Thrombocytopenia with and without thrombosis following COVID-19 vaccination: long-term management

Abstract

Background

Since administration of COVID-19 vaccines, there has been growing evidence of thrombotic and thrombocytopenic events following vaccination. However, there remains limited data on long-term management of these adverse hematologic events.

Key Clinical Question

We report on 9 patients presenting with thrombocytopenia following COVID-19 vaccination, with 4 subsequently diagnosed with vaccine-induced thrombocytopenia and thrombosis (VITT) and 5 with immune thrombocytopenia.

Clinical Approach

A retrospective chart review was completed for adults >18 years of age presenting to a tertiary care center with new-onset thrombocytopenia occurring 4 to 42 days following COVID-19 vaccination. Presenting symptoms, laboratory investigations, and response to treatment are described.

Conclusion

Two of 4 patients with VITT developed refractory thrombocytopenia successfully treated with intravenous immunoglobulin, corticosteroids, and plasma exchange therapy. Patients with VITT remained on anticoagulation for at least 9 months due to persistently positive diagnostic tests. Four of 5 patients with immune thrombocytopenia received intravenous immunoglobulin and corticosteroids with good recovery. Patients who received a subsequent COVID-19 mRNA vaccine had no adverse hematologic effects.

Essentials

• •Vaccine-induced thrombocytopenia and thrombosis (VITT) and immune thrombocytopenia (ITP) are complications of COVID-19 vaccination.
• •We describe the diagnosis and long-term management of VITT and ITP at our tertiary care center.
• •Patients with ITP responded to steroids and immunoglobulin.
• •Patients with VITT received 9 months of anticoagulation for persistently positive diagnostic tests.

1. Introduction

Vaccines against SARS-CoV-2 are being widely distributed worldwide as part of a necessary response to the COVID-19 pandemic, with 7.7 billion vaccinations already administered [1]. Studies emerged reporting unusual thrombotic and thrombocytopenic events following ChAdOx1-S (Astra Zeneca) vaccination and vaccination with mRNA COVID-19 vaccine types. A new entity called vaccine-induced thrombocytopenia and thrombosis (VITT), characterized by thrombocytopenia, elevated D-dimer, presence of platelet factor-4/polyanion antibodies, and thrombosis, was described following Astra Zeneca vaccination [[2], [3], [4], [5], [6], [7]], and reports also included cases of immune thrombocytopenia (ITP) with all COVID-19 vaccines [6,8,9]. We report on the diagnosis and long-term management of patients with VITT or ITP following COVID-19 vaccination at our tertiary care center in Canada.

2. Methods

2.1. Patient selection

The study population included adults >18 years of age presenting to The Ottawa Hospital, a large Canadian tertiary care center with a catchment area of greater than 1.5 million persons between April 1, 2021, and May 31, 2021, with new-onset thrombocytopenia occurring 4 to 42 days following COVID-19 vaccination. Vaccines approved during this time period in Canada were the BNT162b2 (Pfizer-BioNTech, mRNA) vaccine, mRNA-1273 (Moderna, mRNA) vaccine, and ChAdOx1-S (Astra Zeneca, adenovirus vector-based) vaccine. The Astra Zeneca vaccine was subsequently removed from use in Canada after May 2021.

2.2. Data collection

A retrospective cohort was evaluated from June 2021 to March 2022 for patients fulfilling the abovementioned inclusion criteria. Data from 9 months after diagnosis were gathered. Demographic and clinical data collected can be found in Table [10].

Table.

Baseline characteristics, diagnosis, and treatment overview, and 9-month outcomes.

Diagnosis	VITT				ITP
Characteristics	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6	Patient 7	Patient 8	Patient 9a
Age (y)	46	46	46	55	57	65	59	24	73
Sex	F	F	F	M	M	F	M	F	M
Diagnosis	CVT	VTE	CVT	VTE	ITP	ITP	ITP	ITP	ITP/DVT
Vaccine brand	AZ	AZ	AZ	AZ	AZ	AZ	AZ	Pfizer	Pfizer
Time to presentation (d)	11	17	10	31	14	10	18	9	2
Symptoms at presentation	Headache	Dyspnea, chest pain, leg pain	Headache, nausea, vomiting	Dyspnea, chest pain	Petechial rash	Petechial rash	Petechial rash, epistaxis	Petechial rash, epistaxis	Leg pain, swelling
Platelet count (× 109/L) at presentation	94	35	14	136	<5	12	<5	<5	67
Platelet count (× 109/L) post hospital discharge	299	303	225	371b	—	—	—	—	—
D-dimer (μg/L FEU) at presentation	13,000	>44,000	>44,000	>4000	495	<500	539	208	NA
D-dimer (μg/L FEU) post hospital discharge	996	1959	1770	1892b	—	—	—	—	—
HIT ELISA OD at presentation	2.107 (positive)	2.084 (positive)	2.059 (positive)	NAc (serotonin release assay positive)	0.275	0.245	0.230	0.182	0.109
Last HIT ELISA OD	2.073 (positive; 9 mo)	1.513 (positive; 3 mo)	1.573 (positive; 6 mo)	0.380 (negative; 9 mo)	NA	NA	NA	NA	NA
Treatment	Nonheparin AC, IVIG, steroids	Nonheparin AC, IVIG, steroids	Nonheparin AC, IVIG, steroids, therapeutic plasma exchange	DOAC	IVIG, steroids	IVIG, steroids	IVIG, steroids	IVIG, steroids	DOAC
Relapse treatment	NA	IVIG, pulse steroids (day 26)	IVIG, pulse steroids [10]	NA	Pulse steroids (day 9)	NA	NA	Pulse steroids (day 9)	NA
9-mo outcome	Recovered	Recovered	Recovered	Recovered	Recovered	Recovered	Recovered	Recovered	Recovered
Repeat vaccine dose given	Yes (8 mo)	Yes (9 mo)	Yes (9 mo)	Yes (6 mo)	Yes (8 mo)	No	Yes (7 mo)	Yes (5 mo)	No

