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 Table of Contents  
Year : 2022  |  Volume : 55  |  Issue : 4  |  Page : 158-160

Cerebral venous sinus thrombosis-associated hemorrhage in vaccine-induced immune thrombotic thrombocytopenia: Catastrophic outcome if delayed diagnosis and treatment

1 Department of Neurosurgery, Shin Kong Wu Ho-Su Memorial Hospital, New Taipei, Taiwan
2 Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, New Taipei, Taiwan
3 Department of Neurosurgery, Shin Kong Wu Ho-Su Memorial Hospital; School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan

Date of Submission28-Nov-2021
Date of Decision20-Apr-2022
Date of Acceptance21-Apr-2022
Date of Web Publication1-Aug-2022

Correspondence Address:
Ming-Cheng Tsai
No. 95, Wenchang RD, Shilin Dist., Taipei City
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/fjs.fjs_236_21

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The authors reported the clinical course of a 58-year-old female suffering from cerebral venous sinus thrombosis associated with hemorrhage after the ChAdOx1 nCov-19 vaccination. Emergent decompressive craniectomy was performed, and aggressive blood transfusion was given. Nevertheless, progressive intracerebral hemorrhage and thrombocytopenia developed. A delayed diagnosis was made on a rare complication of vaccine-induced immune thrombotic thrombocytopenia (VITT) with a positive result of anti-platelet factor 4 antibodies (PF4 Ab). The patient died 4 days postoperative due to brainstem failure.

Keywords: Anti-platelet factor 4 antibodies, cerebral venous thrombosis, vaccine-induced immune thrombotic thrombocytopenia

How to cite this article:
Lam CT, Lin KY, Kao MC, Tsai MC. Cerebral venous sinus thrombosis-associated hemorrhage in vaccine-induced immune thrombotic thrombocytopenia: Catastrophic outcome if delayed diagnosis and treatment. Formos J Surg 2022;55:158-60

How to cite this URL:
Lam CT, Lin KY, Kao MC, Tsai MC. Cerebral venous sinus thrombosis-associated hemorrhage in vaccine-induced immune thrombotic thrombocytopenia: Catastrophic outcome if delayed diagnosis and treatment. Formos J Surg [serial online] 2022 [cited 2022 Aug 14];55:158-60. Available from: https://www.e-fjs.org/text.asp?2022/55/4/158/353064

  Introduction Top

Global vaccination is the most critical step to battle against the coronavirus-2019 (COVID-19) pandemic. The available vaccines in Taiwan include an adenovirus-based vector vaccine – ChAdOx1 nCov-19 (AstraZeneca); two messenger RNA-based vaccines – BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna); and one protein subunit vaccine – MVC-COV1901 (Medigen). ChAdOx1 nCov-19 vaccine is the most commonly used vaccine in Taiwan. Cerebral venous sinus thrombosis (CVST) following immunization has been increasingly reported. Diagnosis of CVST with vaccine-induced immune thrombotic thrombocytopenia (VITT) is difficult in Taiwan due to limited clinical experience and the lack of related diagnostic tools. We present a case with this complication and related fatality.

  Case Report Top

A 58-year-old female who had no significant past medical history and not taking any medication developed symptoms of dizziness and headache after ChAdOx1 nCov-19 (AstraZeneca) vaccination. The symptoms continued intermittently and deteriorated approximately 10 days after vaccination. Fifteen days after vaccination, the patient was found to be unconscious and was transported to our emergency department. Upon arrival, the patient presented with Glasgow Coma Scale of E3V1M3 and bilaterally dilated pupils (both 6 mm) without light reflex. Brain computed tomography (CT) revealed unusual left parietal intracerebral hemorrhage and brain swelling [Figure 1]a. Brain CT venogram (CTV) revealed the empty delta sign at the superior sagittal sinus [Figure 1]b. Laboratory blood test showed thrombocytopenia (platelet count of 56,000/cubic millimeter). Cerebral venous thrombosis with venous infarct and hemorrhagic transformation was impressed. Emergent decompressive hemicraniectomy and hematoma evacuation were performed. Blood transfusion including platelet and fresh frozen plasma was given. The polymerase chain reaction test result on admission for COVID-19 was negative. Six hours after the operation, the patient's intracranial cerebral pressure increased and brain CT showed multi-foci hemorrhage [Figure 2]. Other abnormal laboratory data included: D-dimer: 26046 ng/mL, fibrinogen: 427 mg/dl, fibrin degradation products: 77.2 ug/mL, and platelet function assay-100 (collagen/epinephrine time: 249 s and Collagen/Adenosine diphosphate time: 262 s). The patient died 4 days postoperative due to brainstem failure. The positive result of anti-PF4 Ab confirmed the diagnosis of VITT.
Figure 1: (a) Brain computed tomography showed left parietal intracerebral hemorrhage (white arrow), dense clot sign at the sagittal sinus (black arrow), and brain swelling. (b) Brain computed tomography venogram revealed the empty delta sign (arrow) at the superior sagittal sinus

