Stalled cerebral capillary blood flow in mouse models of essential thrombocythemia and polycythemia vera revealed by in vivo two‐photon imaging

Abstract

To cite this article: Santisakultarm TP, Paduano CQ, Stokol T, Southard TL, Nishimura N, Skoda RC, Olbricht WL, Schafer AI, Silver RT, Schaffer CB. Stalled cerebral capillary blood flow in mouse models of essential thrombocythemia and polycythemia vera revealed by in vivo two-photon imaging. J Thromb Haemost 2014; 12: 2120-30.Summary. Background: Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPNs) that share the JAK2 V617F mutation in hematopoietic stem cells, leading to excessive production of predominantly platelets in ET, and predominantly red blood cells (RBCs) in PV. The major cause of morbidity and mortality in PV and ET is thrombosis, including cerebrovascular occlusive disease. Objectives: To identify the effect of excessive blood cells on cerebral microcirculation in ET and PV. Methods: We used two-photon excited fluorescence microscopy to examine cerebral blood flow in transgenic mouse models that mimic MPNs. Results and conclusions: We found that flow was 'stalled' in an elevated fraction of brain capillaries in ET (18%), PV (27%), mixed MPN (14%) and secondary (non-MPN) erythrocytosis (27%) mice, as compared with controls (3%). The fraction of capillaries with stalled flow increased when the hematocrit value exceeded 55% in PV mice, and the majority of stalled vessels contained only stationary RBCs. In contrast, the majority of stalls in ET mice were caused by platelet aggregates. Stalls had a median persistence time of 0.5 and 1 h in ET and PV mice, respectively. Our findings shed new light on potential mechanisms of neurological problems in patients with MPNs.

Increased capillary stalling is associated with endothelial glycocalyx loss in subcortical vascular dementia

“…Recent studies have revealed the significance of capillary stalling in aging, stroke, Alzheimer's disease, polycythemia and thrombocythemia 3,4,5,6,11,21,22,23 . In fact, capillary stalling largely impacts on CBF, and cognitive functions can be improved by suppressing capillary stalling in Alzheimer's disease 6,24 .…”

Non‐invasive imaging of retinal blood flow in myeloproliferative neoplasms

“…In transgenic mice with polycythemia and thrombocytosis, two‐photon fluorescence microscopy has shown increased rates of stalled capillary blood flow in brain capillaries compared to control mice (Santisakultarm et al. ), and fluorescein angiography of retinal vessels in patients with PV has shown qualitatively reduced retinal and choroidal blood flow as compared with controls (Yang et al. ).…”

Two-photon imaging of cerebral hemodynamics and neural activity in awake and anesthetized marmosets

“…Branch order was determined by running multiple loops to assign first branch order to capillaries stemming from penetrating arterioles, followed by the subsequent connecting capillaries branches until the segments merged with ascending venules. Identification of stalled capillaries was performed as previously described (Santisakultarm et al, 2014). RBC flow speed and vascular diameter of arteriole, venule, and capillary vessels were measured using previously published methods (Hall et al, 2014; Santisakultarm et al, 2012) with minor modifications (Drew et al, 2011).…”