A Case of Immune Thrombocytopenia After COVID-19 Vaccination: Coincidental or Causal Effect? Running Title: ITP After COVID-19 Vaccination

Abstract The discovery and the introduction of different vaccines in the therapeutic armamentarium against SARS-CoV-2 represents a big hope in the fight against the pandemic. However, safety of SARS-CoV-2 vaccination is continuously monitored for the emergence of potential new side effects, such as recently reported thrombotic events, after the use of certain types of vaccines. In this context, we report a case of 31-year-old woman who developed immune thrombocytopenia (ITP) after 3 weeks from receiving SARS-CoV-2 vaccine. She developed significant widespread petechiae and gum bleeding, with severe thrombocytopenia documented at her hemogram. Over a 10-day period, thrombocytopenia was treated first with high dose corticosteroids, intravenous immunoglobulin and platelet transfusions, without a platelet response. Two days later, she received the TPO-mimetic and after three days, his platelet count began to rise reaching the normal range 18 days from her admission to our Hematology department. These findings cannot actually elucidate if vaccination was causal or coincidental effect of ITP, but further highlights the need of additional pharmacovigilance studies to empower SARS-CoV2 vaccine efficacy.

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Initial romiplostim dosing and time to platelet response in patients with treatment refractory immune thrombocytopenia

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155217748470 ◽

2018 ◽

Vol 25 (3) ◽

pp. 567-576 ◽

Cited By ~ 5

Author(s):

Ryan K DasGupta ◽

Lauren Levine ◽

Tracy Wiczer ◽

Spero Cataland

Keyword(s):

Length Of Stay ◽

Intravenous Immunoglobulin ◽

Initial Dose ◽

Immune Thrombocytopenia ◽

Hospital Length ◽

Hospital Length Of Stay ◽

Bleeding Complications ◽

Severe Thrombocytopenia ◽

Platelet Response ◽

Treatment Refractory

Background/rationale Romiplostim is a thrombopoietin receptor agonist recommended as a second-line therapy for immune thrombocytopenia. An initial dose of 1 mcg/kg/week subcutaneously with weekly 1 mcg/kg dose escalation is recommended per package labeling. Optimizing romiplostim dosing for hospitalized, corticosteroid- and intravenous immunoglobulin-refractory patients with severe thrombocytopenia secondary to immune thrombocytopenia may be critical for improving platelet responses, reducing the risk of bleeding, and decreasing hospital length of stay. Limited data are available evaluating the efficacy and safety of higher initial doses. Objective The primary objective of this study was to compare the time to platelet ≥ 10 × 109/L between patients who received an initial romiplostim dose of ≥2 mcg/kg/week compared to the standard initial dose of 1 mcg/kg/week. Secondary objectives included time to platelet response ≥ 30 × 109/L and ≥50 × 109/L, percentage of patients achieving platelet responses, hospital length of stay, and incidence of adverse events and bleeding complications. Methods This was a retrospective, single-center, cohort study including hospitalized adults with corticosteroid- and intravenous immunoglobulin-refractory immune thrombocytopenia. A baseline platelet < 10 × 109/L was required. Patients were stratified by their initial romiplostim dose into Cohort 1 (1 mcg/kg/week) and Cohort 2 (≥2 mcg/kg/week). A review of electronic medical records and descriptive statistics generated findings. Results A total of 18 patients were included, 4 in Cohort 1 and 14 in Cohort 2. Patients in Cohort 2 had a median initial dose of 4.5 mcg/kg/week. Patients in Cohort 2 achieved a platelet ≥ 10 × 109/L in a median of 2 days versus 4.5 days for Cohort 1. More patients in Cohort 2 achieved a platelet ≥ 30 × 109/L (42.9% vs. 25%) and platelet ≥ 50 × 109/L (28.6% vs. 25%). The median hospital length of stay was shorter in Cohort 2 (13.5 vs. 20 days). Clinically relevant nonmajor bleeding was noted less frequently in Cohort 2 (28.6% vs. 75%), while major bleeding was more frequent in Cohort 2 (14.3% vs. 0%). No thrombotic events occurred. Conclusion Our study suggests that higher initial romiplostim doses may be safe for hospitalized patients with treatment-refractory immune thrombocytopenia. Compared to Food and Drug Administration-approved dosing, higher initial doses may shorten time to platelet responses and hospital length of stay. Further large-scale studies are needed to confirm these findings.

