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1.
Blood ; 139(10): 1564-1574, 2022 03 10.
Article in English | MEDLINE | ID: covidwho-1736325

ABSTRACT

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.


Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , SARS-CoV-2 , Aged , Aged, 80 and over , Blood Platelets/immunology , Blood Platelets/metabolism , COVID-19/blood , COVID-19/epidemiology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Purpura, Thrombocytopenic, Idiopathic/immunology , Retrospective Studies , Risk Factors , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Splenectomy , United Kingdom/epidemiology
2.
Am J Hematol ; 97(6): 691-699, 2022 06 01.
Article in English | MEDLINE | ID: covidwho-1704611

ABSTRACT

Patients with relapsed warm antibody autoimmune hemolytic anemia (wAIHA) have limited treatment options. Fostamatinib is a potent, orally administered spleen tyrosine kinase inhibitor approved in the United States and Europe for the treatment of adults with chronic immune thrombocytopenia (ITP). This phase 2 study evaluated the response to fostamatinib, administered at 150 mg BID orally with or without food in adults with wAIHA and active hemolysis with hemoglobin (Hgb) <10 g/dL who had failed at least one prior treatment. Hemoglobin levels and safety assessments were performed at visits every 2 weeks. The primary endpoint was Hgb >10 g/dL with an increase of ≥2 g/dL from baseline by week 24 without rescue therapy or red blood cell transfusion. Eleven of 24 (46%) patients achieved the primary endpoint. Increases in median Hgb were detected at week 2 and sustained over time. Median lactate dehydrogenase levels and reticulocyte counts generally declined over time with little change in median haptoglobin levels. The most common adverse events (AEs) were diarrhea (42%), fatigue (42%), hypertension (27%), dizziness (27%), and insomnia (23%). AEs were manageable and consistent with the fostamatinib safety database of over 3900 patients across multiple diseases (rheumatoid arthritis, B-cell lymphoma, COVID-19, and ITP). No new safety signals were detected. Fostamatinib may be a promising therapeutic option for wAIHA. A randomized, double-blind, phase 3 study is nearing completion.


Subject(s)
Anemia, Hemolytic, Autoimmune , COVID-19 , Adult , Aminopyridines , Anemia, Hemolytic, Autoimmune/drug therapy , Humans , Morpholines , Oxazines , Pyridines , Pyrimidines
3.
Blood ; 139(10): 1564-1574, 2022 03 10.
Article in English | MEDLINE | ID: covidwho-1443789

ABSTRACT

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.


Subject(s)
COVID-19 Vaccines , COVID-19 , Purpura, Thrombocytopenic, Idiopathic , SARS-CoV-2 , Aged , Aged, 80 and over , Blood Platelets/immunology , Blood Platelets/metabolism , COVID-19/blood , COVID-19/epidemiology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Purpura, Thrombocytopenic, Idiopathic/immunology , Retrospective Studies , Risk Factors , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Splenectomy , United Kingdom/epidemiology
4.
Blood ; 136(Supplement 1):4-5, 2020.
Article in English | PMC | ID: covidwho-1338947

