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1.
Rinsho Ketsueki ; 62(12): 1684-1687, 2021.
Article in Japanese | MEDLINE | ID: covidwho-1622834

ABSTRACT

The Japanese Society of Hematology recently published on acute exacerbation of immune-mediated thrombocytopenia (ITP) after mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. In addition, there is a growing concern for the development of the newly diagnosed ITP after SARS-CoV-2 vaccination. Herein, we report two cases of severe thrombocytopenia associated with bleeding tendencies at 4 and 14 days after BNT162b2 mRNA vaccination. Platelet counts returned to normal following platelet transfusion or treatment with intravenous immunoglobulin and dexamethasone. To our knowledge at the time of the draft of this manuscript, nine cases of SARS-CoV-2 vaccine-induced ITP have been reported. Although most patients showed favorable clinical courses similar to that of our cases, critical thrombocytopenia can lead to unfavorable outcomes. A national survey may be required to examine the causal relationship between SARS-CoV-2 vaccination and the emergence of the newly diagnosed ITP and clinical outcomes of vaccine-induced thrombocytopenia.


Subject(s)
COVID-19 , Thrombocytopenia , COVID-19 Vaccines , Humans , RNA, Messenger , SARS-CoV-2 , Thrombocytopenia/chemically induced , Vaccination/adverse effects
3.
Clin Appl Thromb Hemost ; 27: 10760296211068487, 2021.
Article in English | MEDLINE | ID: covidwho-1575876

ABSTRACT

BACKGROUND: Cases of thrombosis with thrombocytopenia syndrome (TTS) have been reported following vaccination with AZD1222 or Ad26.COV2.S. This review aimed to explore the pathophysiology, epidemiology, diagnosis, management, and prognosis of TTS. METHODS: A systematic review was conducted to identify evidence on TTS till 4th September 2021. Case reports and series reporting patient-level data were included. Descriptive statistics were reported and compared across patients with different sexes, age groups, vaccines, types of thrombosis, and outcomes. FINDINGS: Sixty-two studies reporting 160 cases were included from 16 countries. Patients were predominantly females with a median age of 42.50 (22) years. AZD1222 was administered to 140 patients (87·5%). TTS onset occurred in a median of 9 (4) days after vaccination. Venous thrombosis was most common (61.0%). Most patients developed cerebral venous sinus thrombosis (CVST; 66.3%). CVST was significantly more common in female vs male patients (p = 0·001) and in patients aged <45 years vs ≥45 years (p = 0·004). The mortality rate was 36.2%, and patients with suspected TTS, venous thrombosis, CVST, pulmonary embolism, or intraneural complications, patients not managed with non-heparin anticoagulants or IVIG, patients receiving platelet transfusions, and patients requiring intensive care unit admission, mechanical ventilation, or inpatient neurosurgery were more likely to expire than recover. INTERPRETATION: These findings help to understand the pathophysiology of TTS while also recommending diagnostic and management approaches to improve prognosis in patients. FUNDING: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.


Subject(s)
COVID-19 Vaccines/adverse effects , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Adult , Aged , Female , Humans , Male , Middle Aged , Syndrome
4.
Clin Appl Thromb Hemost ; 27: 10760296211066945, 2021.
Article in English | MEDLINE | ID: covidwho-1574469

ABSTRACT

INTRODUCTION: Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients' baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. METHODS: Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. RESULTS: Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. CONCLUSIONS: We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.


Subject(s)
Arginine/analogs & derivatives , COVID-19/drug therapy , Partial Thromboplastin Time/methods , Pipecolic Acids/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Thrombocytopenia/drug therapy , Thrombosis/drug therapy , Aged , Arginine/pharmacology , Arginine/therapeutic use , COVID-19/complications , Female , Humans , Male , Middle Aged , Pipecolic Acids/pharmacology , Platelet Aggregation Inhibitors/pharmacology , SARS-CoV-2 , Sulfonamides/pharmacology , Thrombocytopenia/chemically induced , Thrombosis/chemically induced
5.
Blood Adv ; 5(21): 4521-4534, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1511718

