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1.
Clin Appl Thromb Hemost ; 28: 10760296221103864, 2022.
Article in English | MEDLINE | ID: covidwho-1879207

ABSTRACT

PURPOSE: Coagulation abnormalities are one of the most important complications of severe COVID-19, which might lead to venous thromboembolism (VTE). Hypercoagulability with hyperfibrinogenemia causes large vessel thrombosis and major thromboembolic sequelae. Statins are potentially a potent adjuvant therapy in COVID-19 infection due to their pleiotropic effect. This study aims to evaluate the effectiveness of statins in reducing the risk of thrombosis among hospitalized critically ill patients with COVID-19. METHODS: A multicenter, retrospective cohort study of all critically ill adult patients with confirmed COVID-19 admitted to Intensive Care Units (ICUs) between March 1, 2020, and March 31, 2021. Eligible patients were categorized based on their usage of statins throughout their ICU stay and were matched with a propensity score. The primary endpoint was the odds of all cases of thrombosis; other outcomes were considered secondary. RESULTS: A total of 1039 patients were eligible; following propensity score matching, 396 patients were included (1:1 ratio). The odds of all thrombosis cases and VTE events did not differ significantly between the two groups (OR 0.84 (95% CI 0.43, 1.66), P = 0.62 and OR 1.13 (95% CI 0.43, 2.98), P = 0.81, respectively. On multivariable Cox proportional hazards regression analysis, patients who received statin therapy had lower 30-day (HR 0.72 (95 % CI 0.54, 0.97), P = 0.03) and in-hospital mortality (HR 0.67 (95 % CI 0.51, 0.89), P = 0.007). Other secondary outcomes were not statistically significant between the two groups except for D-dimer levels (peak) during ICU stay. CONCLUSION: The use of statin therapy during ICU stay was not associated with thrombosis reduction in critically ill patients with COVID-19; however, it has been associated with survival benefits.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Thrombosis , Venous Thromboembolism , Adult , COVID-19/complications , COVID-19/drug therapy , Cohort Studies , Critical Illness , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Intensive Care Units , Retrospective Studies , Thrombosis/chemically induced , Thrombosis/etiology , Venous Thromboembolism/chemically induced , Venous Thromboembolism/etiology
2.
Drug Saf ; 45(6): 685-698, 2022 06.
Article in English | MEDLINE | ID: covidwho-1872804

ABSTRACT

INTRODUCTION: Vaccine-induced thrombotic thrombocytopenia (VITT) has been identified as a rare but serious adverse event associated with coronavirus disease 2019 (COVID-19) vaccines. OBJECTIVES: In this study, we explored the pre-pandemic co-occurrence of thrombosis with thrombocytopenia (TWT) using 17 observational health data sources across the world. We applied multiple TWT definitions, estimated the background rate of TWT, characterized TWT patients, and explored the makeup of thrombosis types among TWT patients. METHODS: We conducted an international network retrospective cohort study using electronic health records and insurance claims data, estimating background rates of TWT amongst persons observed from 2017 to 2019. Following the principles of existing VITT clinical definitions, TWT was defined as patients with a diagnosis of embolic or thrombotic arterial or venous events and a diagnosis or measurement of thrombocytopenia within 7 days. Six TWT phenotypes were considered, which varied in the approach taken in defining thrombosis and thrombocytopenia in real world data. RESULTS: Overall TWT incidence rates ranged from 1.62 to 150.65 per 100,000 person-years. Substantial heterogeneity exists across data sources and by age, sex, and alternative TWT phenotypes. TWT patients were likely to be men of older age with various comorbidities. Among the thrombosis types, arterial thrombotic events were the most common. CONCLUSION: Our findings suggest that identifying VITT in observational data presents a substantial challenge, as implementing VITT case definitions based on the co-occurrence of TWT results in large and heterogeneous incidence rate and in a cohort of patints with baseline characteristics that are inconsistent with the VITT cases reported to date.


