Lambert and colleagues use a cohort of genetically modified mice to demonstrate that platelet factor 4 (PF4) inhibits in vivo megakaryocytopoiesis, and thus propose a novel approach to counter chemotherapy-related thrombocytopenia.
PF4, a member of the CXC family of chemokines, is the most abundant protein in platelet α-granules and is released into the local environment following platelet activation. Although characterized by its heparin-binding activity more than 50 years ago,1 PF4's physiologic activities remain in question. Prior reports have shown that PF4 can inhibit murine and human megakaryocyte colony development in vitro,2,3 an activity that localizes outside of the carboxy-terminal heparin-binding domain.4 However, it remained unclear if this activity also occurs in vivo.
In this issue of Blood, Lambert and coworkers show that the loss of 1 or 2 PF4 alleles leads to a stepwise increase in baseline platelet counts and that transgenic mice expressing progressively higher levels of human PF4 on the same genetic background have proportionately fewer platelets. Platelet transfusion experiments indicate that circulating platelet half-life is independent of platelet PF4 level, suggesting that the inverse relationship between platelet count and endogenous PF4 levels is due to an in vivo platelet production defect. In support of this idea, marrow from mice lacking PF4 yields more megakaryocyte colonies than does marrow from wild-type mice, and antibodies to PF4 restore megakaryocyte colony formation to wild-type levels in marrow from transgenic mice that overexpress PF4.
Given their findings, the authors hypothesize that the inhibitory effect of PF4 on megakaryocytopoiesis may negatively impact platelet recovery following chemotherapy-induced thrombocytopenia, which they tested by monitoring the platelet nadir and recovery time in mice following 5-fluorouracil (5-FU) treatment. There was a small but statistically significant acceleration of recovery following 5-FU treatment in PF4−/− mice relative to that seen in wild-type mice, whereas there was a marked delay in platelet recovery in mice with elevated levels of PF4, a finding that was abrogated by the infusion of anti-PF4 antibody. The authors therefore propose that counteracting the effect of inhibitors of megakaryocytopoiesis such as PF4 offers a novel and transfusion-free approach to reducing treatment-related thrombocytopenia.
While Lambert and colleagues present genetic evidence that PF4 has an inhibitory effect on in vivo megakaryocytopoiesis, they provide little insight into the mechanism by which this is achieved. Nonetheless, they propose an interesting approach to thinking about and treating cytopenias; blocking or inactivating inhibitors of hematopoiesis may offer a useful alternative or complement to the current approach that employs stimulatory molecules and transfusions. This point not withstanding, given that PF4 is selectively packaged into platelet α-granules and released into the immediate environment following platelet activation, it is somewhat difficult to imagine that impairment of megakaryocytopoiesis is high on the list of physiologically significant activities of PF4. The cohort of mice used by Lambert and colleagues should provide these and other investigators with a rich resource for furthering our understanding of the physiologic significance of this prominent platelet protein.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
