...And so on to viscosity

Much as Lewis F. Richardson¹  embraced Jonathan Swift's metaphorical use of smaller and smaller fleas to represent the infinite in his modeling of rheologic disturbance——we now must accede to the infinite complexity of factors that impart viscosity to sickle cell blood.

Considering that Richardson found an infinite potential for turbulence in the blowing wind and flowing river water, both Newtonian fluids lacking particulate constituents, what was to be expected of sickle cell blood? A seminal opinion on the matter, Ham and Castle's²  celebrated description of a “Vicious cycle of erythrostasis,” focused on the deleterious effect of the eye-catching sickle erythrocyte on the viscosity of sickle cell blood. This valuation engendered exhaustive studies of sickling and hemoglobin S polymerization, as well as doctrinal interpretations of disease. The elegance of these formulations notwithstanding, detailed understandings of polymerization could neither predict the occurrence nor identify the triggers of acute painful vasoocclusion.³  Perhaps as a result of dogged research, or maybe imaginative insight, or perchance just idle curiosity, important polymerization-independent processes emerged and defined different targets for investigation. As a result, modern views interpret traditional polymerization-based understandings as part of a broad matrix of pathophysiologies. However, even as the molecular details of platelet activation, coagulation induction, sickle cell adhesion, endothelial cell agonism, heterocellular interactions, and vasomotor dysregulation are established, the question of causality remains.

The agonists of several of the vasoocclusive pathophysiologies include inflammatory cytokines and procoagulant enzymes. Certainly the vascular injury and cell activation caused by circulating sickle cells might account for inflammation, but what of the thrombin? Proposed mechanisms for thrombin generation include the procoagulant effect of phosphatidyl serine (PS) on the exterior of sickled cells, the expression of tissue factor (TF) by activation and interaction of endothelial cells and monocytes, and the procoagulant activity of hypoxic endothelial cells.³ 

In this issue, Shet and colleagues (page 2678) have extended our knowledge of these complex mechanisms. They found an increase in erythroid-derived microparticles and markers of thrombophilia during acute painful episodes, but the absence of TF on erythroid microparticles indicates that these are not the triggers of coagulation. Possible causality derives from the generation of both procoagulant PS-positive sickle cells⁴  and erythroid microparticles by the same process, sickling. However, the surprisingly constant rate of sickling would suggest that bursts of PS-positive sickle cells are unlikely to trigger vasoocclusion, and the data in this paper do not establish whether increased erythroid microparticles precede or follow vasoocclusion. Shet et al also found that during pain crises the levels of TF bearing monocyte-derived microparticles increases and correlates with indicators of thrombophilia. But what is the cause of the monocyte activation? These findings by Shet and his colleagues have taken us deeper into the realm of infinite complexity and may have led us closer to the proximate cause of these important perturbations. As is often the case with infinitely complex mechanisms, the real answer may be hidden among the internal deterministic parameters of chaos.⁵