Subject(s)
COVID-19 Vaccines , COVID-19 , Thrombocytopenia , Thrombosis , Algorithms , COVID-19 Vaccines/adverse effects , Cohort Studies , Humans , Phenotype , Retrospective Studies , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Thrombosis/chemically induced , Thrombosis/etiology
3.
N Engl J Med ; 386(21): 1986-1997, 2022 05 26.
Article in English | MEDLINE | ID: covidwho-1864788

ABSTRACT

BACKGROUND: Perioperative bleeding is common in patients undergoing noncardiac surgery. Tranexamic acid is an antifibrinolytic drug that may safely decrease such bleeding. METHODS: We conducted a trial involving patients undergoing noncardiac surgery. Patients were randomly assigned to receive tranexamic acid (1-g intravenous bolus) or placebo at the start and end of surgery (reported here) and, with the use of a partial factorial design, a hypotension-avoidance or hypertension-avoidance strategy (not reported here). The primary efficacy outcome was life-threatening bleeding, major bleeding, or bleeding into a critical organ (composite bleeding outcome) at 30 days. The primary safety outcome was myocardial injury after noncardiac surgery, nonhemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal venous thromboembolism (composite cardiovascular outcome) at 30 days. To establish the noninferiority of tranexamic acid to placebo for the composite cardiovascular outcome, the upper boundary of the one-sided 97.5% confidence interval for the hazard ratio had to be below 1.125, and the one-sided P value had to be less than 0.025. RESULTS: A total of 9535 patients underwent randomization. A composite bleeding outcome event occurred in 433 of 4757 patients (9.1%) in the tranexamic acid group and in 561 of 4778 patients (11.7%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.67 to 0.87; absolute difference, -2.6 percentage points; 95% CI, -3.8 to -1.4; two-sided P<0.001 for superiority). A composite cardiovascular outcome event occurred in 649 of 4581 patients (14.2%) in the tranexamic acid group and in 639 of 4601 patients (13.9%) in the placebo group (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; upper boundary of the one-sided 97.5% CI, 1.14; absolute difference, 0.3 percentage points; 95% CI, -1.1 to 1.7; one-sided P = 0.04 for noninferiority). CONCLUSIONS: Among patients undergoing noncardiac surgery, the incidence of the composite bleeding outcome was significantly lower with tranexamic acid than with placebo. Although the between-group difference in the composite cardiovascular outcome was small, the noninferiority of tranexamic acid was not established. (Funded by the Canadian Institutes of Health Research and others; POISE-3 ClinicalTrials.gov number, NCT03505723.).


Subject(s)
Antifibrinolytic Agents , Tranexamic Acid , Antifibrinolytic Agents/adverse effects , Antifibrinolytic Agents/therapeutic use , Canada , Hemorrhage/etiology , Hemorrhage/prevention & control , Humans , Surgical Procedures, Operative , Thrombosis/chemically induced , Thrombosis/drug therapy , Tranexamic Acid/adverse effects , Tranexamic Acid/therapeutic use
4.
Arch Med Res ; 53(4): 341-351, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1821136

ABSTRACT

AIM OF THE STUDY: Development of thrombocytopenia and thrombosis after administration of the ChAdox1 nCoV-19 (AstraZeneca-Oxford) vaccine has recently been described. This new condition is called vaccine-induced immune thrombotic thrombocytopenia (VITT). Our objective was to summarize case reports on VITT with/without D-dimer increments in AstraZeneca-Oxford vaccinated individuals. DATA SOURCES: MEDLINE, PubMed, and Scopus databases were searched. STUDY SELECTION: Case series, case reports, letters to the editor; and abstracts of AstraZeneca-Oxford vaccinated patients with a clinical profile of thrombocytopenia (platelet count <150X10 3 /dL) and D-dimer determination, with or without thrombosis, and/or bleeding, and/or antibodies against platelet factor 4 (aPF4), were included. DATA EXTRACTION: Baseline risk factors, symptoms, physical signs; laboratory results, imaging findings, treatment; and outcome in patients with VITT reported in case series, were examined. DATA SYNTHESIS: Patients who developed VITT were more likely to be young women (ages 21 to 77) given the AstraZeneca-Oxford vaccine 5-14 days prior to presentation. Patients' signs, symptoms, and imaging findings were consistent with cerebral venous sinus thrombosis, or deep veins, lung, and other sites. Laboratory findings showed thrombocytopenia, low fibrinogen, and elevated D-dimer levels, while aPF4 was positive in most assays performed. Treatment was non-heparin anticoagulants, IV immunoglobulin, and steroids, as recommended by medical guidelines. CONCLUSIONS: Vaccine-induced immune thrombotic thrombocytopenia is a rare complication with high morbidity, related to administration of the AstraZeneca-Oxford vaccine. Clinicians should prepare for early identification of patients with suspicious symptoms, and prompt treatment initiated to avoid catastrophic events. D-dimer determination is useful for surveillance of cases with suspected VITT.