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Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v100.6.2260.h81802002260_2260_2262 ◽

2002 ◽

Vol 100 (6) ◽

pp. 2260-2262 ◽

Cited By ~ 6

Author(s):

Upendra P. Hegde ◽

Wyndham H. Wilson ◽

Therese White ◽

Bruce D. Cheson

Keyword(s):

Platelet Count ◽

Chronic Lymphocytic Leukemia ◽

Intravenous Immunoglobulin ◽

Immune Thrombocytopenia ◽

Lymphocytic Leukemia ◽

Platelet Response ◽

Idiopathic Thrombocytopenia ◽

Platelet Counts

Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/μL, 118 000/μL, and 70 000/μL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/μL, 1000/μL, and 2000/μL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m2 per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/μL at day 21 and more than 133 000/μL at day 28, patient 2 achieved a platelet count of more than 50 000/μL at day 4 and more than 150 000/μL at day 10, and patient 3 achieved a platelet count of more than 50 000/μL at day 5 and 72 000/μL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP.

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Platelet Variability Index: A measure of platelet count fluctuations in patients with immune thrombocytopenia

Blood Advances ◽

10.1182/bloodadvances.2020004162 ◽

2021 ◽

Author(s):

Na Li ◽

Nancy M. Heddle ◽

Ishac Nazy ◽

John G. Kelton ◽

Donald M. Arnold

Keyword(s):

Platelet Count ◽

Immune Globulin ◽

Immune Thrombocytopenia ◽

Performance Characteristics ◽

Initial Assessment ◽

High Dose ◽

Severe Thrombocytopenia ◽

Count Response ◽

Variability Index ◽

Over Time

Fluctuations in platelet count levels over time may help distinguish immune thrombocytopenia (ITP) from other causes of thrombocytopenia. We derived the platelet variability (PVI) score to capture both the fluctuations in platelet count measurements and the severity of the thrombocytopenia over time. Raw PVI values, ranging from negative (less severe thrombocytopenia and/or low fluctuations) to positive (more severe thrombocytopenia and/or high fluctuations) were converted to an ordinal PVI score, from 0 - 6. We evaluated performance characteristics of the PVI score for consecutive adults with thrombocytopenia from the McMaster ITP Registry. We defined patients with definite ITP as those who achieved a platelet count response after treatment with intravenous immune globulin or high dose corticosteroids; and possible ITP as those who never received ITP treatment or did not respond to treatment. Of 841 thrombocytopenic patients, 104 had definite ITP, 398 had possible ITP, and 339 had non-ITP thrombocytopenia. The median PVI score was 5 (interquartile range [IQR] 5, 6) for definite ITP; 3 (1, 5) for possible ITP; and 0 (0, 2) for non-ITP. A high PVI score correlated with the diagnosis of definite ITP even when calculated at the patient's initial assessment, before any treatment had been administered. Platelet count fluctuations alone contributed to the specificity of the overall PVI score. The PVI score may help clinicians diagnose ITP among patients with thrombocytopenia.

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Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia

Blood ◽

10.1182/blood.v100.6.2260 ◽

2002 ◽

Vol 100 (6) ◽

pp. 2260-2262 ◽

Cited By ~ 57

Author(s):

Upendra P. Hegde ◽

Wyndham H. Wilson ◽

Therese White ◽

Bruce D. Cheson

Keyword(s):

Platelet Count ◽

Chronic Lymphocytic Leukemia ◽

Intravenous Immunoglobulin ◽

Immune Thrombocytopenia ◽

Lymphocytic Leukemia ◽

Platelet Response ◽

Idiopathic Thrombocytopenia ◽

Platelet Counts

Abstract Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/μL, 118 000/μL, and 70 000/μL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/μL, 1000/μL, and 2000/μL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m2 per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/μL at day 21 and more than 133 000/μL at day 28, patient 2 achieved a platelet count of more than 50 000/μL at day 4 and more than 150 000/μL at day 10, and patient 3 achieved a platelet count of more than 50 000/μL at day 5 and 72 000/μL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP.