ABSTRACT

Heparin thromboprophylaxis is routinely administered during hospitalization for COVID-19. Because of the immune stimulation related to COVID-19, there is ongoing concern regarding a heightened incidence of heparin-induced thrombocytopenia (HIT). We performed a literature search using PubMed, EMBASE, Cochrane, and medRxiv database to identify studies that reported clinical and laboratory characteristics and/or the incidence of HIT in patients with COVID-19. The primary aim was to systematically review the clinical features and outcomes of patients with COVID-19 with confirmed HIT. The secondary objective was to perform a meta-analysis to estimate the incidence of HIT in hospitalized patients with COVID-19. A meta-analysis of 7 studies including 5849 patients revealed the pooled incidence of HIT in COVID-19 of 0.8% (95% confidence interval [CI], 0.2%-3.2%; I2 = 89%). The estimated incidences were 1.2% (95% CI, 0.3%-3.9%; I2 = 65%) vs 0.1% (95% CI, 0.0%-0.4%; I2 = 0%) in therapeutic vs prophylactic heparin subgroups, respectively. The pooled incidences of HIT were higher in critically ill patients with COVID-19 (2.2%; 95% CI, 0.6%-8.3%; I2 = 72.5%) compared with noncritically ill patients (0.1%; 95% CI, 0.0%-0.4%: I2 = 0%). There were 19 cases of confirmed HIT and 1 with autoimmune HIT for clinical and laboratory characterization. The median time from heparin initiation to HIT diagnosis was 13.5 days (interquartile range, 10.75-16.25 days). Twelve (63%) developed thromboembolism after heparin therapy. In conclusion, the incidence of HIT in patients with COVID-19 was comparable to patients without COVID-19, with higher incidences with therapeutic anticoagulation and in critically ill patients.


Subject(s)
COVID-19 , Thrombocytopenia , Venous Thromboembolism , Anticoagulants/adverse effects , Humans , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology
7.
BMJ Case Rep ; 14(10)2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1495133

ABSTRACT

Cerebral venous sinus thrombosis (CVST) following novel coronavirus-2019 (nCoV-19) vaccination is a rare adverse effect. We report the first case of CVST associated with ChAdOx1 vaccination, with positive anti-platelet factor 4 (PF4) antibodies, from India. A 44-year-old woman developed a thunderclap headache 4 days after the first dose of the adenoviral vector vaccine ChAdOx1 (Covishield). Physical examination was unremarkable barring mild neck stiffness with no focal neurological deficits. MRI identified right transverse sinus thrombosis. Laboratory tests revealed raised D-dimer and thrombocytopenia; anti-PF4 antibodies were subsequently identified, consistent with thrombosis with thrombocytopenia syndrome (TTS). She was treated with non-heparin anticoagulation and intravenous immunoglobulin and made an uneventful recovery. Early recognition of adenoviral vector vaccine-related TTS, which resembles heparin-induced thrombocytopenia syndrome, is important as heparin and heparin analogues are best avoided in the treatment.


Subject(s)
COVID-19 Vaccines/adverse effects , Sinus Thrombosis, Intracranial , Thrombocytopenia , Thrombosis , Adult , COVID-19 , Female , Humans , Sinus Thrombosis, Intracranial/chemically induced , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Vaccination/adverse effects
8.
Clin Chem Lab Med ; 60(1): 7-17, 2022 01 26.
Article in English | MEDLINE | ID: covidwho-1496577

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a life-threatening infectious disease caused by Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). In response to the still ongoing pandemic outbreak, a number of COVID-19 vaccines have been quickly developed and deployed. Although minor adverse events, either local (e.g., soreness, itch, redness) or systematic (fever, malaise, headache, etc.), are not uncommon following any COVID-19 vaccination, one rare vaccine-associated event can cause fatal consequences due to development of antibodies against platelet factor 4 (PF4), which trigger platelet activation, aggregation, and possible resultant thrombosis, often at unusual vascular sites. Termed thrombosis with thrombocytopenia syndrome (TTS) by reporting government agencies, the term vaccine-induced (immune) thrombotic thrombocytopenia (VITT) is more widely adopted by workers in the field. In response to increasing reports of VITT, several expert groups have formulated guidelines for diagnosis and/or management of VITT. Herein, we review some key guidelines related to diagnosis of VITT, and also provide some commentary on their development and evolution.


Subject(s)
COVID-19 Vaccines/adverse effects , Thrombocytopenia , Thrombosis , COVID-19/prevention & control , Humans , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombosis/chemically induced , Thrombosis/diagnosis
11.
Cancer Discov ; 11(10): 2430-2435, 2021 10.
Article in English | MEDLINE | ID: covidwho-1472319

