Thrombocytopenia in a Mouse Model of Pancreatic Cancer

Background: Pancreatic ductal adenocarcinoma (PDAC) is often associated with hypercoagulability and thrombocytosis. However, a subset of patients experiences thrombocytopenia and bleeding that is typically attributed to chemotherapy and/or anticoagulant treatment. Direct, pathophysiological effects of PDAC on platelet clearance, production, and function are poorly defined.

Aim: Characterize platelet clearance, production, and function in a mouse model of PDAC associated with bleeding to better understand mechanisms that predispose cancer patients to coagulation dysfunction.

Methods: C57BL/6J mice were orthotopically injected with pancreatic tumor cells derived from Kras^G12D/+, p53^R172H/+, Elas^CreER/+ mice (KPC2 cells). Bleeding was assessed with a tail transection model. Complete blood cell counts were measured. Platelet clearance, hematopoietic stem and progenitor cell (HSPC) populations, and platelet activation were characterized by flow cytometry. CD41 in splenic tissue was detected by immunohistochemistry. Plasma thrombopoietin was quantified by ELISA.Results: Compared to control mice, KPC2 tumor-bearing mice exhibited increased tail bleeding, which correlated with decreased platelet count and increased mean platelet volume. Tumor-bearing mice had enhanced platelet clearance and increased spleen mass, and CD41 staining of spleens suggested splenic sequestration of platelets. Thrombopoietin levels were unchanged in tumor-bearing mice. Megakaryocyte progenitors including CD41+ hematopoietic stem cells (LSK, CD41+) were paradoxically increased, suggesting induction of the emergency hematopoiesis pathway. Platelets in tumor-bearing mice showed reduced activation following stimulation with ADP or convulxin.

Conclusion: KPC2 pancreatic tumor-bearing mice had increased bleeding associated with thrombocytopenia, increased platelet clearance, altered hematopoiesis, and decreased platelet activation. Crosstalk between tumor cells, platelets, and bone marrow may contribute to coagulopathy in PDAC.

No relevant conflicts of interest to declare.