Subject(s)
COVID-19 , Fibrin Fibrinogen Degradation Products , Thrombocytopenia , Thrombosis , Adult , Aged , COVID-19/prevention & control , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Middle Aged , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombosis/chemically induced , Thrombosis/complications , Young Adult
5.
J Thromb Thrombolysis ; 53(4): 766-776, 2022 May.
Article in English | MEDLINE | ID: covidwho-1820966

ABSTRACT

This study describes demographics, thrombotic and bleeding events, mortality, and anticoagulant use among hospitalized patients with COVID-19 in the United States. Premier Healthcare Database data were analyzed to identify inpatients with a discharge diagnosis for COVID-19 (ICD-10-CM code: U07.1) from April 1, 2020 to March 31, 2021, and matched historical controls without COVID-19 (inpatients discharged between April 1, 2018 and March 31, 2019). Thrombotic [including venous thromboembolism (VTE)] and bleeding events were based on ICD-10-CM discharge diagnosis codes. Of the 546,656 patients hospitalized with COVID-19, 20.1% were admitted to the ICU, 62.8% were aged ≥ 60 years, 51.5% were male, and 31.0% were non-white. Any thrombotic event was diagnosed in 10.0% of hospitalized and 20.8% of ICU patients with COVID-19 versus (vs) 11.5% and 24.4% for historical controls, respectively. More VTE events were observed in hospitalized and ICU patients with COVID-19 than historical controls (hospitalized: 4.4% vs 2.7%, respectively; ICU: 8.3% vs 5.2%, respectively; both P < 0.0001). Bleeding events were diagnosed in 10.2% of hospitalized and 21.8% of ICU patients with COVID-19 vs 16.0% and 33.2% for historical controls, respectively. Mortality among hospitalized (12.4%) and ICU (38.5%) patients with COVID-19 was higher vs historical controls (2.4%, P < 0.0001 and 9.4%, P < 0.0001, respectively) and higher in hospitalized patients with COVID-19 who had thrombotic events (29.4%) vs those without thrombotic events (10.8%, P < 0.0001). VTE and mortality were higher in hospitalized and ICU patients with COVID-19 vs historical controls. The presence of thrombotic events was associated with worse outcomes.


Subject(s)
COVID-19 , Thrombosis , Venous Thromboembolism , Anticoagulants/adverse effects , COVID-19/complications , Female , Hemorrhage/chemically induced , Humans , Male , Retrospective Studies , Thrombosis/chemically induced , United States/epidemiology , Venous Thromboembolism/chemically induced , Venous Thromboembolism/epidemiology
6.
Intern Med J ; 52(5): 717-723, 2022 05.
Article in English | MEDLINE | ID: covidwho-1816561

ABSTRACT

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare, but serious, syndrome characterised by thrombocytopenia, thrombosis, a markedly raised D-dimer and the presence of anti-platelet factor-4 (PF4) antibodies following COVID-19 adenovirus vector vaccination. VITT occurs at a rate of approximately 2 per 100 000 first-dose vaccinations and appears exceedingly rare following second doses. Our current understanding of VITT pathogenesis is based on the observations that patients with VITT have antibodies that bind to PF4 and have the ability to form immune complexes that induce potent platelet activation. However, the precise mechanisms that lead to pathogenic VITT antibody development remain a source of active investigation. Thrombosis in VITT can manifest in any vascular bed and affect multiple sites simultaneously. While there is a predilection for splanchnic and cerebral venous sinus thrombosis, VITT also commonly presents with deep vein thrombosis and pulmonary embolism. Pillars of management include anticoagulation with a non-heparin anticoagulant, intravenous immunoglobulin and 'rescue' therapies, such as plasma exchange for severe cases. VITT can be associated with a high mortality rate and significant morbidity, but awareness and optimal therapy have significantly improved outcomes in Australia. A number of questions remain unanswered, including why VITT is so rare, reasons for the predilection for thrombosis in unusual sites, how long pathological antibodies persist, and the optimal duration of anticoagulation. This review will provide an overview of the presentation, diagnostic workup and management strategies for patients with VITT.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , Anticoagulants/adverse effects , COVID-19 Vaccines/adverse effects , Humans , Platelet Factor 4/adverse effects , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Thrombosis/complications , Vaccines/adverse effects
8.
Ann Intern Med ; 175(4): 513-522, 2022 04.
Article in English | MEDLINE | ID: covidwho-1811218