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Figure 2: Brain computed tomography postoperative 6 h showed multifoci hemorrhage

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  Discussion Top

Epidemiology of vaccine-induced immune thrombotic thrombocytopenia

The estimated incidence of VITT is about 1 in 150,000 for the ChAdOx1 recipients and 1 in 470,000 for the Ad26. COV2.S recipients.[1] Most VITT victims were observed in recipients of mRNA-based vaccines and rarely described in other adenoviral vaccines.[1],[2] Thrombosis in VITT can occur in typical sites of venous thromboembolism such as pulmonary embolism (PE) and deep-vein thrombosis in the leg. However, the unusual sites including the splanchnic (splenic, portal, and mesenteric) veins, adrenal veins, and the cerebral and ophthalmic veins are distinctive.[3] Based on population data, it is unknown why VITT has a predilection for the cerebral venous sinuses or the splanchnic bed or a predisposition for venous rather than arterial thromboembolism.[4] The majority of reported patients with VITT-associated CVST were females. Most of the cases have no concomitant risk factors, including oral contraceptives, hormone therapy, obesity, diabetes, current malignancy, and active cigarette smoking.[2],[5] Our patient was a middle-aged woman without any predisposition and risk factors for developing CVST except the ChAdOx1 nCov-19 (AstraZeneca) vaccination.

Pathophysiology of vaccine-induced immune thrombotic thrombocytopenia

VITT belongs to a spectrum of platelet-activating anti-PF4 and heparin disorders, including classic heparin-induced thrombocytopenia (HIT), autoimmune HIT (aHIT), and spontaneous HIT. VITT most strongly resembles spontaneous HIT, triggered by an adenoviral vector COVID-19 vaccine.[2] Investigators identified antibodies targeting PF4 in the sera of patients with VITT, suggesting an autoimmune vaccine response. Preliminary theories include the possibility that components of the vaccine (including virus proteins and free DNA) bind to PF4 and generate a neoantigen.[5] This complex then binds to the platelet FcRγIIA receptors and initiates the formation of blood clots and inducing a prothrombotic cascade, which consequently decreases the platelet count and causes thrombocytopenia.[1],[2],[5]

Diagnostic criteria of vaccine-induced immune thrombotic thrombocytopenia

There are five definitive diagnostic criteria for VITT: the onset of symptoms 5–30 days after vaccination against SARS-CoV-2 (or ≤42 days in patients with isolated deep-vein thrombosis or PE), the presence of thrombosis, thrombocytopenia (platelet count <150,000/cubic millimeter), a D-dimer level >4000 fibrinogen-equivalent units (FEUs), and the presence of antibodies to PF4 detected by means of enzyme-linked immunosorbent assay.[6] VITT clinically resembles spontaneous aHIT.[5] The key feature that distinguishes VITT or aHIT from other thrombocytopenic disorders such as infections, immune thrombocytopenia, and thrombotic thrombocytopenic purpura is that anti-PF4 antibodies in those thrombocytopenic disorder are unable to activate platelets and cause thrombosis.[7] Our patient met all the five diagnostic criteria which were: conscious disturbance 15 days after receiving AstraZeneca vaccination, thrombocytopenia upon arrival, brain CT indicating venous sinus thrombosis, elevated D-dimer >4000 FEUs, and most importantly, the positive result of anti-PF4 antibodies.

