Persistently high platelet factor 4 levels in an adolescent with recurrent late thrombotic complications after SARS-CoV-2 mRNA vaccination: A case report

doi:10.21203/rs.3.rs-2441808/v1

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Case Report

Persistently high platelet factor 4 levels in an adolescent with recurrent late thrombotic complications after SARS-CoV-2 mRNA vaccination: A case report

https://doi.org/10.21203/rs.3.rs-2441808/v1

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Background

Thrombosis after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is a serious complication for patients with a thrombophilic predisposition. Factors that predict the risk of post-vaccination thrombosis should be explored. We report a case in which a patient with pediatric antiphospholipid syndrome (APS) developed deep vein thrombosis (DVT) six months after receiving a second dose of the BNT162b2 vaccine.

Case presentation:

A 17-year-old girl with no family history of thrombophilia developed DVT at six years of age. The thrombus was found in the right common iliac vein and the inferior vena cava, with concomitant left pulmonary infarction. After treatment with warfarin, the pulmonary infarction was resolved, but the thrombus became organized and persisted for the next 11 years. The patient was treated with anticoagulants for six years after DVT onset, with subsequent cessation of treatment for five years without thrombosis recurrence. She received the BNT162b2 vaccine at 17 years of age, one week before a routine outpatient visit. Elevation of platelet factor 4 level was detected 14 days after the first vaccination and remained for five months after that, but without thrombotic symptoms. A second dose of the BNT162b2 vaccine was administered; six months later, the DVT in the right common iliac vein recurred and was treated with a direct oral anticoagulant.

Conclusions

The BNT162b2 vaccine exacerbated her antiphospholipid antibody syndrome by activating the coagulation system, thereby exacerbating her thrombosis. Platelet factor 4 may be a useful indicator of the coagulation system. The persistence of high platelet factor 4 levels after vaccination suggests that the vaccine caused DVT by exacerbating the patient’s APS. After vaccination of patients with a predisposition to thrombosis, coagulation status and platelet activation markers should be monitored to prevent the development of DVT.

PF4 (Platelet Factor 4)

COVID-19 Vaccines

Venous Thrombosis

Anti-Phospholipid Syndrome

Anticoagulants

The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a pandemic beginning in 2019. Numerous SARS-CoV-2 vaccines have been developed, and various adverse reactions to the vaccines have been reported. In particular, anti-Platelet Factor 4 (PF4)-adenovirus complexes are involved in vaccine-induced immune thrombotic thrombocytopenia (VITT) after adenovirus vector vaccines [1], which is said to occur within three months after vaccination. On the other hand, VITT is rare with the SARS-CoV-2 mRNA vaccine (BNT162b2 vaccine). However, it is important to predict the possibility of developing deep vein thrombosis (DVT) after SARS-CoV-2 vaccination in patients with a thrombophilic predisposition.

In this study, we report a pediatric Anti-phospholipid syndrome (APS) case in which PF4, a platelet activation marker, was persistently elevated after administration of SARS-CoV-2 mRNA vaccine (BNT162b2 vaccine), and DVT developed six months after the second vaccination.

A 17-year-old female was diagnosed with deep vein thrombosis after experiencing sudden abdominal and right groin pain and vomiting at six years of age. There was no family history of thrombophilia. A thrombus was found in the right common iliac vein to the inferior vena cava, with concomitant left pulmonary infarction. Blood tests showed PT INR 1.3, APTT 37.0 sec, D-dimer 88.4 µg/ml, FDP 221.6 µg/ml, TAT 49.1ng/ml, PIC 17.6 µg/ml, cardiolipin antibody IgG 44U/ml. Anticoagulation with unfractionated heparin was initiated, and treatment was changed to warfarin. The pulmonary infarction improved, but the thrombus from the right common iliac vein to the inferior vena cava became organized and has remained to the present time. The patient was treated with anticoagulation medications, warfarin, and beraprost sodium (prostaglandin I2 analog) for six years. She continued to have thrombosis without further DVTs for five years.

Laboratory analysis showed a lupus anticoagulant (LA) level of 1.0-1.26 (normal range, < 1.3) by Diluted Russell Viper Venom Time, anti-beta-2 glycoprotein I IgG antibody (aβ2GPI-IgG) < 0.7 U/ml, anti-cardiolipin antibody IgG (aCL) 39–44 U/ml, and moderately elevated aCL for more than 2 years, leading to antiphospholipid antibody syndrome diagnosis based on the 2006 Sydney criteria. Eight years ago, one of her markers of platelet activation, platelet factor 4 (PF4), was 57 ng/ml (normal range, ≤ 20 ng/ml). Blood test results did not indicate a significant change in APTT, LA, aCL, and aβ2GPI-IgG at the end of anticoagulant medication.