Patients 1 to 3: nonheparin anticoagulation was argatroban followed by DOAC.

AC, anticoagulation; AZ, AstraZeneca; CVT, cerebral vein thrombosis; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; F, female; HIT ELISA, heparin-induced thrombocytopenia enzyme-linked immunosorbent assay; ITP, immune thrombocytopenia; IVIG, intravenous immunoglobulin; M, male; NA, not applicable/not available; OD, optical density; SRA, serotonin release assay; VITT, vaccine-induced thrombocytopenia and thrombosis; VTE, venous thromboembolism.

^aPatient 9: the patient was known to have ITP, and the presentation was <4 days.

^bPatient 4: the patient was not hospitalized, and platelet count and D-dimer reflect the next measured value as an outpatient.

^cHIT ELISA was not available.

2.3. Treatment regimen

For ITP and VITT, a corticosteroid regimen of prednisone 1 mg/kg daily was generally initiated for the first few days, followed by a taper over 2 to 3 months.

Additionally, for VITT, nonheparin anticoagulation was recommended [7]; thus, a direct oral anticoagulant (DOAC), sometimes with a lead-in argatroban phase for 2 to 12 days, was administered. In those requiring intravenous immunoglobulin (IVIG), IVIG 1 g/kg daily for 2 days was prescribed as per American Society of Hematology guidance [11]. The protocol for plasma exchange therapy was that as previously described [10].

2.4. Immunoassays and serologic testing

Heparin-induced thrombocytopenia (HIT) testing was sent for all patients with a platelet count of <150 and COVID-19 vaccination 4 to 42 days prior to time of presenting symptoms. HIT testing involved the assessment of anti-PF4 autoantibodies using the Immucor PF4 Enhanced enzyme-linked immunosorbent assay (ELISA), according to manufacturer instructions. In patients with a positive PF4 binding assay, serotonin release assay (SRA) was completed as VITT confirmatory testing. SRA testing involved incubating patient serum with heparin and ¹⁴C-serotonin–labeled platelets and then analyzing ¹⁴C reactivity using the BioRad PR3100 TSC Microplate Reader.

2.5. Ethical considerations

Approval was obtained from the Human Research Ethics Board to identify and review medical records of eligible patients. Individual informed patient consent was not required.

3. Results

3.1. Presenting characteristics

Nine patients with thrombocytopenia following COVID-19 vaccination were included. The median age was 55 years (range, 24-73), and 5 patients (56%) were female. Seven patients received Astra Zeneca vaccine, and 2 patients received Pfizer-BioNTech vaccine. None of the patients had previous exposure to heparin. All patients admitted to hospital (N = 9) tested negative for COVID-19 by polymerase chain reaction. See Table for a summary of presenting characteristics, treatment, and 9-month outcomes of patients.

HIT ELISA tests were sent for all 9 patients and were positive in 3 patients. SRA testing confirmed a diagnosis of VITT in 4 patients. See Table and Figure for a summary of presenting symptoms and laboratory findings.

Figure.

Laboratory trends over time in patients with vaccine-induced thrombocytopenia and thrombosis (VITT) and immune thrombocytopenia (ITP). Inset figures show trends up to 14 days.

Five patients developed ITP. Four of these patients did not have associated thrombosis. The fifth patient (patient 9 in Table) had a history of ITP and was maintained on eltrombopag. He presented with an ITP flare and was diagnosed with deep vein thrombosis. HIT ELISA was negative.