ABSTRACT

We had previously reported short-term efficacy, immunogenicity, and safety of the BNT162b2 vaccine among cancer patients with solid tumors. We aimed to evaluate these outcomes at six months postvaccination. The study cohort comprised patients who were on treatment during vaccination and throughout six months postvaccination. Serologic tests were performed after second vaccination and six months afterward. An age-matched cohort of health care workers served as controls. Documentation of COVID-19 infection, blood tests, and imaging studies during the study period was reviewed. Participants included 154 patients and 135 controls. Six months postvaccination, 122 (79%) patients were seropositive compared with 114 (84%) controls (P = 0.32). Serology titer dramatically decreased in a similar manner in both cohorts. No COVID-19 cases were documented in controls, and one case occurred in patient cohort. All previously reported adverse effects resolved. Taken together, the pattern of immunogenicity, efficacy, and safety of BNT162b2 in patients with cancer with solid tumors at six months postvaccination resembles that of the general population. SIGNIFICANCE: Evidence regarding efficacy and safety of COVID-19 vaccines in patients with cancer indicate a favorable short-term profile. Immunomodulation due to anticancer treatments may affect immunity and immunogenicity of patients with cancer to the BNT162b2 vaccine over time. Our study sheds light on these long-term outcomes and portrays a trend that resembles the general population.This article is highlighted in the In This Issue feature, p. 2355.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/pharmacology , Neoplasms , Adult , Aged , Aged, 80 and over , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Health Personnel , Humans , Male , Middle Aged , Neoplasms/drug therapy , Neutropenia/chemically induced , Thrombocytopenia/chemically induced , Time-to-Treatment , Vaccination
12.
Ann Rheum Dis ; 80(11): 1376-1384, 2021 11.
Article in English | MEDLINE | ID: covidwho-1462911

ABSTRACT

OBJECTIVES: There are no head-to-head trials of different dose escalation strategies of methotrexate (MTX) in RA. We compared the efficacy, safety and tolerability of 'usual' (5 mg every 4 weeks) versus 'fast' (5 mg every 2 weeks) escalation of oral MTX. METHODS: This multicentre, open-label (assessor blinded) RCT included patients 18-55 years of age having active RA with disease duration <5 years, and not on DMARDs. Patients were randomized 1:1 into usual or fast escalation groups, both groups starting MTX at 15 mg/week till a maximum of 25 mg/week. Primary outcome was EULAR good response at 16 weeks, secondary outcomes were ΔDAS28 and adverse effects (AE). Analyses were intention-to-treat. RESULTS: 178 patients with mean DAS28-CRP of 5.4(1.1) were randomized to usual (n=89) or fast escalation groups (n=89). At 16 weeks, there was no difference in good EULAR response in the usual (28.1%) or fast escalation (22.5%) groups (p=0.8). There was no difference in mean ΔDAS28-CRP at 8 weeks (-0.9, -0.8, p=0.72) or 16 weeks (-1.3, -1.3, p=0.98). Even at 24 weeks (extended follow-up), responses were similar. There were no inter-group differences in ΔHAQ, or MTX-polyglutamates 1-3 levels at 8 or 16 weeks. Gastrointestinal AE were higher in the fast escalation group over initial 8 weeks (27%, 40%, p=0.048), but not over 16 weeks. There was no difference in cytopenias, transaminitis, or drug discontinuation/dose reduction between the groups. No serious AE were seen. CONCLUSION: A faster MTX escalation strategy in RA was not more efficacious over 16-24 weeks, and did not significantly increase AE, except higher gastrointestinal AE initially. TRIAL REGISTRATION NUMBER: CTRI/2018/12/016549.


Subject(s)
Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Methotrexate/administration & dosage , Adolescent , Adult , Arthritis, Rheumatoid/physiopathology , Chemical and Drug Induced Liver Injury/epidemiology , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Gastrointestinal Diseases/chemically induced , Gastrointestinal Diseases/epidemiology , Humans , Leukopenia/chemically induced , Leukopenia/epidemiology , Male , Methotrexate/analogs & derivatives , Methotrexate/blood , Middle Aged , Polyglutamic Acid/analogs & derivatives , Polyglutamic Acid/blood , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Treatment Outcome , Young Adult
15.
Blood Adv ; 5(22): 4662-4665, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1443790

ABSTRACT

We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a young man diagnosed 13 days after Ad26.COV2.S COVID-19 (Johnson & Johnson/Janssen) vaccination. He presented to us with 5 days of progressive left leg pain, thrombocytopenia, hypofibrinogenemia, and markedly elevated d-dimers, but without radiographically demonstrable thrombosis. Despite negative imaging, we initiated treatment of presumptive VITT given the striking clinical picture that included the timing of his recent adenovirus-based COVID-19 vaccine, leg symptoms, marked thrombocytopenia, and consumptive coagulopathy. He received intravenous immune globulin, prednisone, and argatroban and was discharged 7 days later much improved. His positive platelet factor 4 enzyme-linked immunosorbent assay antibody test returned after treatment was initiated. To our knowledge, this is the first reported case of VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis. Our patient highlights the importance of knowing vaccine status and initiating treatment as soon as possible in the right clinical setting, even in the absence of radiographic evidence of thrombus. Early VITT recognition and treatment provide an opportunity to prevent serious thrombotic complications.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 , Thrombocytopenia , Thrombosis , COVID-19/prevention & control , Humans , Male , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Thrombosis/drug therapy , Vaccination/adverse effects
16.
JAMA Neurol ; 78(11): 1314-1323, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1439655

ABSTRACT

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS. Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination. Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria. Main Outcomes and Measures: Clinical characteristics and mortality rate. Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later. Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.