In 2021, Japan enacted a policy offering the BNT162b2 vaccine to 12- to 17-year-olds. Our patient received the first dose of the BNT162b2 vaccine 1 week before the routine outpatient visit (Fig. 1). After two months, her PF4 level was markedly elevated at 282 ng/ml and even higher at 640 ng/ml. However, platelet, FDP, and D-dimer levels were within the reference range, so anticoagulants were not prescribed. Five months after the initial vaccination, she was advised to opt out of the second vaccination because of the high PF4 value. However, since two vaccinations were required as a condition for studying abroad, she was vaccinated for the second time. As PF4 peaked at 350 ng/ml five months after the first vaccination, a second dose of the BNT162b2 vaccine was administered. A GPI-IgG level of 1.1 U/ml, and a transient increase, were observed.

At a routine visit two months after returning to Japan, which was 6 months after the second vaccination, blood tests showed a normal platelet count and coagulation parameters, but PF4 levels were elevated again (540 ng/ml). Therefore, aspirin (81 mg) was readministered as an antiplatelet agent. On the fourth day after initiation, the patient developed chest pain, hypoxemia, and pain/edema in the right lower extremity. Blood test showed the following results: thrombin-antithrombin III complex (TAT) 2.2 ng/ml, plasmin-α2 plasmin inhibitor complex (PIC) 0.7 µg/ml, FDP 7.4 µg/ml, D dimer 5.3 µg/ml, PF4 563 ng/ml, and aCL 28.2 U/ml. Abdominal ultrasonography also showed a further increase of thrombus in the right common iliac vein, and a recurrent deep vein thromboembolism diagnosis was made (Fig. 2). The patient's symptoms and laboratory values improved three days after the start of direct oral anticoagulants (DOAC: rivaroxaban). Lung single photon emission computed tomography (99mTc-MAA, 81 mKr) was performed, but there was no complication of pulmonary infarction.

Blood tests showed levels of PF4 at 341 ng/ml and β-thromboglobulin (βTG) as high as 845 ng/ml, but TAT (< 1.0 ng/ml) and D-dimer (< 0.5 µg/ml) were below detection sensitivity at seven months after the second vaccination. SARS-CoV-2 S protein antibody titer was 7610 U/ml (< 0.80 U/ml).

Nine months after the second vaccination, the vaccine antibody level is 7230 U/ml, and PF4, which is not related to the vaccine antibody level, remains high (659 ng/ml). Currently, thrombosis is being controlled with rivaroxaban.

This is a case of a patient with pediatric APS who developed DVT six months after the second dose of the BNT162b2 vaccine (11 months after the first vaccination). The persistence of high PF4 levels from post-vaccine administration to DVT suggested an association between the vaccine and DVT due to APS exacerbation by the vaccine.

PF4 is released when the overexpression of tissue factor activates platelets due to vascular endothelial cell injury or monocyte activation and promotes platelet aggregation, and it tends to be elevated when platelet activity is triggered by avascularization or infection. However, in this case, the reproducibility of consistently high PF4 levels after BNT162b2 vaccination and the recurrence of DVT during high PF4 levels suggested that APS and the BNT162b2 vaccine may be related. Therefore, the test results should be evaluated with caution.

Differential diagnosis is Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT). SARS-CoV-2 vaccine-associated VITT has been proposed to occur 4–30 days after vaccination [2]. The most common causative vaccine is ChAdOx1 nCoV-19 [1], and there are few reports of DVT caused by the BNT162b2 vaccine [3, 4]. Although mRNA vaccines are expected to induce thrombosis by a different mechanism than adenovirus vector vaccines, mRNA vaccine-associated DVT mechanism remains unclear. Many large trials have shown that mRNA vaccines do not increase the risk of DVT [5]. Our patient developed DVT due to BNT162b2 vaccination six months after the second dose (11 months after the first dose), and the disease course could not be described as VITT.

