusBA result, of which only one was detected with the NBA. There was no correlation between NusBA and FVIII half-life. In three of the AHA patients the NusBA remained positive, when the NBA became negative. DISCUSSION: The NusBA is able to detect very low-titer FVIII inhibitors of ≥0.10 NBU/mL. Thereby, it may have added value in early inhibitor detection and therapy adjustments in patients with congenital HA and AHA.

Aspirin and clopidogrel resistance; a neglected gap in stroke and cardiovascular practice in Iran: a systematic review and meta-analysis.

OBJECTIVE: Antiplatelet drugs, such as Aspirin and Clopidogrel (Plavix) are effective in the primary prevention of thromboembolic events. They are commonly used to reduce the risk of recurrence of thromboembolism. The body's hemostatic system responds differently to these drugs in different people. Resistance testing for aspirin and Clopidogrel is now recommended before starting antiplatelet therapy. METHODS: A systematic literature search was performed on May 12, 2021, using the medical search engines PubMed, Scopus, and Web of Science, and the local databases SID and Magiran. After data extraction, a meta-analysis was performed using Comprehensive Meta-Analysis (CMA2) software. The I2 statistic was used to measure heterogeneity between estimates. RESULTS: Among the 949 papers, Clopidogrel resistance was assessed in 136 patients and Aspirin resistance in 400 patients. The prevalence of Aspirin resistance was found to be 52.1% and the prevalence of Clopidogrel resistance was found to be 20.5%. CONCLUSION: It seems that in Iran, the issue of Aspirin and Clopidogrel resistance is suboptimally addressed. This pattern could also occur in other developing countries in the Middle East region.

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.

Trend of fluctuations of antithrombin in plasma of patients with COVID-19: a meta-analysis and systematic review.

BACKGROUND: Antithrombin is considered as one of the accused markers for the development of thrombosis in patients with COVID-19. Because plasma levels of antithrombin vary in patients with COVID-19, a meta-analysis was performed to determine the trend of antithrombin levels in patients with COVID-19. RESEARCH DESIGN AND METHODS: A literature search was performed on PubMed, Scopus, and the Web of Science to find papers on antithrombin levels in patients with COVID-19. After removing duplicate papers, inclusion and exclusion criteria were applied. The full texts of the articles were read to select relevant articles and then to identify the data needed. All meta-analyses were performed using Stata software v16.0. RESULTS: Testing for differences between subgroups showed a significant difference between ICU and non-ICU patients. Analysis showed a significant decrease in antithrombin level in patients with severe COVID-19. Analysis showed that the mean value of antithrombin level was 89.65% in all patients. The antithrombin level was significantly lower in the non-survivor group (87.52%) than in the survivor group (92.38%). CONCLUSION: Determination of antithrombin may be useful to determine the susceptibility of COVID-19 patients to hypercoagulability and to indicate the severity of COVID-19 infection.

Female case with misdiagnosis of hemophilia A who underwent total knee arthroplasty: A case report.

A female was diagnosed with hemophilia A. She had undergone bilateral total knee arthroplasty. She had a history of numerous hemorrhages including hemarthrosis. After further investigations, the diagnosis of von Willebrand disease type 2N was confirmed. The differential diagnoses for hemophilia A include von Willebrand disease, rare bleeding disorders, and severe platelet disorders.

Elevated levels of C3, C4, and CH50 of the complement system in ICU and non-ICU patients with COVID-19.

PURPOSE: SARS-CoV-2 infection has spread in each corner of the world. Many health systems have dealt with it intensively. The complement system is an instrumental component in the inflammatory immune response and plays a role in the activation of blood coagulation. Our understanding of the pathophysiology of SARS-CoV-2 is still limited but is constantly expanding. This study aimed to determine changes in the complement system in intensive care unit (ICU) and non-ICU patients with COVID-19. METHODS: In a cross-sectional study, plasma levels of C3, C4, and CH50 were determined in two groups of ICU and non-ICU patients with COVID-19 to understand the potential effects of SARS-CoV-2 on the innate immune system. The assays of C3 and C4 were conducted using turbidimetry method. The CH50 test was conducted using the functional method. RESULTS: The present study revealed that the C3, C4, and CH50 plasma levels were 142.48 ± 30.38 mg/dL, 32.58 ± 8.78 mg/dL, and 61.74 ± 19.54%, respectively. These results indicate high levels of complement components C3 and C4 and complement function (CH50) in patients with COVID-19 than normal ranges. Plasma levels of C3, C4, and CH50 were higher in ICU patients than in non-ICU COVID-19 groups. CONCLUSION: These results indicate that the innate immune system was activated in both ICU and non-ICU patients in response to SARS-CoV-2 infection. Further studies with a larger number of COVID-19 patients and additional testing of complement components (C3a and C5a) may reveal the role of COVID-19 infection in the activation of the complement system.

