Thrombotic thrombocytopenic purpura after vaccination for COVID-19: lesson for the clinical nephrologist.

The case

A 63-year-old male patient with a known history of untreated arterial hypertension and positive hepatitis B serology was admitted to the hospital due to general health deterioration, confusion, chest pain, and dyspnoea one week after the second vaccination against coronavirus using ChAdOx1 nCoV-19 (second immunisation date 22nd June, 2021; first immunisation date 22nd April, 2021). The patient did not smoke, drink alcohol or use recreational drugs. Upon clinical examination, there were no electrocardiographic signs of heart disease but the patient had elevated high sensitive Troponin-T, a slightly enlarged spleen, and hepatic steatosis. Ultrasound, chest X-ray, and magnetic resonance imaging showed normal kidneys, no signs of lung infiltration and no signs of intracranial bleeding or ischaemia.

Laboratory findings are presented in Table 1. The patient had pronounced anaemia, haemolysis, and thrombocytopenia. Schistocytes were detectable in the blood smear. Acute kidney failure was moderate. The Coombs test and severe acute respiratory syndrome coronavirus (SARS-CoV) 2 polymerase chain reaction (PCR) were negative. Total Plasmic score reached 7 out of a possible 7 points indicating a 72% risk of severe ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency < 15% [1]. This was subsequently confirmed with the ADAMTS13 work-up, which showed an activity of < 1% and an antibody titre of 33 U/ml (cut-off < 16 U/ml). The patient was diagnosed with acquired thrombotic thrombocytopenic purpura (aTTP).

Table 1

Baseline laboratory and ADAMTS13

	Normal range	Admission (30th June)	Referral (8th July)	Discharge (20th July)
Baseline laboratory
Haemoglobin, g/dL	14–17.5	5.2	6.2	9.2
Haemolysis
Haptoglobin	0.3–2.0 g/l	< 0.1	< 0.1	0.60
Reticulocyte count	5–15 o/oo	57.10	106.50	250
Indirect bilirubin	0.2–0.8	2.15
MCV, fl	80–96	88.8	110.3	105
Platelets, /µl	150,000–400,000	8000	20,000	280,000
Creatinine, mg/dl	0.67–1.17	1.34	1.01	0.96
Schistocytes, o/oo	0–5	7.0	26.0	18
Troponin-T hs, pg/ml	0–14	37	132	30
INR	0.89–1.28	1.03	1.13	1.01
LDH, U/l	135–225	972	844	395
ADAMTS13
Activity, %	50–110	< 1	< 1	21
Antigen, IU/ml	0.35–1.2	0.02	0.02	0.06
Antibodies, U/ml	< 16	33	32	0
Differential diagnosis
HIT2-antibody-IgG; U/l	< 1.00	0.08	Negative
D-dimer levels, ng/ml	< 500		15,622
Fibrinogen, g/l	2.0–3.93		2.23

ADAMTS13 “a desintegrin and metallprotease with thrombospondin-1-like-domains”, HIT heparin-induced thrombocytopenia, hs high sensitive, LDH lactate dehydrogenase, INR international normalized ratio, MCV mean corpuscular volume

The patient was further investigated for possible causes of secondary aTTP, such as autoimmune disease and human immunodeficiency virus infection; both of which were excluded. As two of the patient’s siblings were reported having lupus erythematosus, the patient was also investigated for the presence of anti-nuclear antibodies, hypocomplementaemia and lupus anticoagulant, which were all negative. Antiphospholipid syndrome was also excluded. We ruled out heparin-induced thrombocytopenia (HIT) 2 in our patient based on a negative immunoglobulin G (IgG) antibody titre (0.08 U/ml with an upper bound of normal < 1.0 U/ml).

The patient was admitted to the first hospital on 30th June, 2021 and the diagnosis was confirmed on day 3 as aTTP due to vaccination. The patient was started on plasmapheresis on the admission day with added administration of prednisolone, which increased his platelet count. Rituximab was administered on 5th July and plasmapheresis was continued until 8th July. The patient was referred to the second hospital on 8th July due to a relapse, with platelets dropping to 18,000/µl. Caplacizumab 10 mg was started on the same day, plasmapheresis was stopped and rituximab was administered on 12th and 19th July. The patient was discharged home on the 20th July with a platelet count of > 150,000/µl, ADAMTS13 activity was 21%, and caplacizumab treatment was stopped. The patient continued with prednisolone (60 mg) with a recommendation to reduce the dose by 10 mg/week.

