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    Oral Communication

    Fibrinolysis and Proteolysis

    Fibrinolysis and Proteolysis

    OC 37.5 - Vaccine-induced immune thrombotic thrombocytopenia produces a marked hyperfibrinolytic state and generates a plasma cofactor that potentiates tPA-mediated plasminogen activation

    Monday, June 26, 2023
    11:45 – 12:00 ET
    Room: 524
    Session Available As: On-Demand
    Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but severe complication of adenovirus vector-based COVID-19 vaccines, ChAdOx1 nCoV19 (Oxford/Astra-Zeneca) and the Ad26.COV2.S COVID-19 (Janssen/Johnson & Johnson). VITT is characterised by development of thrombosis in conjunction with thrombocytopaenia and the presence of antibodies that react with platelet factor-4. VITT is also associated with markedly raised levels of D-dimer, yet how VITT modulates the fibrinolytic system is unknown.

    Aims: To compare changes in baseline and inducible fibrinolytic activity in plasma from patients with confirmed VITT, patients diagnosed with venous thromboembolism post-vaccination but without VITT (VTE-noVITT), and age matched healthy controls who experienced no adverse effects following vaccination. All patients received the Astra-Zeneca vaccine.

    Methods: Levels of plasmin-antiplasmin (PAP) complexes, plasminogen, and alpha2-anti-plasmin in citrated plasma from 11 patients with VITT, 9 patients with VTE-noVITT, and 27 healthy COVID-19 vaccinated controls were evaluated by ELISA (presented as mean+/- SD) and/or western blotting. Fibrinolytic capacity was tested by quantitating PAP levels at baseline and after ex-vivo plasma stimulation with 50nM tissue-type plasminogen activator (tPA) for 5 minutes.

    Results: Baseline plasma PAP complex levels from control (358178ng/ml) and VTE-noVITT (518+/-378ng/ml) individuals were not significantly different. In contrast, PAP levels were 7-fold higher in plasma from VITT patients (2,584+/-1,370ng/ml) compared to healthy controls (p < 0.0001) (Figure 1A). The VITT-induced hyperfibrinolytic state did not alter plasminogen levels, but caused consumption of antiplasmin (Figure 1B & C). VITT patient plasma also produced significantly higher PAP levels after ex-vivo tPA treatment (13,917+/-3,369ng/ml) compared to the VTE-noVITT (8,896+/-4,504ng/ml; p< 0.005) and healthy controls (7,008+/-1,973ng/ml; p< 0.0001) (Figure 1D).

    Conclusion(s): VITT induces a marked hyperfibrinolytic state that is consistent with the marked increase in D-dimer levels seen in these patients. Plasma from patients with VITT also harbours an unidentified cofactor that potentiates tPA-mediated plasminogen activation.

    Learning Objectives:

    • Upon completion, participants will be able to describe the fibrinolytic changes at baseline in patients with Vaccine induced immune thrombotic thrombocytopenia (VITT).
    • Upon completion, participants will be able to describe the fibrinolytic response to ex-vivo treatment of VITT plasma with tissue-type plasminogen activator (tPA) and how this differs from samples with venous thrombo-embolism without VITT (VTE-no VITT) and healthy controls.
    • Upon completion, participants will be able to generate a list of potential causes of enhanced plasmin generation in plasma from patients with VITT following ex-vivo tPA treatment.