A long-sought animal model for congenital human thrombocytopenias that result from myosin gene mutations reveals defects in platelet production as well as platelet function.
May first reported on the unusual combination of large platelets and leukocyte inclusions (Döhle bodies) in 1909.1 The May-Hegglin anomaly is an autosomal dominant inherited disorder related to the equally rare Epstein, Sebastian, and Fechtner syndromes, which encompass other clinical features besides the presence of giant platelets in reduced numbers.2,3 Macrothrombocytopenia is the common feature, although bleeding symptoms are mild and the disorders typically come to light in the context of surgery. The diagnosis, which relies on 4 features (thrombocytopenia, large platelet size, leukocyte inclusion bodies, and a family history) avoids further work-up and draws attention toward associated clinical manifestations.
As few centers encounter patients with hereditary thrombocytopenia in large numbers and individual variation is considerable, platelet function in the May-Hegglin anomaly has resisted definition. Some studies report decreased platelet adhesion and aggregation, but the present view is that platelet function is largely intact and that hemostasis is compromised only by thrombocytopenia. Positional cloning implicates the myosin heavy chain gene MYH9 in all syndromes listed previously, which are hence collectively called Myh9-related disorders. MYH9 is the major nonmuscle myosin expressed in megakaryocytes and platelets, and associates with the actin cytoskeleton in other cells to enable morphogenesis. As shape change is important in both platelet biogenesis and activation, MYH9 malfunction can plausibly account for clinical features related to platelets. However, early lethality of Mhy9-null mouse embryos4 precluded establishment of a suitable animal model.
In this issue of Blood, Léon and colleagues report on findings that followed their use of Cre-Lox recombination to create a conditional-null Myh9 allele. Besides macrothrombocytopenia, which may have been expected, Myh9-null mice have a prolonged bleeding time, which does not seem to reflect low platelet numbers alone, and dramatic deficiency in clot retraction. Aggregation response to platelet agonists is intact, but cellular shape changes, which transiently attenuate light transmission in platelet aggregometry, are lost and platelets lacking Myh9 fail to form actin stress fibers or extend lamellipodia properly. These deficits may account for abnormal thrombus morphology in collagen-coated flow chambers, as well as for the formation of small, unstable thrombi in a model of FeCl3-induced carotid artery injury. Outside-in signaling through the αIIbβ3 integrin receptor is impaired in response to platelet activation in vitro by thrombin but not by collagen.
These uniform observations contrast with the disparate results reported in patients with Myh9-related disorders, a contrast that may reflect species differences or the authors' diligent application of specific, precise assays of platelet function. Their creation of a reliable animal model will enable critical assessment of Myh9 pathophysiology and, as rare diseases often inform us about normal biology, of normal megakaryocyte and platelet mechanisms. It remains unclear if the May-Hegglin anomaly results from Myh9 haploinsufficiency or dominant activity of mutant alleles; heterozygotic mice seem to be normal in every respect that Léon and colleagues have studied. Thrombocytopenia in Myh9-related disorders is attributed to defects in terminal megakaryocyte maturation. In addition to examining the precise role of actin-myosin complexes in platelet activation, conditional Myh9-null mutant mice can help test specific hypotheses about mechanisms of platelet release.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
