Impaired Hemostatic and Immune Functions of Platelets After Acute Thrombocytopenia.

Background: Platelets are pivotal in maintaining vascular integrity, hemostasis, and immune modulation, with newly generated, immature platelets being the most responsive in fulfilling these tasks. Therefore, the immature platelet fraction provides insights into thrombopoiesis dynamics and clinical prognostication. However, it is currently unclear how immature platelet functions change in settings of acute thrombocytopenia.

Objectives: We aimed to investigate the functional consequences of acute thrombocytopenia on newly generated immature platelets in various mouse models and human subjects.

Methods: To examine platelet functionality after acute thrombocytopenia, we depleted either megakaryocytes using a PF4-specific iDTR transgenic mouse model or platelets via antibody-mediated depletion in mice, and collected blood from acute myeloid leukemia (AML) patients before and after consolidation or induction chemotherapy. Chemotherapy treatment was further repeated in an animal model. We assessed surface receptor expression of activation markers (CD62P, active GPIIb/IIIa, CD40L, CD63, CD107a) and toll-like receptors (TLR2, TLR4, TLR9) on immature and mature platelets following activation. Additionally, we investigated procoagulant platelet formation and platelet-leukocyte interactions in mouse models and AML patients.

Results: In murine models, acute thrombocytopenia led to impaired hemostatic function and altered surface receptor expression in newly generated immature platelets. Similarly, AML patients during regeneration post-chemotherapy exhibited reduced platelet activation and procoagulant function, alongside altered receptor expression and diminished platelet-leukocyte interactions.

Conclusions: After acute thrombocytopenia platelet-mediated hemostasis and immune modulation by newly generated platelets are impaired, underscoring the clinical relevance of understanding platelet function alterations in (post)thrombocytopenic conditions for therapeutic optimization.