High levels of Von Willebrand factor markers in COVID-19: a systematic review and meta-analysis.

The SARS-CoV-2 virus has spread to all corners of the world. Thrombosis is the cause of organ failure and subsequent death in COVID-19. The pathophysiology of thrombosis in COVID-19 needs to be further explored to shed light on its downside. For this reason, this meta-analysis of Von Willebrand Factor profile (VWF: Ag, VWF: activity, VWF: RCo), ADAMTS-13, and factor VIII levels in COVID-19 was performed. To obtain data on the status of the aforementioned hemostatic factors, a systematic literature review and meta-analysis were performed on COVID-19. After reviewing the evaluation of 348 papers, 28 papers included in the meta-analysis, which was performed using STATA. The analysis showed an increase in VWF: Ag levels in COVID-19 patients. VWF: Ac was higher in all COVID-19 patients, while it was lower in the COVID-19 ICU patients. The pooled mean of VWF: RCO in all patients with COVID-19 was 307.94%. In subgroup analysis, VWF: RCO was significantly higher in ICU patients than in all COVID-19 patients. The pooled mean of ADAMTS-13 activity was 62.47%, and 58.42% in ICU patients. The pooled mean of factor VIII level was 275.8%, which was significantly higher in ICU patients with COVID-19 than all patients with COVID-19. Levels of VWF: Ag, VWF: activity, VWF: ristocetin, and factor VIII are increased in patients with COVID-19. The elevated levels in ICU patients with COVID-19 suggest that these markers may have prognostic value in determining the severity of COVID-19. New therapeutic programs can be developed as a result.

Determining causes of death among individuals with haemophilia in Afghanistan.

INTRODUCTION: Haemophilia is a well-known bleeding disorder that affects people worldwide. The main therapeutic strategy is regular infusion of exogenous factor VIII to ensure an optimal haemostatic standard. Morbidity and mortality of individuals with haemophilia has decreased in developing countries due to improvement in early detection, advanced treatments, and comprehensive population outreach efforts. However, individuals with bleeding disorders in developing countries like Afghanistan do not have access to such therapeutic facilities. AIMS: The goals of this study were to determine the causes of death and findings related to death among in individuals with bleeding disorders in Afghanistan. METHODS: This study conducted as a retrospective cross-sectional study of 387 individuals with bleeding disorders (mainly haemophilia) in Afghanistan. RESULTS: All registered individuals with bleeding disorders in Afghanistan were interviewed by telephone. Among the 387 individuals with bleeding disorders, there were 136 deaths. Most deaths occurred in individuals aged 1-15 years (66.2%). Intracranial haemorrhage was the leading cause of death in individuals with haemophilia A and B. CONCLUSION: These findings revealed that supply of coagulation factor concentrates, facilities for haemostasis diagnosis, and trained haematologists is inadequate in Afghanistan.

Hemostatic System (Fibrinogen Level, D-Dimer, and FDP) in Severe and Non-Severe Patients With COVID-19: A Systematic Review and Meta-Analysis.

SARS-CoV-2 in COVID-19 triggers abnormalities in coagulation parameters that can contribute to thrombosis. The goals of this research were to determine the levels of fibrinogen, D-dimer and FDP in COVID-19 patients. Following a systematic study, among 1198 articles, 35 studies were included in the meta-analysis of fibrinogen levels in both severe and non-severe groups. The funnel plot, Egger's regression asymmetry test, and Begg's test used to measure the bias of publications. All meta-analysis performed by comprehensive meta-analysis version 2 (CMA2). The pooled findings of fibrinogen levels revealed a significant rise in fibrinogen levels in severe COVID-19 than non-severe patients with COVID-19. The D-dimer and FDP levels were significantly higher in severe patients than non-severe patients with COVID-19 were. The levels of fibrinogen, D-dimer, and FDP have increased significantly in ICU patients compared to non-ICU patients. Although, levels of clotting parameters do not always correlate with the severity of disease, these findings showed the diagnostic importance for fibrinogen, D-dimer, and FDP in COVID-19. The presence of a continuous rise in serial measurements of fibrinogen, D-dimer, and FDP may predict that patients with COVID-19 may become critically ill.