ABSTRACT

BACKGROUND: Thrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. It presents similarly to spontaneous heparin-induced thrombocytopenia. Twelve cases of cerebral venous sinus thrombosis after vaccination with the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson) have previously been described. OBJECTIVE: To describe surveillance data and reporting rates of all reported TTS cases after COVID-19 vaccination in the United States. DESIGN: Case series. SETTING: United States. PATIENTS: Case patients receiving a COVID-19 vaccine from 14 December 2020 through 31 August 2021 with thrombocytopenia and thrombosis (excluding isolated ischemic stroke or myocardial infarction) reported to the Vaccine Adverse Event Reporting System. If thrombosis was only in an extremity vein or pulmonary embolism, a positive enzyme-linked immunosorbent assay for antiplatelet factor 4 antibodies or functional heparin-induced thrombocytopenia platelet test result was required. MEASUREMENTS: Reporting rates (cases per million vaccine doses) and descriptive epidemiology. RESULTS: A total of 57 TTS cases were confirmed after vaccination with Ad26.COV2.S (n = 54) or a messenger RNA (mRNA)-based COVID-19 vaccine (n = 3). Reporting rates for TTS were 3.83 per million vaccine doses (Ad26.COV2.S) and 0.00855 per million vaccine doses (mRNA-based COVID-19 vaccines). The median age of patients with TTS after Ad26.COV2.S vaccination was 44.5 years (range, 18 to 70 years), and 69% of patients were women. Of the TTS cases after mRNA-based COVID-19 vaccination, 2 occurred in men older than 50 years and 1 in a woman aged 50 to 59 years. All cases after Ad26.COV2.S vaccination involved hospitalization, including 36 (67%) with intensive care unit admission. Outcomes of hospitalizations after Ad26.COV2.S vaccination included death (15%), discharge to postacute care (17%), and discharge home (68%). LIMITATIONS: Underreporting and incomplete case follow-up. CONCLUSION: Thrombosis with thrombocytopenia syndrome is a rare but serious adverse event associated with Ad26.COV2.S vaccination. The different demographic characteristics of the 3 cases reported after mRNA-based COVID-19 vaccines and the much lower reporting rate suggest that these cases represent a background rate. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , /adverse effects , Adolescent , Adult , Aged , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , Female , Humans , Male , Middle Aged , RNA, Messenger , Syndrome , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Thrombosis/chemically induced , Thrombosis/etiology , United States/epidemiology , Vaccination/adverse effects , Vaccines/adverse effects , Young Adult
9.
Pril (Makedon Akad Nauk Umet Odd Med Nauki) ; 43(1): 49-55, 2022 Apr 22.
Article in English | MEDLINE | ID: covidwho-1809274

ABSTRACT

Vaccine-induced thrombotic thrombocytopenia (VITT) is a condition similar to heparin-induced thrombocytopenia (HIT), but it is associated with prior administration of COVID-19 vaccines without prior exposure to heparin. The incidence of VITT is not certain, but it appears to be extremely rare. Reports of unusual and severe thrombotic events, including cerebral and splanchnic venous thrombosis and other autoimmune adverse reactions, such as immune thrombocytopenia or thrombotic microangiopathies in connection with some of the SARS-CoV-2 vaccines, have caused a great deal of concern within the population and the medical community. We would like to present 4 clinical cases of VITT, hospitalized and treated in intensive care unit (ICU) of University clinic of cardiology in Skopje.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombosis/chemically induced , Thrombosis/complications , Vaccines/adverse effects
10.
J Investig Med High Impact Case Rep ; 10: 23247096211060581, 2022.
Article in English | MEDLINE | ID: covidwho-1799135

ABSTRACT

Antiphospholipid syndrome (APS) may be either as a primary or in association with an underlying systemic autoimmune etiology (36.2%), particularly systemic lupus erythematosus (SLE). Thrombocytopenia is infrequently observed in APS patients, with an occurrence of 22% to 42% with the frequency of thrombocytopenia, higher in APS and SLE combination than in primary APS. There have been some controversial reports regarding the treatment of APS syndrome with thrombocytopenia with TPO agonists. We like to report a case with APS syndrome with severe thrombocytopenia treated with TPO-RA and developed severe thrombocytosis and thrombosis. Our case represented the first case of TPO-RA in treating APS syndrome developed severe thrombocytosis and our case also concurred that use of TPO-RA agents should be strongly discouraged in APS until larger studies clarify the safety of TPO-RA agents in APS.


