Thrombotic thrombocytopenic purpura following administration of the Moderna booster vaccine
- 1 Internal Medicine, Beaumont Health, Royal Oak, Michigan, USA
- 2 Hematology and Medical Oncology, Oakland University William Beaumont School of Medicine, Troy, Michigan, USA
- Correspondence to Dr Emma Herrman; emma.herrman@beaumont.org
Abstract
Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy that is characterized by microangiopathic haemolytic anaemia, consumption thrombocytopenia and organ injury. It is caused by a severe deficiency of ADAMTS13, which can be either congenital or acquired. There is a plethora of things that can cause the acquired form, including medications and infections. Vaccines have also been shown to cause TTP. In the midst of the COVID-19 pandemic, with multiple new vaccines being developed and distributed to the masses, the medical community needs to be aware of adverse events associated with these new vaccines. We present a case of TTP following administration of the Moderna booster vaccine.
Background
The recent COVID-19 pandemic has shattered the roots of healthcare in a way no one could have ever imagined. In a timely battle against the pandemic, emergency use for various vaccines were approved in many countries. In the USA, three vaccines are currently authorised, namely: Pfizer, Moderna and Johnson & Johnson/Janssen.1 These vaccines are manufactured through different mechanisms: Pfizer and Moderna are mRNA-based vaccines whereas Janssen uses replication-incompetent adenovirus vector.1 Given that these vaccines are the first of their kind working through these mechanisms, many adverse effects of the vaccines are still unknown. Studies and literature are limited in that regard. COVID-19 vaccine induced thrombocytopenia2 and vaccine-induced thrombotic thrombocytopenia (VITT)3–5 have been largely reported in the literature. However, vaccine-related thrombotic thrombocytopenic purpura (TTP) has rarely been described. There are only scattered case reports suggesting possible association between the two, with only one such case documented after the Moderna vaccine.6 TTP can be life threatening without prompt diagnosis and treatment, so it is imperative to learn more about its causal relation with the COVID-19 vaccines, if any.
Case presentation
An elderly woman presented to urgent care for an 8 day history of fatigue, generalised weakness, headache, abdominal pain and haematuria. She has a history of chronic myeloid leukaemia (CML), diagnosed 5 years prior. Her CML is being treated with dasatinib, and she is currently in molecular remission. Other medical history includes hyperlipidaemia and current tobacco use.
Of note, she began to develop symptoms 2 days after receiving her Moderna booster vaccine and presented to urgent care 8 days after receiving it. She was asymptomatic following her first 2 Moderna vaccines. There were no recent medication changes, and she has been on dasatinib for years.
On admission, all vitals were within normal limits. Physical exam was pertinent only for wheezing bilaterally on lung exam and prolonged capillary refill at 2–3 s. There were no gross ecchymoses or petechiae. COVID-19 testing was negative.
On complete blood count, her haemoglobin (Hb) was 78 g/L (normal range 121–150 g/L), white cell count 7.7 bil/L (normal range 3.3–10.7 bil/L), and, most shocking, platelets of 10 bil/L (normal range 150–400 bil/L). The most recent blood count 4 years prior showed a haemoglobin of 15.3 g/dL and platelet count of 312 bil/L. Pathologist review of the sample showed marked thrombocytopenia with schistocytes about 3–5/HPF (normal <1, absent), worrisome for thrombotic microangiopathy. Therefore, further workup was ordered stat.
Investigations
Further haematological labs included haptoglobin <8 mg/dL (normal range 40–250 mg/dL) and lactate dehydrogenase 1381 U/L (normal range 100–240 U/L). D-dimer was 5838 ng/mL FEU (normal range 0/499 ng/mL FEU) and fibrinogen was 444 mg/dL (normal range 200–400 mg/dL). Heparin platelet factor 4 (HPF4) antibody was 0.050 (normal <0.400 OD).