Consanguineous marriage and rare bleeding disorders.

Introduction: Rare bleeding disorders (RBDs) are a heterogeneous group of bleeding disorders. Consanguineous marriage is the favorite partnership in many communities among a population of more than a billion. Consanguineous marriages allow the defective recessive genes in RBDs to remain in the family. Clinical approach to RBDs is not as straightforward as typical bleeding disorders, which are secondary to scarcity and variation of RBDs. However, in many developing countries, the limitations of diagnostic facilities, the supply of therapeutic coagulation concentrates, health budgets, and optimal health-care infrastructures may intensify the clinical practice of RBDs.Areas covered: The author addresses the role of consanguineous marriage in the incidence of RBDs and what preventive steps can be considered to minimize the incidence of RBDs. A literature review of PubMed and google Scholar was conducted in November of 2020 using the relevant keywords.Expert opinion: This review addresses the prevalence of consanguineous marriages in Middle Eastern countries and the various reasons behind the coexistence of consanguineous marriage with RBDs. Finally, prevention steps that may be considered by health-care systems to minimize the incidence of rare bleeding disorders have been discussed. Health-care systems should train partners with the intention of consanguineous marriage on the downside of consanguinity.

Parvovirus 4 in Individuals with Severe Hemophilia A and Matched Control Group.

Background: Hemophilia is a well-known bleeding disorder with worldwide distribution. Replacement therapy, using plasma-derived or recombinant coagulation factors, comprises a gold standard regimen for the treatment. Regardless of the advancements made in viral inactivation methods in the production of plasma-derived coagulation factors, the possibility of transmission of new viral infections remained as a noticeable concern yet. The aim of the current study was to investigate the status of parvovirus 4 (PARV4) in severe hemophilia A, von Willebrand disease (vWD), and healthy control. Materials and Methods: In the current case-control study, 76 patients with hemophilia and vWD and 60 individuals from their family members entered the study. Nested PCR used to determine the presence of PARV4 in study subjects (76 cases). To characterize the PARV4 genotype, positive samples subjected to sequencing and phylogenetic analysis. Results: PARV4 genome detected in 11 (14.47%) patients with bleeding disorders. Among whom, nine patients (14.75%) were with severe hemophilia A and two (13.33%) patients with vWD. Only five healthy controls (8.33%) were positive for PARV4. All PARV4 sequences were found to be genotype 1. Conclusion: PARV4 infection in patients with hemophilia and vWD was higher than the control group. While detection of PARV4 DNA in patients with bleeding disorders may not necessarily reflect a clinical urgency, future investigations are needed to define the clinical significance of PARV4. It seems the detection of the virus immune signature of PARV4 infection, particularly in the context of acute and persistent infections, needs to focus on cellular and tissue targets.

Mining of mortality-related findings in rare bleeding disorders: a retrospective study from two centers.

BACKGROUND: Rare bleeding disorders include inherited coagulation disorders except for von Willebrand disease and hemophilia A and B. These disorders affect both men and women worldwide and mainly have an autosomal recessive pattern of inheritance. Given the paucity of cases of rare bleeding disorders, there are limited data regarding some topics among bleeding disorders. METHODS: This retrospective study from 2005-2019 collected demographic data and the causes of death among cases with rare bleeding disorders from 2 provinces of Iran. RESULTS: Overall, 5 deaths were reported, including 3 cases with factor V deficiency, a case with factor XIII deficiency, and a case with combined factor V and factor VIII deficiencies. The main causes of death were bleeding in the central nervous system (2 cases; 1 with factor V deficiency and 1 with combined factor XIII deficiency). Post-partum hemorrhage was the cause of death in a woman with factor V deficiency while anaphylaxis shock was the cause of death in the case with combined factor V and factor VIII deficiencies. A woman with factor V deficiency died from an internal bleeding episode. CONCLUSION: Gathering data on the causes of death in rare bleeding disorders through worldwide registries can be helpful for the management of this rare group of bleeding disorders.

D-dimer level in COVID-19 infection: a systematic review.