ABSTRACT

Introduction: Coronavirus disease 2019 (COVID-19) may cause a hypercoagulable state. The D-dimer is frequently elevated in COVID-19, but other markers of coagulation activation, including the prothrombin fragment 1.2 (PF1.2) are poorly described. Given the near universal D-dimer elevation in critically ill patients with COVID-19, the PF1.2 may be a more specific marker to identify thrombotic complications.Methods: We studied hospitalized adults with COVID-19 and PF1.2 measurement performed at any point during hospitalization. We evaluated the relationship between PF1.2 and synchronously measured D-dimer. We utilized receiver operating characteristic (ROC) analysis to evaluate optimal thresholds for diagnosing thrombosis and multivariable logistic regression to evaluate association with thrombosis. Thresholds for each assay for multivariable regression were determined from ROC analysis. To avoid confounding of therapeutic anticoagulation on PF1.2 or D-dimer measurement, patients receiving therapeutic anticoagulation at the time of assay measurement were excluded from these analyses.Results:Patients and Thrombotic Events. 115 hospitalized patients with COVID-19 were included [110 (95.7%) critically ill], encompassing 3318 patient-days (474 patient-weeks) analyzed for thrombotic and critical illness complications. At the data cutoff date, 74 patients (64.3%) had been discharged from the hospital alive, 24 patients (20.9%) died in the hospital, and 17 patients (14.8%) remained hospitalized, having been hospitalized for a median of 44 (range, 30-62) days. Over a median follow-up of 29 (range, 2-62) hospital days, 26 patients developed radiographically-confirmed VTE (22.6%, a rate of 5.49 per 100 patient-weeks);including arterial, extracorporeal circuit, and recurrent line thrombosis, 56 patients (48.7%) developed a thrombotic complication. At the time of PF1.2 and synchronous D-dimer measurement, 37 patients (32.1%) were receiving therapeutic anticoagulation, 77 patients (67.0%) were receiving prophylactic anticoagulation, and 1 patient (0.9%) was not receiving pharmacologic thromboprophylaxis.Association of PF1.2 with D-dimer. Synchronously measured PF1.2 and D-dimer were moderately positively correlated (r=0.542, P<0.001, Figure 1) but significant discordance was observed in elevation of each marker above the laboratory reference range (59.0% patients with elevated PF1.2 vs. 98.5% elevated D-dimer).Association of PF1.2 with Hypercoagulability. Median PF1.2 levels were higher in patients with thrombosis than those without (611 vs. 374 pmol/L, P=0.006, Figure 2). Therapeutic anticoagulation suppressed median PF1.2 levels: median (IQR) PF1.2 in patients not receiving therapeutic anticoagulation (N=29) was 611 pmol/L (333-1148 pmol/L), significantly higher than the median (IQR) PF1.2 in patients receiving therapeutic anticoagulation (N=27) of 347 pmol/L (195-506 pmol/L), P=0.0017.ROC and Multivariable Regression Analyses. In ROC analysis, PF1.2 had superior specificity and conferred a higher positive likelihood ratio in identifying patients with thrombosis than did the D-dimer (PF1.2 threshold of >523 pmol/L: 69.2% sensitivity, 67.7% specificity;>924 pmol/L: 37.9% sensitivity, 87.8% specificity, Figure 3). In multivariable analysis controlling for age, sex, and BMI, a PF1.2 >500 pmol/L was significantly associated with VTE [adjusted odds ratio (OR) 4.26, 95% CI, 1.12-16.21, P=0.034] and any thrombotic manifestation (adjusted OR 3.85, 95% CI, 1.39-10.65, P=0.010);conversely, synchronously measured D-dimer >2,500 ng/mL was not significantly associated with VTE (OR 5.91, 95% CI, 0.69-50.56, P=0.11) or any thrombotic manifestation (OR 2.47, 95% CI, 0.78-7.78, P=0.12). The vast majority (90.6%) of patients with a non-elevated PF1.2 result did not develop VTE and 75% did not develop any thrombotic complication.Conclusions: When measured at any point during hospitalization in patients not receiving therapeutic anticoagulation, PF1.2 was more specific than synchronously measured D-dimer in identifying patients w o experienced thrombosis and was significantly associated with thrombotic manifestations in multivariable analyses while the D-dimer was not. PF1.2 may be a useful assay, and potentially more discriminant than D-dimer, in identifying thrombotic manifestations in hospitalized patients with COVID-19.