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Long Term Discontinuation of Eltrombopag after Remission in Primary Immune Thrombocytopenia: 8-Year Follow-up Data from 15 Spanish Centers

Blood ◽

10.1182/blood-2019-129274 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2352-2352

Author(s):

Tomas Jose Gonzalez-Lopez ◽

Fernando Fernandez-Fuertes ◽

Maria Cristina Pascual Izquierdo ◽

Isabel Caparros ◽

Silvia Bernat ◽

...

Keyword(s):

Platelet Count ◽

Median Time ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Previous Treatment ◽

Complete Response ◽

Platelet Response ◽

Platelet Counts

Background: Successful discontinuation of eltrombopag in certain immune thrombocytopenia (ITP) patients after complete response has already been demonstrated. However, the frequency of this phenomenon and type of candidate patients are still matter of discussion. Moreover, possibility of long term discontinuation responses is not clearly established. Methods: Here we retrospectively evaluated our whole cohort of 508 adult patients (aged 18 years or more) with primary ITP treated with eltrombopag included in the Spanish Eltrombopag Registry with a focus on the patients who achieved a durable (at least six months) platelet response after stopping eltrombopag. Successful discontinuation of eltrombopag (SDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 6 months in absence of eltrombopag or any rescue therapies administered. Long term discontinuation of eltrombopag (LTDOE) was defined as those patients who reached remission and maintained platelet counts ≥ 50x109/l for at least 36 months in the absence of eltrombopag or any rescue therapies administered. The study was approved by the Hospital Universitario de Burgos Ethics Committee and fulfilled Helsinki declaration standards. Results: While 37.4% of our patients relapsed of ITP with subsequent platelet count drop sometime during first six months of discontinuation of eltrombopag, a total of 74 patients (14.6%) were able to achieve SDOE. The median age of SDOE patients was 62 [range, 47-79] years. There were 47 women and 27 men. According to the standard definition, patients were allocated to newly diagnosed (n=17), persistent (n=15) and chronic (n=42) ITP groups. The median time from diagnosis to eltrombopag initiation was 31 [range, 4-104] months. The median number of previous therapies was 2 [range, 1-2], including splenectomy (14%), rituximab (18%) and romiplostim (12%). As expected, all patients but 1 achieved a complete response (platelet count ≥100 x 109/L) prior to eltrombopag discontinuation The median duration of eltrombopag treatment was 7 [range, 2-19] months. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n=43), platelet count >400x109/L (n=16), aspartate aminotransferase elevation (n=5), diarrhea (n=4), thrombosis (n=3), patient's request (n=2) and other reasons (n=1). Analysis of these SDOE discontinued patients show that with a median follow-up of 55 [range, 29-79] months, 38 patients (51.3%) maintained treatment-free response 36 months after stopping eltrombopag with no need of additional ITP therapies (median time of eltrombopag discontinuation was 70 [range, 50-77] months).This condition is what we define now as LTDOE. Nevertheless, 36 patients relapsed beyond 6 months but before 36 months of eltrombopag discontinuation (median time of eltrombopag discontinuation was 10 [range,7 -22] months). Characteristics of LTDOE population were a median time since ITP diagnosis of 32 [range, 5-88] months with 15/38 patients having ITP <1 year. 9 patients (24%) were male and their median age was 50 [range, 37-64] years. They had received a median of only two previous treatment lines [range: 1-2 lines]. The median platelet count before starting eltrombopag was 19 x 109/L [range, 8-40]. Meanwhile, platelet count before eltrombopag stop was 218 x 109/L [range, 123-356]. The main characteristics (age, gender, duration of ITP, prior ITP lines, platelet count before starting eltrombopag, duration of eltrombopag treatment, and platelet count before eltrombopag withdrawal) of the 38 patients with LTDOE were compared with those of the SDOE cohort who did not achieve a LTDOE. Unfortunately, no predictive factors of LTDOE could be identified. Conclusion: Durable platelet response following eltrombopag cessation may be observed in only 15% of primary ITP patients treated with this drug. On the contrary, half of patients who achieve a sustained response after eltrombopag withdrawal will get a long term discontinuation. However, we are lacking predictor factors for successful and long-term discontinuation of eltrombopag in primary ITP. Disclosures Gonzalez-Lopez: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy. Sánchez-González:Amgen: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Navartis: Consultancy, Speakers Bureau; Shire: Speakers Bureau; Takeda: Consultancy, Speakers Bureau. Jarque:Takeda: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; Shionogi: Consultancy, Speakers Bureau; Servier: Speakers Bureau; Roche: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Grifols: Consultancy; Gilead: Consultancy, Speakers Bureau; CellTrion: Consultancy; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Abbie: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