Subject(s)
Antiphospholipid Syndrome , Lupus Erythematosus, Systemic , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombocytosis , Thrombosis , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/drug therapy , Benzoates , Humans , Hydrazines , Lupus Erythematosus, Systemic/complications , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/complications , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Pyrazoles , Thrombocytopenia/chemically induced , Thrombocytopenia/complications , Thrombocytosis/chemically induced , Thrombocytosis/complications , Thrombosis/chemically induced
11.
Semin Hematol ; 59(2): 89-96, 2022 04.
Article in English | MEDLINE | ID: covidwho-1788341

ABSTRACT

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a novel prothrombotic disorder characterized by thrombosis, thrombocytopenia, and disseminated intravascular coagulation identified in hundreds of recipients of ChAdOx1 nCoV-19 (Oxford/AstraZeneca), an adenovirus vector coronavirus disease 2019 (COVID-19) vaccine. VITT resembles heparin-induced thrombocytopenia (HIT) in that patients have platelet-activating anti-platelet factor 4 antibodies; however, whereas heparin typically enhances platelet activation by HIT antibodies, VITT antibody-induced platelet activation is often inhibited in vitro by pharmacological concentrations of heparin. Further, the thrombotic complications in VITT feature much higher frequencies of atypical thrombosis, most notably cerebral vein thrombosis and splanchnic vein thrombosis, compared with HIT. In this review, we outline the treatments that have been used to manage this novel condition since its recognition in March 2021, including anticoagulation, high-dose intravenous immune globulin, therapeutic plasma exchange, corticosteroids, rituximab, and eculizumab. We discuss the controversial issue of whether heparin, which often inhibits VITT antibody-induced platelet activation, is harmful in the treatment of VITT. We also describe a case of "long VITT," describing the treatment challenges resulting from platelet-activating anti-PF4 antibodies that persisted for more than 9 months.


Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombosis , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Heparin/adverse effects , Humans , Platelet Factor 4 , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Thrombosis/chemically induced
12.
Phytomedicine ; 100: 154083, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1788182

ABSTRACT

BACKGROUND: The high incidence of thrombotic events is one of the clinical characteristics of coronavirus disease of 2019 (COVID-19), due to a hyperinflammatory response caused by the virus. Gegen Qinlian Pills (GQP) is a Traditional Chinese Medicine that is included in the Chinese Pharmacopoeia and played an important role in the clinical fight against COVID-19. Although GQP has shown the potential to treat thrombosis, there is no relevant research on its treatment of thrombosis so far. HYPOTHESIS: We hypothesized that GQP may be capable inhibit inflammation-induced thrombosis. STUDY DESIGN: We tested our hypothesis in a carrageenan-induced thrombosis mouse model in vivo and lipopolysaccharide (LPS)-induced human endothelial cells (HUVECs) in vitro. METHODS: We used a carrageenan-induced mouse thrombus model to confirm the inhibitory effect of GQP on inflammation-induced thrombus. In vitro, studies in human umbilical vein endothelial cells (HUVECs) and in silico network pharmacology analyses were performed to reveal the underlying mechanisms of GQP and determine the main components, targets, and pathways of GQP, respectively. RESULTS: Oral administration of 227.5 mg/kg, 445 mg/kg and 910 mg/kg of GQP significantly inhibited thrombi in the lung, liver, and tail and augmented tail blood flow of carrageenan-induced mice with reduced plasma tumor necrosis factor α (TNF-α) and diminished expression of high mobility group box 1 (HMGB1) in lung tissues. GQP ethanol extract (1, 2, or 5 µg/ml) also reduced the adhesion of platelets to LPS stimulated HUVECs. The TNF-α and the expression of HMGB1, nuclear factor kappa B (NF-κB), and NLR family pyrin domain containing 3 (NLRP3) in LPS stimulated HUVECs were also attenuated. Moreover, we analyzed the components of GQP and inferred the main targets, biological processes, and pathways of GQP in the treatment of inflammation-induced thrombosis through network pharmacology. CONCLUSION: Overall, we demonstrated that GQP could reduce inflammation-induced thrombosis by inhibiting HMGB1/NFκB/NLRP3 signaling and provided an accurate explanation for the multi-target, multi-function mechanism of GQP in the treatment of thromboinflammation, and provides a reference for the clinical usage of GQP.