Treatment strategy of vaccine-induced immune thrombotic thrombocytopenia

CVST-associated hemorrhage in VITT is unlikely to stabilize with platelet transfusion unless a life-threatening hemorrhage is present.[8] Although decompressive hemicraniectomy is mandatory in the initial treatment of brain herniation, restoration of venous outflow in the form of therapeutic anticoagulation or endovascular venous thrombectomy is critical to reduce local venous congestion and intracranial pressure. The American Heart Association and the American Stroke Association guidelines recommend anticoagulants to be initiated or continued in the presence of hemorrhagic venous congestion.[9] Given the overlapping mechanism of anti-PF4-induced platelet activation in VITT and heparin-induced thrombocytopenia thrombosis (HITT), nonheparin-based intravenous anticoagulants (argatroban, bivalirudin, and fondaparinux) and intravenous immunoglobulin (IVIg) 1 g/kg daily for 2 days is recommended. High-dose corticosteroids, plasma exchange, and fibrinogen substitution may be considered for severe thrombocytopenia.[5],[8],[10] Due to the delayed recognition of VITT and the rapid development of complications, we were not able to conduct the aforementioned treatments except emergent decompressive craniectomy. Aggressive platelet and fresh frozen plasma transfusion alone without concomitant immune-suppression therapy such as IVIg or steroids in our patient probably aggravated thrombocytopenia and caused more thrombus formation according to the pathophysiology of VITT.

  Conclusion Top

Although the incidence of the complication of VITT is relatively rare, the reported mortality rate of CVST with VITT was quite high, about 20% to 30%.[1] Early recognition or diagnosis and early management warrant for testing of anti-PF4 Ab. However, quality control for anti-PF4 Ab in different laboratories is difficult. We appeal that increasing the diagnostic tool in the majority of medical institutions is of paramount importance, especially on the issue of compensation regarding postvaccination complications.

Declaration of patient consent

The authors certify that they have obtained appropriate patient's children consent form. In the form, patient's children have given the consent for the patient's images and other clinical information to be reported in the journal. Patient's children understand that the patient's name and initial will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.


The authors would like to thank all colleagues who contributed to this study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Siegler JE, Klein P, Yaghi S, Vigilante N, Abdalkader M, Coutinho JM, et al. Cerebral vein thrombosis with vaccine-induced immune thrombotic thrombocytopenia. Stroke 2021;52:3045-53.  Back to cited text no. 1
Sharifian-Dorche M, Bahmanyar M, Sharifian-Dorche A, Mohammadi P, Nomovi M, Mowla A. Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; a systematic review. J Neurol Sci 2021;428:117607.  Back to cited text no. 2
Gabarin N, Patterson S, Pai M, Afzaal T, Nazy I, Sheppard JA, et al. Venous thromboembolism and mild thrombocytopenia after ChAdOx1 nCoV-19 vaccination. Thromb Haemost. 2021 Aug 12.  Back to cited text no. 3
Pottegård A, Lund LC, Karlstad Ø, Dahl J, Andersen M, Hallas J, et al. Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: Population based cohort study. BMJ 2021;373:n1114.  Back to cited text no. 4
Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 vaccination. N Engl J Med 2021;384:2092-101.  Back to cited text no. 5
Pavord S, Scully M, Hunt BJ, Lester W, Bagot C, Craven B, et al. Clinical features of vaccine-induced immune thrombocytopenia and thrombosis. N Engl J Med 2021;385:1680-9.  Back to cited text no. 6
Cuker A, Arepally GM, Chong BH, Cines DB, Greinacher A, Gruel Y, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Heparin-induced thrombocytopenia. Blood Adv 2018;2:3360-92.  Back to cited text no. 7
Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021;384:2202-11.  Back to cited text no. 8
Saposnik G, Barinagarrementeria F, Brown RD Jr., Bushnell CD, Cucchiara B, Cushman M, et al. American Heart Association Stroke Council and the Council on Epidemiology and Prevention. Diagnosis and management of cerebral venous thrombosis: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:1158-92.  Back to cited text no. 9
Schultz NH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021;384:2124-30.  Back to cited text no. 10


  [Figure 1], [Figure 2]


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