APS is an autoimmune disease in which the production of antiphospholipid antibodies (aPLs) causes arteriovenous thrombosis. Pediatric APS is defined as APS that develops at less than 18 years of age[6]; it is rare, accounting for 2.8% of all APS patients [7]. BNT162b2 vaccination was speculated as the reason for the second thrombosis 11 years later, even though the patient had developed thrombosis at age six without a recurrence since then. We hypothesized that the thrombosis was because the vaccine exacerbated APS. Exacerbating factors for pediatric APS include trauma, surgery, neoplasms, nephrotic syndrome, congenital heart disease, obesity, central venous catheters, prolonged immobilization, stays in the intensive care unit, burns, and mechanical ventilation [8, 9]. Typical risk factors such as malignant disease and tobacco were not observed in this patient.

In a case report of a 22-year-old woman who developed pulmonary infarction after SARS-CoV-2 mRNA vaccination, Balbona et al. reported that APS contributed to her thrombosis because aCL was elevated more than 10 times above the normal range [10]. Rios et al. reported the development of systemic lupus erythematosus (SLE) and secondary APS in a 42-year-old woman two weeks after the first BNT162b2 vaccination [11]. Although the reason is unclear, it has been suggested that mRNA vaccines are highly immunogenic and induce marked inflammation, which may promote APS development even in asymptomatic aPL-positive patients [12]. Furthermore, studies on the mRNA vaccines have reported elevated aPL after SARS-CoV-2 infection [13], suggesting it is an exacerbating factor for APS.

Monitoring platelet activity after SARS-CoV-2 vaccination in pediatric patients with APS, such as in the present case, is necessary to prevent DVT. Prospective studies have shown that platelet activation by SARS-CoV-2 vaccines is seen with both adenovirus vector and mRNA vaccines [14]. Therefore, monitoring platelet activity after vaccination should be a concern for patients with thrombophilic disorders. In pediatric patients with a thrombophilic predisposition, platelet activity and coagulability should be monitored before and after SARS-CoV-2 mRNA vaccination using PF4, βTG, D-dimer, and TAT levels.

Regarding prophylaxis for thrombosis after mRNA vaccination in patients with APS, it is difficult to choose between warfarin, DOAC, aspirin, or other drugs. In a previous case report [11], warfarin was used. In the present case, 81 mg of aspirin was administered to decrease PF4 activity and resulting in a PF4 level reduction by half. However, the patient developed DVT while on aspirin, so the treatment was switched to DOAC, which improved clinical symptoms. Some reports suggest that warfarin is preferable to DOAC in patients at high risk of thrombosis, such as those with APS [15]. The suitability of DOAC treatment for patients demonstrating APS exacerbation after mRNA vaccination, as in this case, requires further investigation.

The limitation of this case is that PF4 was measured only eight years before the SARS-Cov2 vaccination and could not be monitored immediately before the vaccination. However, it should be emphasized that the patient continued to show abnormally high PF4 levels 20 ~ 30 times higher than the reference value after vaccination and subsequently developed DVT.

The PF4 level may be useful in monitoring the course of thrombosis after SARS-CoV-2 vaccination in children with APS. Although the mechanism by which mRNA vaccines cause thrombosis has not yet been clarified, coagulation status and platelet activation markers should be monitored in vaccinated patients predisposed to thrombophilia to allow for interventions to hopefully prevent DVT.

aβ2GPI-IgG, anti-beta-2 glycoprotein I IgG antibody

aCL, anti-cardiolipin antibody IgG

aPL, antiphospholipid antibody

APS, anti-phospholipid syndrome

DOAC, direct oral anticoagulant

DVT, deep vein thrombosis

PIC, plasmin-α2 plasmin inhibitor complex

PF4, platelet factor 4

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2

TAT, thrombin-antithrombin III complex

VITT, vaccine-induced immune thrombotic thrombocytopenia

Ethics approval and consent to participate

Not applicable. Informed consent was obtained from the patient and her mother.

Consent for publication

Consent for publication was obtained from the patient and her mother.

Data availability statement

Data sharing is not applicable as no datasets were generated or analyzed during the current study.

Competing interests

The authors of this work have nothing to disclose.

Funding

Funding information is not available.

Authors’ contributions

YH, AO, AY, MU, MM, AY, and HT analyzed and interpreted the patient data regarding hematological disease and thrombosis. TY performed the ultrasonographic examination of the DVT. All authors read and approved the final manuscript.

Acknowledgments

We would like to thank Editage (www.editage.com) for English language editing.

Authors’ information

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No competing interests reported.

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Persistently high platelet factor 4 levels in an adolescent with recurrent late thrombotic complications after SARS-CoV-2 mRNA vaccination: A case report

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Background

Case presentation:

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