Fatal Cerebral Venous Sinus Thrombosis and Thrombocytopenia due to Anti-PF4 Disorder Following Adenovirus Infection in a 3-year-old Boy

Introduction

Vaccination against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been crucial in managing the COVID-19 pandemic. In 2021, a rare syndrome characterized by thrombotic events and thrombocytopenia was identified in individuals who received the ChAdOx1 nCoV-19 or the Ad26.COV2.S vaccine, both of which use adenoviral vectors.[1] [2] [3] [4] [5] This syndrome, known as vaccine-induced immune thrombocytopenia and thrombosis (VITT), is linked to high levels of immunoglobulin G (IgG) antibodies targeting platelet factor 4 (PF4), a chemokine released from platelet α-granules.[6] Similar conditions associated with anti-PF4 antibodies include classic heparin-induced thrombocytopenia (HIT), autoimmune HIT (aHIT), and spontaneous HIT.[7] Additionally, prothrombotic, platelet-activating anti-PF4 antibodies not associated with heparin have been identified in a patient with monoclonal gammopathy.[8] These anti-PF4 disorders present with thrombosis and thrombocytopenia following exposure of PF4 to polyanions like DNA, heparin, or polyphosphate.[9] [10] Recently, anti-PF4 antibodies were detected in two individuals who developed a VITT-like syndrome after adenovirus infection, despite not receiving COVID-19 vaccination or heparin treatment.[11] In the meantime, further such cases, some of them with a preceding respiratory infection and positive testing for adenovirus, have been reported (see [Table 1]).[12] [13] [14] Here, we report the case of a 3-year-old boy who developed fatal cerebral venous sinus thrombosis (CVST) and thrombocytopenia several days after an adenovirus infection. Postmortem studies revealed the presence of anti-PF4 antibodies in his serum. This case further confirms the existence of adenovirus-triggered anti-PF4 antibodies, emphasizing the need to study anti-PF4 antibodies in patients with unexplained thrombosis and thrombocytopenia.

Table 1 Summary of published cases of VITT-like syndrome without prior vaccination or heparin treatment

Patient number	Sex	Age (years)	Preceding infection/pathogen	Underlying disease	Clinical diagnosis	Outcome	Source
#1	M	5	Yes/Adenovirus	None	CVST	Fatal	Warkentin et al[11]
#2	F	58	Yes/Adenovirus	None	Multiple arterial strokes, MI, multiple DVT	Survived	Warkentin et al[11]
#3	F	40	Yes/Adenovirus	None	PE, DVT, ICB	Survived	Campello et al[12]
#4	F	70–80[1]	None	Monoclonal gammopathy	Multiple DVT, PE, stroke	Survived	Schönborn et al[13]
#5	F	30–40	Yes/Unknown	None	CVST	Fatal	Schönborn et al[13]
#6	F	70–80	None	None	PE	Survived	Schönborn et al[13]
#7	M	60–70	None	None	Stroke with secondary ICB	Survived	Schönborn et al[13]
#8	F	20–30	Yes/RSV	None	CVST, PE, DVT	Survived	Schönborn et al[13]
#9	F	30–40	None	None	Multiple TE	Survived	Schönborn et al[13]
#10	M	60–70	Yes (UTI)/Unknown	Crohn‘s disease	DVT, PE	Fatal	Schönborn et al[13]
#11	M	20–30	Yes/Unknown	None	CVST	Survived	Schönborn et al[13]
#12	M	5–10	Yes/Adenovirus	None	CVST	Survived	Schönborn et al[13]
#13	F	7	Yes/Adenovirus	None	CVST	Survived	Uzun et al.[14]
#14	M	3	Yes/Adenovirus, bocavirus	None	CVST	Fatal	This case

Abbreviations: CVST, cerebral venous sinus thrombosis; DVT, deep venous thrombosis; ICB, intracerebral bleeding; MI, myocardial infarction; PE, pulmonary embolism; RSV, respiratory syncytial virus; TE, thrombotic events; UTI, urinary tract infection; VITT, vaccine-induced immune thrombocytopenia and thrombosis.

Note: Schönborn et al reported patients’ ages as ranges to respect confidentiality.

Publication History

Article published online:
31 January 2025

• References

• 1 Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021; 384 (22) 2092-2101
• 2 Schultz NH, Sørvoll IH, Michelsen AE. et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021; 384 (22) 2124-2130
• 3 Scully M, Singh D, Lown R. et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021; 384 (23) 2202-2211
• 4 Wiedmann M, Skattør T, Stray-Pedersen A. et al. Vaccine induced immune thrombotic thrombocytopenia causing a severe form of cerebral venous thrombosis with high fatality rate: a case series. Front Neurol 2021; 12: 721146
• 5 Tomassini L, Paolini D, Petrasso PEY. et al. What about cerebral venous sinus thrombosis? A series of three autopsy cases. Leg Med (Tokyo) 2022; 56: 102052
• 6 Greinacher A, Selleng K, Palankar R. et al. Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia. Blood 2021; 138 (22) 2256-2268
• 7 Warkentin TE. Platelet-activating anti-PF4 disorders: an overview. Semin Hematol 2022; 59 (02) 59-71
• 8 Greinacher A, Langer F, Schönborn L. et al. Platelet-activating anti-PF4 antibodies mimic VITT antibodies in an unvaccinated patient with monoclonal gammopathy. Haematologica 2022; 107 (05) 1219-1221
• 9 Greinacher A, Selleng K, Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost 2017; 15 (11) 2099-2114
• 10 Brandt S, Krauel K, Jaax M. et al. Polyphosphates form antigenic complexes with platelet factor 4 (PF4) and enhance PF4-binding to bacteria. Thromb Haemost 2015; 114 (06) 1189-1198
• 11 Warkentin TE, Baskin-Miller J, Raybould AL. et al. Adenovirus-associated thrombocytopenia, thrombosis, and VITT-like antibodies. N Engl J Med 2023; 389 (06) 574-577
• 12 Campello E, Biolo M, Simioni P. More on adenovirus-associated thrombocytopenia, thrombosis, and VITT-like antibodies. N Engl J Med 2023; 389 (18) 1729
• 13 Schönborn L, Esteban O, Wesche J. et al. Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure. Blood 2023; 142 (26) 2305-2314
• 14 Uzun G, Zlamal J, Althaus K. et al. Cerebral venous sinus thrombosis and thrombocytopenia due to heparin-independent anti-PF4 antibodies after adenovirus infection. Haematologica 2024; 109 (06) 2010-2015
• 15 Tang HT, Nörz D, Grunwald M. et al. Analytical and clinical validation of a novel, laboratory-developed, modular multiplex-PCR panel for fully automated high-throughput detection of 16 respiratory viruses. J Clin Virol 2024; 173: 105693
• 16 Baker AT, Boyd RJ, Sarkar D. et al. ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome. Sci Adv 2021; 7 (49) eabl8213
• 17 Warkentin TE, Arnold DM, Sheppard JI, Moore JC, Kelton JG, Nazy I. Investigation of anti-PF4 versus anti-PF4/heparin reactivity using fluid-phase enzyme immunoassay for 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia (HIT), autoimmune HIT, vaccine-induced immune thrombotic thrombocytopenia, and spontaneous HIT. J Thromb Haemost 2023; 21 (08) 2268-2276