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Immune Thrombocytopenia Associated with COVID-19 - Case Series

Blood ◽

10.1182/blood-2020-142611 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-14

Author(s):

Ramil Fatkhullin ◽

Vasily Shuvaev

Keyword(s):

Immune Thrombocytopenia ◽

Meta Analysis ◽

Case Series ◽

Cervix Uteri ◽

First Episode ◽

High Dose ◽

Platelet Response ◽

Pulmonary Infiltrates ◽

High Dose Dexamethasone ◽

History Of

Increased numbers of COVID-19 infection make the study of its systemic manifestations more and more important. Despite of SARS-Cov-2 main clinical respiratory syndrome other clinical infection signs as immune thrombocytopenia without respiratory failure were identified. We have seen case series of patients with thrombocytopenia and active COVID-19 infection during present epidemic outbreak. Patient 1, female, 31 years old was admitted at our hospital with ecchymoses, epistaxis, gingival hemorrhage and metrorrhagia. There were also signs of COVID-19 infection - fever up to 40oC, short of breathes with room air. The pulmonary infiltrates about to 25% were revealed by CT scan. The CBC parameters were as follows: WBC 8.9x109/l, Hb 11,2 g/dl, PLT 3 x109/l by microscopy. The patient was treated with high-dose dexamethasone 40 mg QD for 4 days. The treatment resulted to stable complete platelet response as 189x109/l in fourteen days after start of therapy. At that time, the cancer in situ of cervix uteri there was revealed by gynecologic examination, that was successfully local treated. Patient 2, female 30 years old presented epistaxis, metrorrhagia, cutaneous and gingival hemorrhagic syndrome as previous patient. There were WBC 6.4x109/l, Hb 12,6 g/dl, PLT 3x109/l by microscopy in CBC. She had no respiratory signs and abnormality in pulmonary CT. The COVID-19 infection was identified by PCR and antibody screening. The patient also received high-dose dexamethasone 40 mg QD for 4 days and yielded of platelet elevation to 25x109/l with no hemorrhagic syndrome in five days of treatment. Patient 3, female 68 years old with chronic course of immune thrombocytopenia and resistance to glucocorticoid, after splenectomy and presence of HBsAg. All relapses of thrombocytopenia in this patient were associated with virus infection. The first episode was in 2009, patient was treated with glucocorticoid with no effect. The complete platelet response was achieved after splenectomy. The relapse occurred in 2015 and was associated with acute respiratory distress syndrome (probably H7N9 flu). There treatment with prednisone 1 mg/day resulted to complete platelet response. At present time, the COVID-19 infection on this patient manifested with 75% of pulmonary volume lesions. At the recovery (25% of pulmonary infiltrates) the relapse of immune thrombocytopenia with cutaneous bleeding occurred. In CBC there were WBC 5.9x109/l, Hb 15,1 g/dl, PLT 5x109/l by microscopy. Given that history of therapy we treated this patient with high-dose dexamethasone 40 mg QD for 4 days and romiplostime 2 mqg/kg. The complete resolution of hemorrhagic signs and platelet response (65x109/l) was reached in seven days of treatment. Discussion. The virus-associated thrombocytopenia is usual in common practice. In recent COVID-19 infection outcome meta-analysis (G. Lippi et al. Clinica Chimica Acta 506 (2020) 145-148) the platelet count was significantly lower in severe course of disease. The presence of platelet below the lower limit was associated with fivefold of risk of severe COVID-19 and was a factor of mortality. The platelet decline could be as sign of disease worsening at one hand and have an own risk of mortality by bleeding at other hand. There is a need for guideline to thrombocytopenia management in COVID-19 patients. Now we are continuing to search and include the patients with COVID-19 infection and thrombocytopenia in our study. Disclosures Shuvaev: Novartis:Honoraria, Speakers Bureau;BMS:Honoraria, Speakers Bureau;Pfizer:Honoraria, Speakers Bureau.