Lessons for the clinical nephrologist

Several cases of vaccine-associated or triggered TTP (n = 17) have been described in the literature with the majority of cases associated with the BioNTech/Pfizer vaccine (n = 12), 2 cases each with the AstraZeneca and Moderna vaccines, and one case reported after administration of the Johnson & Johnson vaccine (Table S1). Cases were observed in patients with an age range of 14–84 years, with 11 out of 17 patients being female. While the majority of cases were considered aTTP, there was one case of a relapse in congenital TTP (cTTP) [2] reported with the Moderna vaccine. Twelve out of 17 patients had their first TTP episode, while in 5 patients it was a relapse of known disease. Nine of 17 patients experienced TTP after their first dose of vaccination with a delay of between 5 and 37 days (median 12 days; mean 12.7 days). ADAMTS13 activity was always severely deficient and in all aTTP cases, ADAMTS13 antibodies were present (information was missing for one case). Previously published treatments for TTP have included plasma exchange (16 out of 16) and steroids (15 out of 16)—the mainstay of treatment in patients with aTTP, rituximab (9 out of 16 patients) and caplacizumab (7 out of 16) (Table S1). This is surprising given the registration of caplacizumab in 2018 for the treatment of aTTP. Following the International Society on Thrombosis and Haemostasis (ISTH) guidance, caplacizumab should be initiated as early as possible—even before the availability of the ADAMTS13 activity results [3]—as it is superior to the standard therapy [4-6].

In a separate case study, a 50-year-old female patient [2] with cTTP developed vaccine-associated TTP 7 days after the second vaccination with the Moderna vaccine. This patient had an ADAMTS13 activity of < 5% with no proof of ADAMTS13 antibodies. She received fresh frozen plasma and OctaPlas, rather than plasma exchange and steroids, as is appropriate for cTTP.

Differential diagnosis of vaccine-induced immune thrombotic thrombocytopenia (VITT)

There are a few reports showing that vaccination with ChAdOx1 nCov-19 may also lead to rare cases of VITT. Greinacher et al. [7] assessed the clinical and laboratory features of 11 patients in whom thrombosis or thrombocytopenia had developed after vaccination with the AstraZeneca vaccine. Thrombotic events began between 5 and 16 days post-vaccination; 9 patients had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism and 4 had other thromboses. All patients tested positive on the platelet-activation assay for the presence of PF4 independent of heparin. Schultz et al. [8] reported on the fate of five patients who developed venous thrombosis and thrombocytopenia 7–10 days after receiving the first dose of ChAdOx1 nCoV-19. All patients had high levels of antibodies to PF4-polyanion complexes but no patient had prior exposure to heparin. We ruled out this option in our patient based on a negative HIT2 IgG antibody titre (0.08 U/ml with an upper bound of normal < 1.0 U/ml). Furthermore, depleted fibrinogen, as would be expected in VITT, was not present in our patient.

Clinical implications

Patients presenting with thrombocytopenia and haemolytic anaemia should receive a thorough work-up. In particular, after corona virus disease (COVID) vaccination, the possibility of a VITT needs to be assessed as a differential diagnosis and separated from cases with aTTP. Running the Plasmic or French score, in addition to reduced ADAMTS13 activity and negative test for antibodies against platelet factor 4 (PF4) heparin, will guide diagnoses in these cases. Prompt initiation of plasma exchange together with steroids, and considering the use of rituximab and caplacizumab, is key to a positive clinical outcome.

It is extremely important to know whether a patient is prone to developing TTP after vaccination with any of the available vaccines against COVID-19. This is particularly evident for patients with a known history of either cTTP or aTTP. Determining ADAMTS13 activity beforehand and potentially using immunosuppressive strategies may impair a relapse of TTP upon vaccination.

After taking the decision to vaccinate a person with TTP, close monitoring of ADAMTS13 activity, antibody levels for aTTP and platelet counts can only be recommended. This would enable a tailored treatment approach with the provision of caplacizumab ± steroids until ADAMTS13 recovery.

In conclusion, the potential occurrence of TTP in cases of post vaccination thrombocytopenia should always be kept in mind to initiate treatment early.

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 21 kb)