3.2. Treatment and outcomes

Among the 4 patients who developed VITT, 3 were admitted to hospital for treatment with nonheparin parenteral anticoagulation, IVIG, and corticosteroids (Table). Patient 1 responded well to treatment. Patient 2 was initially responsive to treatment. However, 3 weeks later, she developed a recurrence of thrombocytopenia during steroid taper, requiring readmission for IVIG and steroids. Patient 3 had a prolonged hospital admission of 15 days complicated by 2 episodes of cerebral venous sinus thrombosis progression and refractory thrombocytopenia requiring 7 plasma exchange treatments [10]. She developed recurrent thrombocytopenia 3 weeks later, successfully treated with IVIG and repeat steroid pulse and taper. Patient 4 was treated with a DOAC for pulmonary emboli as an outpatient with good clinical outcome. All 4 patients remained on oral anticoagulation after 9 months of treatment, including 3 with a persistently positive HIT ELISA.

Among the 5 patients who developed ITP, 4 patients were admitted to hospital and received IVIG ± steroids. Two patients had recurrent severe thrombocytopenia within 14 days of discharge, requiring a repeat course of steroids. One patient (patient 9) was successfully treated as an outpatient with apixaban and an increased dose of eltrombopag.

All patients with VITT received their next dose of COVID-19 vaccine with the mRNA subtype. All patients with ITP except 2 received their next dose of COVID-19 vaccine. Patient 6 declined vaccination due to previous hematologic adverse effects. Patient 9 was not recommended another COVID-19 vaccine dose as he had experienced thrombocytopenia with 2 subsequent COVID-19 mRNA vaccine doses (both received outside of the study period). There was no recurrence of thrombocytopenia or thrombotic events in patients 1 to 8 following this next vaccine dose received during the study period.

4. Discussion

Hematologic adverse events following COVID-19 vaccination require early recognition and prompt implementation of appropriate therapies. Early research communications facilitated the identification of 9 patients with thrombocytopenia with or without thrombosis following COVID-19 vaccination. Four cases were diagnosed with VITT, confirmed on HIT ELISA and SRA, following Astra Zeneca (adenovirus vector-based) vaccination, and 5 patients had ITP.

The patients with VITT generally responded well to management according to guidance recommendations [11,12], involving nonheparin parenteral anticoagulation (argatroban, DOAC), IVIG, and corticosteroids. Though most, but not all, studies document the use of corticosteroids [2,5,[12], [13], [14]], there is no consensus or comprehensive data to date on its use and duration [10]. World Health Organization guidance also states that corticosteroids are often used but does not provide specific recommendations on corticosteroid duration [12]. Other studies [2,5,[12], [13], [14]] have also reported the use of high-dose corticosteroids followed by a taper. In our patients, we elected to prescribe a prednisone taper over 2 to 3 months, with a preference for a more gradual taper in patients with recurrence of thrombocytopenia. Regarding anticoagulation, there are no guidelines or consensus on treatment duration. It has been suggested that anticoagulation should be continued until the SRA result becomes negative [13], which can correspond to a treatment duration of 3 to 7 months [13,15,16]. In our study, anticoagulation was continued for at least 9 months due to a persistently positive HIT ELISA. Anticoagulation was also continued until booster doses of the COVID-19 vaccine were obtained by patients.

Importantly, 2 of 4 patients with VITT experienced refractory thrombocytopenia 3 weeks after initial treatment. This was successfully treated with repeat IVIG and steroids with or without plasma exchange therapy. These cases highlight the need for close monitoring of blood work and clinical status during the weeks to months following diagnosis. Our experiences can be used to inform management of refractory cases of VITT, as there are few reported cases and no specific guidelines on this.

In our cohort, ITP was seen with both mRNA and adenovirus vector-based COVID-19 vaccines. ITP cases largely responded well to standard treatment of steroid therapy with or without IVIG, similar to nonvaccine-related ITP cases.

Regarding future vaccination against COVID-19 in patients diagnosed with VITT, there are no comprehensive guidelines on approach to this. World Health Organization recommends that patients with VITT following adenovirus-vector-based vaccination should not receive a second dose of this vaccine type [12]. In previous studies [15,16], patients received the mRNA vaccine around 2 to 7 months after their first vaccination with no hematologic complications noted. Similarly, our patients with VITT remained on anticoagulation and received the mRNA COVID-19 vaccine with no recurrence of thrombosis or thrombocytopenia. This suggests that patients with VITT may safely receive mRNA vaccination against COVID-19.

The primary strength of this study is the prolonged 9-month follow-up. Although initial diagnosis and management of VITT are well-described in literature, the long-term monitoring and management of VITT are less documented. We also provide information on diagnosis and management of ITP following COVID-19 vaccination. Our results add to the currently limited literature regarding management of refractory cases, duration of positivity of HIT assays, duration of anticoagulation, and safety of subsequent COVID-19 vaccination. The primary limitation of this study is the small patient cohort. Although the study was held at a tertiary care center with a large catchment area, only a relatively limited number of people were diagnosed with VITT during the study timeframe. Our findings correlate with results from larger studies, suggesting that our cohort seems to reflect the experiences of other patient populations.

5. Conclusions

Early identification was key to the successful management of VITT and ITP events following COVID-19 vaccination. The patient cases described in our study add to the currently limited literature on long-term management of VITT and ITP, particularly in refractory cases, and provide guidance around future COVID-19 vaccinations.