Subject(s)
Drugs, Chinese Herbal , HMGB1 Protein , Thrombosis , Animals , Carrageenan , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides , Mice , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Thrombosis/chemically induced , Thrombosis/drug therapy , Tumor Necrosis Factor-alpha/metabolism
13.
Hum Vaccin Immunother ; 18(5): 2050654, 2022 Nov 30.
Article in English | MEDLINE | ID: covidwho-1784264

ABSTRACT

Cases that experienced COVID-19 postvaccination-related thrombosis have been reported after the first dose of ChAdOx1 nCov-19 (Vaxzevria, AstraZeneca) or Ad26.COV2.S (Johnson & Johnson/Janssen) vaccine. These rare thrombotic events were observed within the expected vaccine-induced seroconversion period and could be attributed to platelet-activating (auto)antibodies against platelet factor 4 (PF4). Newly, vaccine-induced, cross-reactive anti-PF4 antibodies could explain this observation. An in-silico analysis using the Basic Local Alignment Search Tool was used to identify sequence similarity between PF4 and antigens contained in or encoded by ChAdOx1 nCov-19 or Ad26.COV2.S vaccines. Only one sequence within the signaling peptide of the SARS-CoV-2 spike protein exhibited a high percent identity (85.71%) with PF4. This sequence overlaps with a proven immunogenic peptide recognized from convalescent COVID-19 sera and could be responsible for the formation of platelet-activating immunocomplexes in susceptible patients. Manipulation of the immunogenicity of this particular sequence within the encoded SARS-CoV-2 spike protein signaling peptide may eliminate this iatrogenic severe adverse effect.


Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , /adverse effects , COVID-19/prevention & control , Humans , Platelet Factor 4 , Purpura, Thrombocytopenic, Idiopathic/chemically induced , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Thrombosis/chemically induced
14.
Semin Hematol ; 59(2): 108-114, 2022 04.
Article in English | MEDLINE | ID: covidwho-1778659

ABSTRACT

In hundreds of patients worldwide, vaccination against COVID-19 with adenovirus vector vaccines (ChAdOx1 nCoV-19; Ad26.COV2.S) triggered platelet-activating anti-platelet factor 4 (PF4) antibodies inducing vaccine-induced immune thrombotic thrombocytopenia (VITT). In most VITT patients, platelet-activating anti-PF4-antibodies are transient and the disorder is discrete and non-recurring. However, in some patients platelet-activating antibodies persist, associated with recurrent thrombocytopenia and sometimes with relapse of thrombosis despite therapeutic-dose anticoagulation. Anti-PF4 IgG antibodies measured by enzyme-immunoassay (EIA) are usually detectable for longer than platelet-activating antibodies in functional assays, but duration of detectability is highly assay-dependent. As more than 1 vaccination dose against COVID-19 is required to achieve sufficient protection, at least 69 VITT patients have undergone subsequent vaccination with an mRNA vaccine, with no relevant subsequent increase in anti-PF4 antibody titers, thrombocytopenia, or thrombotic complications. Also, re-exposure to adenoviral vector-based vaccines in 5 VITT patients was not associated with adverse reactions. Although data are limited, vaccination against influenza also appears to be safe. SARS-CoV-2 infection reported in 1 patient with preceding VITT did not influence anti-PF4 antibody levels. We discuss how these temporal characteristics of VITT provide insights into pathogenesis.


Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombosis , /adverse effects , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Platelet Factor 4/adverse effects , Purpura, Thrombocytopenic, Idiopathic/chemically induced , SARS-CoV-2 , Thrombosis/chemically induced , Thrombosis/complications
16.
Semin Hematol ; 59(2): 97-107, 2022 04.
Article in English | MEDLINE | ID: covidwho-1768934

ABSTRACT

Vaccine-induced immune thrombotic thrombocytopenia (VITT; synonym, thrombosis with thrombocytopenia syndrome, is associated with high-titer immunoglobulin G antibodies directed against platelet factor 4 (PF4). These antibodies activate platelets via platelet FcγIIa receptors, with platelet activation greatly enhanced by PF4. Here we summarize the current concepts in the pathogenesis of VITT. We first address parallels between heparin-induced thrombocytopenia and VITT, and provide recent findings on binding of PF4 to adenovirus particles and non-assembled adenovirus proteins in the 2 adenovirus vector-based COVID-19 vaccines, ChAdOx1 nCoV-19 and Ad26.COV2.S. Further, we discuss the potential role of vaccine constituents such as glycosaminoglycans, EDTA, polysorbate 80, human cell-line proteins and nucleotides as potential binding partners of PF4. The immune response towards PF4 in VITT is likely triggered by a proinflammatory milieu. Human cell-line proteins, non-assembled virus proteins, and potentially EDTA may contribute to the proinflammatory state. The transient nature of the immune response towards PF4 in VITT makes it likely that-as in heparin-induced thrombocytopenia -marginal zone B cells are key for antibody production. Once high-titer anti-PF4 antibodies have been formed 5 to 20 days after vaccination, they activate platelets and granulocytes. Activated granulocytes undergo NETosis and the released DNA also forms complexes with PF4, which fuels the Fcγ receptor-dependent cell activation process, ultimately leading to massive thrombin generation. Finally, we summarize our initial observations indicating that VITT-like antibodies might also be present in rare patients with recurrent venous and arterial thrombotic complications, independent of vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombosis , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Edetic Acid/adverse effects , Humans , Platelet Factor 4 , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Thrombosis/chemically induced
17.
Blood ; 139(23): 3430-3438, 2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-1759684