Subject(s)
COVID-19 Vaccines/therapeutic use , Drug-Related Side Effects and Adverse Reactions/mortality , Registries , Sinus Thrombosis, Intracranial/mortality , Thrombocytopenia/mortality , Venous Thromboembolism/mortality , Adult , Aged , COVID-19 Vaccines/adverse effects , Cohort Studies , Female , Hospital Mortality , Humans , Male , Middle Aged , Outcome Assessment, Health Care , Sex Factors , Sinus Thrombosis, Intracranial/blood , Sinus Thrombosis, Intracranial/chemically induced , Syndrome , Thrombocytopenia/blood , Thrombocytopenia/chemically induced , Venous Thromboembolism/blood , Venous Thromboembolism/chemically induced , Young Adult
17.
Clin Appl Thromb Hemost ; 27: 10760296211040110, 2021.
Article in English | MEDLINE | ID: covidwho-1430348

ABSTRACT

Since the outbreak of Covid-19 in December, 2019, scientists worldwide have been committed to developing COVID-19 vaccines. Only when most people have immunity to SARS-CoV-2, COVID-19 can reduce even wholly overcome. So far, nine kinds of COVID-19 vaccines have passed the phase III clinical trials and have approved for use. At the same time, adverse reactions after COVID-19 vaccination have also reported. This paper focuses on the adverse effects of thrombosis and thrombocytopenia caused by the COVID-19 vaccine, especially the adenovirus-vector vaccine from AstraZeneca and Pfizer, and discusses its mechanism and possible countermeasures.


Subject(s)
Adenoviridae/genetics , COVID-19 Vaccines/adverse effects , Genetic Vectors , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Vaccination/adverse effects , Antibodies/blood , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Humans , Platelet Factor 4/immunology , Risk Assessment , Risk Factors , Thrombocytopenia/blood , Thrombocytopenia/immunology , Thrombosis/blood , Thrombosis/immunology
18.
S Afr Med J ; 111(9): 841-848, 2021 07 20.
Article in English | MEDLINE | ID: covidwho-1404039

ABSTRACT

The increased use of heparin during the current COVID-19 pandemic has highlighted the risk of a rare but potentially serious complication of heparin therapy, viz. heparin-induced thrombocytopenia (HIT). This is a short review on the pharmacology of heparin and its derivatives, and the pathophysiology of HIT. Guidance on laboratory testing for and clinical management of HIT is presented in accordance with international guidelines. There are important similarities and differences between HIT and the new entity of vaccine-induced immune thrombotic thrombocytopenia, also known as thrombosis with thrombocytopenia syndrome, which clinicians need to be aware of.


Subject(s)
Anticoagulants/adverse effects , COVID-19 , Heparin/adverse effects , Thrombocytopenia/chemically induced , Anticoagulants/administration & dosage , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , Heparin/administration & dosage , Humans , Thrombocytopenia/diagnosis , Thrombocytopenia/physiopathology
19.
Cancer Discov ; 11(10): 2430-2435, 2021 10.
Article in English | MEDLINE | ID: covidwho-1394287

ABSTRACT

We had previously reported short-term efficacy, immunogenicity, and safety of the BNT162b2 vaccine among cancer patients with solid tumors. We aimed to evaluate these outcomes at six months postvaccination. The study cohort comprised patients who were on treatment during vaccination and throughout six months postvaccination. Serologic tests were performed after second vaccination and six months afterward. An age-matched cohort of health care workers served as controls. Documentation of COVID-19 infection, blood tests, and imaging studies during the study period was reviewed. Participants included 154 patients and 135 controls. Six months postvaccination, 122 (79%) patients were seropositive compared with 114 (84%) controls (P = 0.32). Serology titer dramatically decreased in a similar manner in both cohorts. No COVID-19 cases were documented in controls, and one case occurred in patient cohort. All previously reported adverse effects resolved. Taken together, the pattern of immunogenicity, efficacy, and safety of BNT162b2 in patients with cancer with solid tumors at six months postvaccination resembles that of the general population. SIGNIFICANCE: Evidence regarding efficacy and safety of COVID-19 vaccines in patients with cancer indicate a favorable short-term profile. Immunomodulation due to anticancer treatments may affect immunity and immunogenicity of patients with cancer to the BNT162b2 vaccine over time. Our study sheds light on these long-term outcomes and portrays a trend that resembles the general population.This article is highlighted in the In This Issue feature, p. 2355.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/pharmacology , Neoplasms , Adult , Aged , Aged, 80 and over , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Health Personnel , Humans , Male , Middle Aged , Neoplasms/drug therapy , Neutropenia/chemically induced , Thrombocytopenia/chemically induced , Time-to-Treatment , Vaccination
20.
N Engl J Med ; 384(23): 2254-2256, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1387597
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