5.
Br J Haematol ; 195(3): 365-370, 2021 11.
Article in English | MEDLINE | ID: covidwho-1255364

ABSTRACT

There is concern that COVID-19 vaccination may adversely affect immune thrombocytopenia (ITP) patients. Fifty-two consecutive chronic ITP patients were prospectively followed after COVID-19 vaccination. Fifteen percent had no worsening of clinical symptoms but no post-vaccination platelet count; 73% had no new symptoms and no significant platelet count decline. However, 12% had a median platelet count drop of 96% within 2-5 days post vaccination with new bleeding symptoms; after rescue therapy with corticosteroids +/- intravenous immunoglobulin (IVIG), platelets recovered to >30 × 109 /l a median three days later. ITP exacerbation occurred independently of remission status, concurrent ITP treatment, or vaccine type. Safety of a second vaccine dose needs careful assessment.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Hemorrhage/etiology , Purpura, Thrombocytopenic, Idiopathic/complications , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , COVID-19/complications , COVID-19/pathology , Female , Follow-Up Studies , Hemorrhage/pathology , Hemorrhage/therapy , Humans , Immunoglobulins, Intravenous/therapeutic use , Male , Middle Aged , Platelet Count , Prospective Studies , Purpura, Thrombocytopenic, Idiopathic/pathology , Purpura, Thrombocytopenic, Idiopathic/therapy , Severity of Illness Index , Young Adult
6.
Am J Hematol ; 95(12): 1479-1485, 2020 12.
Article in English | MEDLINE | ID: covidwho-763014

ABSTRACT

Coronavirus disease 2019 (COVID-19) may cause a hypercoagulable state. The D-dimer is frequently elevated in COVID-19, but other markers of coagulation activation, including the prothrombin fragment 1.2 (PF1.2) are poorly described. We studied hospitalized adults with COVID-19 and PF1.2 measurements performed at any time during hospitalization. We evaluated the relationship between PF1.2 and synchronously measured D-dimer. We utilized receiver operating characteristic (ROC) analysis to evaluate optimal thresholds for diagnosing thrombosis and multivariable logistic regression to evaluate association with thrombosis. A total of 115 patients were included [110 (95.7%) critically ill]. Both PF1.2 and D-dimer were moderately positively correlated (r = 0.542, P < .001) but significant discordance was observed in elevation of each marker above the laboratory reference range (59.0% elevated PF1.2 vs 98.5% elevated D-dimer). Median PF1.2 levels were higher in patients with thrombosis than those without (611 vs 374 pmol/L, P = .006). In ROC analysis, PF1.2 had superior specificity and conferred a higher positive likelihood ratio in identifying patients with thrombosis than D-dimer (PF1.2 threshold of >523 pmol/L: 69.2% sensitivity, 67.7% specificity; >924 pmol/L: 37.9% sensitivity, 87.8% specificity). In multivariable analysis, a PF1.2 >500 pmol/L was significantly associated with VTE [adjusted odds ratio (OR) 4.26, 95% CI, 1.12-16.21, P = .034] and any thrombotic manifestation (adjusted OR 3.85, 95% CI, 1.39-10.65, P = .010); conversely, synchronously measured D-dimer was not significantly associated with thrombosis. 90.6% of patients with a non-elevated PF1.2 result did not develop VTE. So, PF1.2 may be a useful assay, and potentially more discriminant than D-dimer, in identifying thrombotic manifestations in hospitalized patients with COVID-19.


Subject(s)
COVID-19/blood , Peptide Fragments/blood , SARS-CoV-2 , Thrombosis/blood , Aged , Biomarkers/blood , Critical Illness , Female , Fibrin Fibrinogen Degradation Products/analysis , Hospitalization , Humans , Male , Middle Aged , Prothrombin , ROC Curve , Sensitivity and Specificity , Venous Thromboembolism/blood
7.
Blood ; 136(4): 489-500, 2020 07 23.
Article in English | MEDLINE | ID: covidwho-704282

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels. Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited. This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation. Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications. Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death. The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8). The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively. In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively. Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death. Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]). ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without. DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations. Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.


Subject(s)
Betacoronavirus/metabolism , Blood Coagulation , Coronavirus Infections/blood , Hemorrhage/blood , Pneumonia, Viral/blood , Thrombosis/blood , Adult , Aged , Aged, 80 and over , Biomarkers/blood , C-Reactive Protein/metabolism , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Female , Fibrin Fibrinogen Degradation Products/metabolism , Hemorrhage/epidemiology , Hemorrhage/therapy , Hospitalization , Humans , Male , Middle Aged , Pandemics , Platelet Count , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , SARS-CoV-2 , Thrombosis/epidemiology , Thrombosis/therapy
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