Abnormal megakaryopoiesis and platelet function in cyclooxygenase-2-deficient mice

Thromb Haemost. 2015 Nov 25;114(6):1218-29. doi: 10.1160/TH14-10-0872. Epub 2015 Aug 13.

Abstract

Previous studies suggest that cyclooxygenase-2 (COX-2) might influence megakaryocyte (MK) maturation and platelet production in vitro. Using a gene deletion model, we analysed the effect of COX-2 deficiency on megakaryopoiesis and platelet function. COX-2-/- mice (10-12 weeks old) have hyper-responsive platelets as suggested by their enhanced aggregation, TXA2 biosynthesis, CD62P and CD41/CD61 expression, platelet-fibrinogen binding, and increased thromboembolic death after collagen/epinephrine injection compared to wild-type (WT). Moreover, increased platelet COX-1 expression and reticulated platelet fraction were observed in COX-2-/- mice while platelet count was similar to WT. MKs were significantly reduced in COX-2-/- bone marrows (BMs), with high nuclear/cytoplasmic ratios, low ploidy and poor expression of lineage markers of maturation (CD42d, CD49b). However, MKs were significantly increased in COX-2-/- spleens, with features of MK maturation markers which were not observed in MKs of WT spleens. Interestingly, the expression of COX-1, prostacyclin and PGE2 synthases and prostanoid pattern were modified in BMs and spleens of COX-2-/- mice. Moreover, COX-2 ablation reduced the percentage of CD49b+ cells, the platelet formation and the haematopoietic stem cells in bone marrow and increased their accumulation in the spleen. Splenectomy decreased peripheral platelet number, reverted their hyper-responsive phenotype and protected COX-2-/- mice from thromboembolism. Interestingly, fibrosis was observed in spleens of old COX-2-/- mice (28 weeks old). In conclusion, COX-2 deletion delays BM megakaryopoiesis promoting a compensatory splenic MK hyperplasia, with a release of hyper-responsive platelets and increased thrombogenicity in vivo. COX-2 seems to contribute to physiological MK maturation and pro-platelet formation.

Keywords: COX-2; megakaryocytes; platelets; thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / biosynthesis
  • Antigens, CD / genetics
  • Antigens, Differentiation / biosynthesis
  • Antigens, Differentiation / genetics
  • Blood Platelets / physiology*
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Crosses, Genetic
  • Cyclooxygenase 1 / biosynthesis
  • Cyclooxygenase 1 / genetics
  • Cyclooxygenase 2 / deficiency*
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / physiology
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Hyperplasia
  • Megakaryocytes / metabolism
  • Megakaryocytes / ultrastructure
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Platelet Count
  • Ploidies
  • Purpura, Thrombocytopenic, Idiopathic / physiopathology
  • Purpura, Thrombocytopenic, Idiopathic / surgery
  • Receptors, Thromboxane A2, Prostaglandin H2 / biosynthesis
  • Receptors, Thromboxane A2, Prostaglandin H2 / genetics
  • Spleen / metabolism
  • Spleen / pathology
  • Splenectomy
  • Thromboembolism / chemically induced
  • Thromboembolism / etiology
  • Thromboembolism / prevention & control
  • Thrombophilia / enzymology
  • Thrombophilia / genetics
  • Thrombopoiesis / physiology*
  • Thromboxane B2 / blood

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Membrane Proteins
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Thromboxane B2
  • Ptgs2 protein, mouse
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Ptgs1 protein, mouse