ABSTRACT

Life-threatening thrombotic events at unusual sites have been reported after vector-based vaccinations against severe acute respiratory syndrome coronavirus 2. This phenomenon is now termed vaccine-induced immune thrombotic thrombocytopenia (VITT). The pathophysiology of VITT is similar to that of heparin-induced thrombocytopenia (HIT) and is associated with platelet-activating antibodies (Abs) against platelet factor 4 (PF4). Therefore, current guidelines suggest nonheparin anticoagulants to treat VITT patients. In this study, we investigated the interactions of heparin, danaparoid, fondaparinux, and argatroban with VITT-Ab/PF4 complexes using an ex vivo model for thrombus formation as well as in vitro assays to analyze Ab binding and platelet activation. We found that immunoglobulin Gs (IgGs) from VITT patients induce increased adherent platelets/thrombus formation in comparison with IgGs from healthy controls. In this ex vivo flow-based model, the procoagulant activity of VITT IgGs was effectively inhibited with danaparoid and argatroban but also by heparin. Interestingly, heparin and danaparoid not only inhibited IgG binding to PF4 but were also able to effectively dissociate the preformed PF4/IgG complexes. Fondaparinux reduced the in vitro generation of procoagulant platelets and thrombus formation; however, it did not affect platelet aggregation. In contrast, argatroban showed no effect on procoagulant platelets and aggregation but significantly inhibited VITT-mediated thrombus formation. Taken together, our data indicate that negatively charged anticoagulants can disrupt VITT-Ab/PF4 interactions, which might serve as an approach to reduce Ab-mediated complications in VITT. Our results should be confirmed, however, in a clinical setting before a recommendation regarding the selection of anticoagulants in VITT patients could be made.


Subject(s)
Anticoagulants , COVID-19 Vaccines , Thrombocytopenia , Thrombosis , Anticoagulants/therapeutic use , COVID-19 Vaccines/adverse effects , Fondaparinux/therapeutic use , Heparin/therapeutic use , Humans , Immunoglobulin G , Platelet Factor 4 , Thrombocytopenia/chemically induced , Thrombocytopenia/drug therapy , Thrombosis/chemically induced , Thrombosis/drug therapy
18.
Hematology ; 27(1): 318-321, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1713441

ABSTRACT

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with thrombosis. Clinical scoring systems and the presence of anti-platelet factor 4 (anti-PF4)/heparin antibodies determine the diagnosis. CASE PRESENTATION: A 57-year-old man who was treated with acenocoumarol due to a chronic left ventricular thrombus was admitted to the hospital for severe SARS-CoV-2 pneumonia and pulmonary embolism. The patient was started on bemiparin and discharged. Left lower limb acute arterial ischemia and thrombocytopenia were diagnosed 18 days later. Computed tomography angiography revealed a large left ventricular thrombus and multiple arterial thrombi. Left femoral-popliteal thromboembolectomy was performed. Anti-PF4/heparin antibodies confirmed an HIT diagnosis. Fondaparinux (7.5 mg/24 h) was initiated, but cardiac surgery was necessary. Bivalirudin was used during surgery, with an initial load (1.25 mg/kg) and maintenance infusion (2.5 mg/kg/h). The cardiac thrombus was extracted, but the patient experienced a postsurgical myocardial infarction. Percutaneous cardiovascular intervention (PCI) required a bivalirudin load (0.75 mg/kg) and maintenance infusion (1.75 mg/kg/h). No coronary lesions were detected, and argatroban was started afterwards (0.5 µg/kg/min). When the platelet count exceeded 100 × 109/L, acenocoumarol was initiated. Thereupon, acetylsalicylic acid (100 mg/24 h) was added. No other complications have been reported to date. CONCLUSION: The clinical presentation of intraventricular and multiple arterial thrombi is remarkable. SARS-CoV-2 infection likely contributed to a hypercoagulable state. The management of patients with HIT undergoing cardiac surgery is challenging. If surgery cannot be delayed, then treatment with bivalirudin is recommended. Additionally, this drug is recommended for PCI. Bivalirudin is safe and well-tolerated in both procedures.