Erythrocyte sedimentation rate was 46 mm/hour (normal range 0–18 mm/hour) and C reactive protein was 28.2 mg/L (normal range <8.0 mg/L). Urinalysis was significant for 3+blood (normal=absent). Blood cultures were also sent. Flow cytometric analysis showed no evidence of a paroxysmal nocturnal haemoglobinuria clone based on analysis of glycosylphosphatidylinositol-linked antibodies. Monoclonal gammopathy evaluation was only significant for a slightly low total protein level of 5.8 g/dL (normal 6.2–8.1 g/dL). No monoclonal proteins were detected. Free kappa was slightly elevated at 5.02 mg/dL (normal 0.33–1.94) and free lambda was normal at 1.46 mg/dL (normal 0.57–2.63 mg/dL). Free kappa/lambda ratio was elevated at 3.44 (normal 0.26–1.65). IgA was 69 mg/dL (normal 70–365 mg/dL) and IgG and IgM were within normal limits. Bone marrow examination of the left iliac crest showed normocellular bone marrow with adequate trilineage haematopoiesis. No overt evidence of marrow involvement by chronic myeloid leukaemia, lymphoma or metastatic malignancy was identified. Severe normocytic anaemia with schistocytes and severe thrombocytopenia were seen, which was consistent with microangiopathic haemolytic anaemia. These findings were consistent with TTP. ADAMTS13 activity was ordered but as this lab value can take time to result, TTP treatment was initiated in the meantime. Eventually, ADAMTS13 level returned at 7% (normal range >/=70%) and testing was negative for an ADAMTS13 inhibitor. HIV-1 p24 antigen/HIV-½ antibody screen was non-reactive. Renal function was normal with creatinine of 0.98 mg/dL (normal range 0.50–1.10 mg/dL) and glomerular filtration rate of 58 mL/min/1.73 m2 (normal >60 mL/min/1.73 m2). Genetic testing for congenital TTP was not completed on our patient.
Differential diagnosis
On initial presentation, the differential diagnosis for acute thrombocytopenia was quite broad. It was narrowed down to a type of thrombotic microangiopathy once peripheral smear showed schistocytes and lab values indicated haemolysis with elevated lactate dehydrogenase and low haptoglobin. Fibrinogen levels were high and Coombs’ test was negative making disseminated intravascular coagulation and autoimmune haemolytic anaemia less likely, respectively. Bone marrow biopsy was negative for clonal plasma cells and there was no M protein present nor renal involvement, making multiple myeloma and monoclonal gammopathy of undetermined significance less likely. The presence of headaches raised concern for TTP and thus PLASMIC score was calculated, which was 7, indicating high risk for severe ADAMTS13 deficiency (defined as ADAMTS13 activity level <15%). Due to the high mortality rate of TTP if left untreated, steroids and plasmapheresis were started and ADAMTS13 level was ordered. CT head was ordered to rule out intracranial bleed, which was negative.
A new phenomenon called VITT has also been described after COVID-19 vaccine administration which was also considered in our patient. However, our patient’s HPF4 antibodies were negative, decreasing the likelihood of this diagnosis.
Treatment
As soon as concern for thrombotic thrombocytopenia arose, the patient was started on methylprednisolone 250 mg every 6 hours. Therapeutic plasma exchange was ordered and initiated within 24 hours of admission after a central line was placed by interventional radiology. She underwent daily therapeutic plasma exchange with 100% plasma volume replacement with 4000 mL of fresh frozen plasma. She completed daily exchanges for 4 days, and then these were stopped, as the platelet count had recovered to greater than 150 bil/L.
Outcome and follow-up
Three days after treatment was initiated with steroids and plasmapheresis, the diagnosis of TTP was confirmed when ADAMTS13 activity resulted at 7% (normal range >/=70%). With initiation of the above treatments, the platelets recovered quickly, increasing to 23 bil/L, followed by 135 bil/L. They were back to the normal range by the fourth day of treatment. The patient recovered well and continues to follow with her haematologist.
Discussion
TTP is a rare disorder with a prevalence of ~10 cases per million, characterised by microangiopathic haemolytic anaemia, severe thrombocytopenia, organ ischaemia and presence of severe deficiency of ADAMTS13 activity (<10%). It is most commonly acquired with autoantibodies developed against ADAMTS13, and rarely inherited with a mutation in the ADAMTS13 gene.7 Historically, TTP was defined as a pentad of fever, thrombocytopenia, microangiopathic anaemia, neurological symptoms and renal insufficiency. However, not all patients develop all of these symptoms.7 The most common conditions associated with TTP are bacterial infections, autoimmune diseases, pregnancy, certain medications and malignancy.7 Vaccine-induced TTP is a known phenomenon and has been reported after the use of pneumococcal,8 influenza,9–11 rabies12 and H1N113 vaccines.
