May-June 2015, Volume 12, Issue 3
Too Many RBCs or Platelets Stall Blood Flow in Cerebral Capillaries
Published on: April 03, 2015
Santisakultarm TP, Paduano CQ, Stokol T, et al. 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;12:2120-2130.
The myeloproliferative neoplasms (MPNs) polycythemia vera (PV) and essential thrombocythemia (ET) are associated with cerebrovascular complications. Although thrombosis in PV and ET is a frequent cause of more serious neurological complications, reduced microvascular blood flow seems to have an important role in transient, reversible CNS deficits such as headaches, dizziness, vision loss, dysphasia, and focal paresis. The higher incidence of these temporary neurologic problems in PV appears to involve increased red blood cell (RBC) numbers and aggregation contributing to whole-blood hyperviscosity.1 In PV with increased platelets, and in ET, increased neurological problems appear to involve increased platelet numbers and activation, resulting in enhanced platelet aggregation.2 Blood hyperviscosity with accompanying reversible neurological deficits is also commonly encountered in secondary polycythemias, including those found in chronic pulmonary diseases, elevated carboxyhemoglobin levels, altitude sickness, and exogenous EPO or testosterone therapies.2 Studies of tissue clearance of labeled isotope (133Xe dissolved in saline and injected intravenously) demonstrated phlebotomy-reversible decreases in cerebral blood flow in subjects with various ailments who had hematocrits in the 47 percent to 53 percent range compared with matched controls with hematocrits in the 36 percent to 46 percent range.3 Fluorescein angiography in PV patients with transient blindness demonstrated retinal arterial-venous transit times that were twice those of normal controls, and phlebotomy and hydroxyurea treatment of the patients with PV corrected the delayed transit times.4
Direct 3-dimensional observation of the murine cerebral cortical blood flow in microvascular beds from the penetrating arterioles through capillary beds to ascending venules was developed using 2-photon excited fluorescence (2PEF) microscopy and stacking of 2-dimensional images.5 In these images, the motion of the RBCs, which are unstained, is tracked through fluorescently labeled plasma. RBCs in normal cerebral capillaries had pulsatile flow rates of about 1 mm/s.5 Dr. Thom Santisakultarm and colleagues, who developed the 3-dimensional method of 2PEF microscopy in the laboratory of Dr. Chris Schaffer, now report the effects of polycythemia and/or thrombocythemia on cerebral capillary blood flow using mouse models of PV, ET, mixed MPN (see definition below), and secondary polycythemia due to exogenous erythropoietin (EPO) administration. In the murine MPN models, the ratio of human mutant JAK2 V617F relative to the wild-type mouse JAK2 (after transplantation of hematopoietic cells from JAK2 V617F transgenic mice) determined whether the phenotype was PV (polycythemia only) for high ratios, ET (thrombocythemia only) for low ratios, or "mixed" MPN (combined thrombocythemia and polycythemia) for intermediate ratios.6 The flow rates and vessel diameters of the examined cerebral microvascular beds were surprisingly similar for all of these disease models and wild-type controls. The blood flow rates were slightly skewed in the PV mice, with slowest capillary rates ranging from 0.1 to 0.2 mm/s. However, the striking difference between each of the disease models and wild-type mice was in the percentage of capillaries with stalled blood flow (Figure). About 3 percent of cerebral capillaries were stalled in wild-type mice, whereas percentages of stalled cerebral capillaries were 14 percent in “mixed” MPN, 18 percent in ET, 19 percent in EPO-treated animals, and 27 percent in PV mice. An additional fluorescent label allowed identification of leukocytes and platelets as well as unlabeled RBCs. Platelet aggregates were associated with 50 percent of stalled capillaries in ET, whereas RBC aggregates were associated with 48 percent, 50 percent, and 65 percent of stalled capillaries in mixed MPN, PV, and EPO-treated mice, respectively. Serial monitoring demonstrated prolonged persistence of the stalled capillaries ranging from a median of 30 minutes in ET mice to more than two hours in MPN mice. Capillary stalls that were observed during their resolution had an abrupt onset of reduced flow for a few seconds or less, followed by re-establishment of rapid blood flow.
The demonstration by Dr. Santisakultarm and colleagues of stalled blood flow in increased percentages of cerebral capillaries in PV and ET provides a mechanism other than thrombosis for focal cerebral hypoxia and subsequent microinfarction. The abrupt, spontaneous resolution of these capillary stalls with re-established rapid blood flow may explain the frequent but transient central nervous system symptoms including headaches, dizziness, vision loss, dysphasia, and focal paresis that are associated with PV, ET, and secondary polycythemia. Stalled blood flow in cerebral capillaries may also help explain how increased hematocrit is associated with reduced reperfusion and enhanced infarct size on serial MRIs following ischemic strokes.7 Therefore, stalled cerebral capillary blood flow may play a role in microinfarcts and in exacerbation of ischemic damage from compromised blood flow in larger cerebral vessels.
Sequential 2PEF images that demonstrate flowing (left panels) and stalled (right panels) capillaries in the cerebral cortex (images captured every 0.3 s for a total of 1.2 s of observation). Texas Red-dextran was intravenously injected to label blood plasma (bright), leaving the cellular components unlabeled (dark). Figure reprinted from Santisakultarm TP et al., J Thromb Haemost. 2014;12:2120-2130.
Kwaan HC, Wang J. Hyperviscosity in polycythemia vera and other red cell abnormalities. Semin Thromb Hemost. 2003;29:451-458.
Michiels JJ, Berneman Z, Schroyens W, et al. Platelet-mediated erythromelalgic, cerebral, ocular and coronary microvascular ischemic and thrombotic manifestations in patients with essential thrombocythemia and polycythemia vera: a distinct aspirin-responsive and Coumadin-resistant arterial thrombophilia. Platelets. 2006;17:528-544.
Thomas DJ, Marshall J, Russell RW, et al. Effect of haematocrit on cerebral blood-flow in man. Lancet. 1977;2:941-943.
Yang HS, Joe SG, Kim JG, et al. Delayed choroidal and retinal blood flow in plycythaemia vera patients with transient ocular blindness: a preliminary study with fluorescein angiography. Br J Haematol. 2013;161:745-747.
Santisakultarm TP, Cornelius NR, Nishimura N, et al. In vivo two-photon excited fluorescence microscopy reveals cardiac- and respiration-dependent pulsatile blood flow in cortical blood vessels in mice. Am J Physiol Heart Circ Physiol. 2012;302:H1367-H1377.
Tiedt R, Hao-Shen H, Sobas MA, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111:3931-3940.
Allport LE, Parsons MW, Butcher KS, et al. Elevated hematocrit is associated with reduced reperfusion and tissue survival in acute stroke. Neurology. 2005;65:1382-1387.
Conflict of Interests
Dr. Koury indicated no relevant conflicts of interest.
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