Subject(s)
Acenocoumarol/administration & dosage , Anticoagulants/administration & dosage , Arginine/analogs & derivatives , COVID-19/drug therapy , Heparin , Hirudins/administration & dosage , Peptide Fragments/administration & dosage , Percutaneous Coronary Intervention , Pipecolic Acids/administration & dosage , SARS-CoV-2 , Sulfonamides/administration & dosage , Thrombocytopenia , Thrombosis , Arginine/administration & dosage , COVID-19/complications , Heparin/administration & dosage , Heparin/adverse effects , Humans , Male , Middle Aged , Recombinant Proteins/administration & dosage , Thrombocytopenia/chemically induced , Thrombocytopenia/therapy , Thrombosis/chemically induced , Thrombosis/therapy
19.
Neuroradiology ; 64(5): 865-874, 2022 May.
Article in English | MEDLINE | ID: covidwho-1699643

ABSTRACT

Cerebral venous and sinus thrombosis (CVST) after adenovirus-vectored COVID-19 ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson) is a rare complication, occurring mainly in individuals under 60 years of age and more frequently in women. It manifests 4-24 days after vaccination. In most cases, antibodies against platelet factor-4/polyanion complexes play a pathogenic role, leading to thrombosis with thrombocytopenia syndrome (TTS) and sometimes a severe clinical or even fatal course. The leading symptom is headache, which usually increases in intensity over a few days. Seizures, visual disturbances, focal neurological symptoms, and signs of increased intracranial pressure are also possible. These symptoms may be combined with clinical signs of disseminated intravascular coagulation such as petechiae or gastrointestinal bleeding. If TTS-CVST is suspected, checking D-dimers, platelet count, and screening for heparin-induced thrombocytopenia (HIT-2) are diagnostically and therapeutically guiding. The imaging method of choice for diagnosis or exclusion of CVST is magnetic resonance imaging (MRI) combined with contrast-enhanced venous MR angiography (MRA). On T2*-weighted or susceptibility weighted MR sequences, the thrombus causes susceptibility artefacts (blooming), that allow for the detection even of isolated cortical vein thromboses. The diagnosis of TTS-CVST can usually be made reliably in synopsis with the clinical and laboratory findings. A close collaboration between neurologists and neuroradiologists is mandatory. TTS-CVST requires specific regimens of anticoagulation and immunomodulation therapy if thrombocytopenia and/or pathogenic antibodies to PF4/polyanion complexes are present. In this review article, the diagnostic and therapeutic steps in cases of suspected TTS associated CSVT are presented.


Subject(s)
COVID-19 , Intracranial Thrombosis , Sinus Thrombosis, Intracranial , Thrombocytopenia , Thrombosis , Adenoviridae , COVID-19 Vaccines/adverse effects , Female , Humans , Intracranial Thrombosis/complications , Sinus Thrombosis, Intracranial/diagnostic imaging , Sinus Thrombosis, Intracranial/etiology , Syndrome , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnostic imaging , Thrombosis/chemically induced , Thrombosis/complications , Vaccination/adverse effects
20.
Semin Hematol ; 59(2): 115-119, 2022 04.
Article in English | MEDLINE | ID: covidwho-1692508

ABSTRACT

This review paper explores the potential psychiatric and psychological sequelae of vaccine-induced immune thrombotic thrombocytopenia, also called vaccine-induced immune thrombocytopenia, and thrombosis (VITT). In the absence of any literature to date we have extrapolated data from similar conditions, particularly data pertaining to the critical care population. We discuss both the direct and indirect effects of thrombosis, likely psychiatric and psychological challenges during recovery, and ethical issues around vaccination. We have also suggested a comprehensive guide to the psychiatric assessment and management of patients presenting with VITT with the aim of early identification of problems and maximizing rehabilitation potential and quality of life.


Subject(s)
Purpura, Thrombocytopenic, Idiopathic , Thrombosis , Vaccines , Humans , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/psychology , Quality of Life , Thrombosis/chemically induced , Vaccines/adverse effects
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