COVID-19 vaccine-related TTP, however, has rarely been described as there are only case reports and a case series documenting the possibility of this event. Until now, a total of 11 cases of TTP attributed to one of the three currently authorised vaccines in the USA, Pfizer, Moderna and Johnson & Johnson/Janssen, have been reported in the literature. Ruhe et al,14 de Brujin et al,15 Sissa et al,16 Kirpalani et al 17 and Waqar et al 18 each describes a case of TTP (fitting laboratory results) after administration of the Pfizer vaccine. Maayan et al 19 presents a case series of four cases of TTP after the Pfizer vaccine. There has only been one reported diagnosis of TTP each after the Moderna6 and AstraZeneca20 vaccines. However, these cases should not be confused with a different entity named VITT that has been described in various studies, in which patients develop thrombotic events along with thrombocytopenia after COVID-19 vaccination. This disorder is associated with antibodies to platelet factor 4 (PF4)—polyanion complexes present in the absence of heparin use.3–5 COVID-19 vaccine-induced thrombocytopenia without thrombosis has also been reported in literature.2
Our patient had laboratory findings suggesting TTP including: severe thrombocytopenia, microangiopathic anaemia with elevated haemolytic markers, the presence of schistocytes in peripheral blood, and low ADAMTS13 activity, along with typical clinical symptoms. Her PLASMIC score was 7 indicating severe disease, and she also had a negative PF4 antibody arguing against VITT. As completed in our patient, urgent plasmapheresis is the cornerstone of TTP management and should be implemented at the time of suspicion. Additional treatment includes corticosteroids and rituximab.7
Despite the lack of an ADAMTS13 inhibitor identified in our patient, we still believe she carries the diagnosis of immune-mediated TTP as opposed to hereditary TTP. Those with hereditary TTP present at two peak ages, in childhood and in pregnancy, making the median age 31 in one study.21 Hereditary TTP represents less than 5% of all TTP cases and is often characterised by more mild and non-specific symptoms, whereas immune-mediated TTP often has a more discreet onset and remission, as seen in our patient. Our patient also lacks a family history of TTP or thrombotic events, and she had no prior documentation of thrombocytopenia.21 In one study, it was found that up to 10% of patients may never demonstrate an inhibitor against ADAMTS13.22 In another study, about 1/5 of patients with immune-mediated TTP did not have a detectable inhibitor.23 Given the clinical presentation and characteristics of our patient, she most likely has immune-mediated TTP with a non-neutralising or undetected antibody. Thus, hereditary testing was not completed in our patient.
She began to develop symptoms 2 days after receiving the Moderna (mRNA 1273) vaccine, and symptoms continued to worsen until she presented to urgent care and subsequently the emergency department 8 days after receiving the vaccine. This is the second reported case of TTP following the Moderna vaccination. This is, however, the first such incident in a patient without history of TTP, as the case described by Karabulut et al was a recurrence of the disease after vaccination. Our patient was also taking dasatinib at the time, which has rarely been associated with TTP as well.24 However, she continues to take dasatinib after the TTP episode without issues, making this less likely. The temporal relationship to receiving the Moderna vaccine and development of TTP makes the vaccine more likely the culprit. However, there is no way to prove the vaccine was the cause of TTP and a causal association cannot be established based on a single case. This case and other limited cases in the literature warrant further studies and reporting of this adverse event. With more time and increasing vaccine administration, we will be able to determine if the Moderna vaccine is indeed a causative factor of immune-mediated TTP.
Learning points
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This is only the second documented case, to our knowledge, where immune-mediated thrombotic thrombocytopenic purpura was observed following the Moderna vaccine. We are unable to establish causality based on such few cases. Our identification of a possible case of a vaccine-related adverse event must lead to further research before firm conclusions regarding a causal association can be made.
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As the COVID-19 vaccines are new entities created by novel mechanisms, it is important we identify adverse events that may happen in relation to the vaccine.
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Thrombotic thrombocytopenic purpura (TTP) is a disease that can be detrimental if left untreated. It is important to consider this in patients who present with thrombocytopenia after receiving the Moderna vaccine.
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The diagnosis of immune-mediated TTP can still be made despite a negative ADAMTS13 antibody, as some patients may have an undetectable or non-neutralising antibody present.
Ethics statements
Patient consent for publication
Footnotes
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Contributors EH and BG: Researching, writing and editing of manuscript. MMC: Care of patient, idea for case report and final editing of manuscript. All authors approved the final version.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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