INTRODUCTION: COVID-19 disease has spread worldwide from December 2019 to the present day; the early stage of this disease can be associated with high D-dimer, prolonged PT, and elevated levels of fibrinogen, indicating activation of coagulation pathways and thrombosis. In this article, we analyze the levels of D-dimer in patients with COVID-19. AREA COVERED: In the current study, three databases, PubMed, Scopus, Web of Science, searched using related keywords and information extracted from articles such as location, sample size, gender, age, coagulation test values, patient results, and disease severity. EXPERT OPINION: D-dimer level is one of the measures used in patients to detect thrombosis. Studies have reported an increase in D-dimer and fibrinogen concentrations in the early stages of COVID-19 disease a 3 to 4-fold rise in D-dimer levels is linked to poor prognosis. In addition, underlying diseases such as diabetes, cancer, stroke, and pregnancy may trigger an increase in D-dimer levels in COVID-19 patients. Measuring the level of D-dimer and coagulation parameters from the early stage of the disease can also be useful in controlling and managing of COVID-19 disease.

Current methods of measuring platelet activity: pros and cons.

: Platelets play a pivotal role in controlling hemorrhaging from vessels of the human body. The impairment of platelets may lead to the development of bleeding manifestations. Unraveling the precise defects of platelets by means of suitable laboratory methods paves the way for the effective control and management of platelet disorders. Choosing the most appropriate approach for the detection of platelet disorders may be difficult for a researcher or clinical internist when faced with ordering a platelet-function test. The aim of the current study was to provide a user-friendly overview of the advantages and disadvantages of the available detection systems. To reach this goal, 11 commonly used methods of studying platelet activity were evaluated and compared in detail. A literature search, with no time or language limitations, was conducted in Google Scholar and Medline. All publications published before June 2019 were analyzed. The following laboratory methods were compared: number and size of platelets, bleeding time, clot retraction time, platelet function assay 100 & 200, Rapid platelet function assay, flow cytometry, light transmission aggregometry, multiple electrode aggregometry, 96-well plate aggregometry, cone and plate(let) analyzer (Impact-R), and Plateletworks (single platelet counting system). This article provides the reader with a rapid comparison of the different systems used to study platelets activities.

Is the Detection of Factor IX Inhibitors in Hemophilia B Orphan than Factor VIII Inhibitors in Hemophilia A? A Concise, Systematic Review.

OBJECTIVE: Development of inhibitors in hemophilia A and B comprise significant challenge for patients, hematologists, and health provider systems. It has recommended by the World Federation of Hemophilia (WFH) to check inhibitors every 3-4 months. The incidence of inhibitor in hemophilia B is lower than hemophilia A. Here, it tried to unravel whether the detection of inhibitors in hemophilia B neglected compared to hemophilia A or not? METHODS: A comprehensive review carried out using six international and local medical search engines on published contributions about inhibitors in hemophilia A and B in Iran. RESULTS: From 699 titles, 12 relevant papers were selected. The mean of factor VIII inhibitors in hemophilia A was 14.8%. The mean of factor IX inhibitors in hemophilia B was 6%. The minimum and maximum reported percentages of factor VIII inhibitors were 4% and 19.6%, while the minimum and maximum of reported percentages of factor IX inhibitors were 0% and 11.8%, respectively. The inhibitors in hemophilia A had reported in 6 papers. One paper had covered the inhibitors in hemophilia B. There were five papers on inhibitors in both hemophilia A and B. The comparison between the reported patients showed that 3020 patients with hemophilia A and 314 patients with hemophilia B had studied. CONCLUSION: Consistent with the lower frequency of hemophilia B and the lower development of inhibitors in hemophilia B compared to hemophilia A, it was concluded that hemophilia B had not neglected in Iran. It seems to be rational that each country, check rates of detection of inhibitors in hemophilia B to identify whether it has neglected or not.

Clinical Care of Bone Health in Patients on the Immune Tolerance Induction's Protocols With an Immunosuppressive Agent for Inhibitor Eradication in Hemophilia.

Nowadays, the development of factor VIII and IX inhibitors in patients with hemophilia is considered as the most challenging in the treatment of hemophilia. Immune tolerance induction (ITI) therapy is an approach for eradication of inhibitors. Some ITI protocols are routinely in use for the eradication of inhibitors in patients with hemophilia. Moreover, such a therapeutic regimen may facilitate the tendency to reduced bone density in patients with inhibitor. This study scheduled to investigate whether that predisposing role of ITI protocols with an immunosuppressive agent has considered or not. By a literature review, published ITI protocols in hemophilia with inhibitors were evaluated. Among them, 51 papers found and studied thoroughly. None of them had performed the bone mineral examination in patients with hemophilia and inhibitor under treatment. Since there are 2 coexisting facilitating factors in these protocols, considering the bone mineral density study for patients with inhibitor who are undergoing ITI protocols with an immunosuppressive agent is recommended.