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Yersinia Enterocolitica Infection Complicated by Severe Thrombocytopenia Resistant to High-dose Intravenous Immunoglobulin

Acta Medica Scandinavica ◽

10.1111/j.0954-6820.1985.tb01661.x ◽

2009 ◽

Vol 217 (2) ◽

pp. 233-234 ◽

Cited By ~ 1

Author(s):

TORBEN K. GLUD ◽

BENEDICTE LAURSEN

Keyword(s):

Intravenous Immunoglobulin ◽

Yersinia Enterocolitica ◽

High Dose ◽

Severe Thrombocytopenia ◽

Enterocolitica Infection

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Regulation of thrombopoiesis: effects of the degree of thrombocytopenia on megakaryocyte ploidy and platelet volume

Blood ◽

10.1182/blood.v70.1.177.177 ◽

1987 ◽

Vol 70 (1) ◽

pp. 177-185 ◽

Cited By ~ 89

Author(s):

L Corash ◽

HY Chen ◽

J Levin ◽

G Baker ◽

H Lu ◽

...

Keyword(s):

Bone Marrow ◽

Platelet Count ◽

Immune Thrombocytopenia ◽

Temporal Relationship ◽

Recovery Phase ◽

Severe Thrombocytopenia ◽

Detectable Change ◽

Platelet Volume ◽

Murine Bone Marrow ◽

Ploidy Class

Abstract We have established a murine model and techniques with which to serially study thrombocytopoiesis after induction of experimental immune thrombocytopenia of variable severity and duration. Bone marrow megakaryocyte ploidy distribution was determined by using unfractionated bone marrow, a polyclonal megakaryocyte-specific probe, and two-color, fluorescence-activated flow cytometry. With these techniques, the modal megakaryocyte ploidy class in normal murine bone marrow was 16N. Serial studies of bone marrow megakaryocyte ploidy after the induction of acute, severe thrombocytopenia (platelet count, less than 0.05 X 10(6) microL) demonstrated no detectable change in the ploidy distribution at 12, 24, and 36 hours after the onset of thrombocytopenia. At 48 hours, the modal ploidy class shifted from 16N to 32N, and the 64N class increased significantly (P less than .001). The ploidy distribution returned to normal 120 hours after the onset of thrombocytopenia. A lesser degree of thrombocytopenia (platelet count reduction to 0.100 to 0.200 X 10(6)/microL) delayed the modal ploidy class shift from 16N to 32N until 72 hours after the onset of thrombocytopenia. Chronic, severe thrombocytopenia (platelet count, less than 0.05 X 10(6)/microL for seven days) resulted in a modal ploidy class shift from 16N to 32N during the thrombocytopenic phase and an enhanced increase in the 64N megakaryocyte class during the recovery phase. Mean platelet volume (MPV) was simultaneously measured on isolated total platelet populations after induction of thrombocytopenia. MPV was significantly increased (P less than .001) as early as eight hours after the onset of acute, severe thrombocytopenia, 40 hours before a shift in the ploidy distribution. Mild thrombocytopenia (platelet count reduction to 0.400 X 10(6)/microL) was not associated with a ploidy shift but did result in a significantly increased MPV (P less than .001). These studies demonstrate that the temporal relationship and magnitude of the effects of thrombocytopenia upon megakaryocyte ploidy distribution are dependent upon the degree and the duration of the thrombocytopenic stimulus and that the effects of experimental thrombocytopenia on platelet volume and megakaryocyte ploidy are dissociated.

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