Clinical Hemorheology and Microcirculation - Volume 68, issue 2-3

Authors: Connes, Philippe

Article Type: Editorial

DOI: 10.3233/CH-189001

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 103-104, 2018

Authors: Ballas, Samir K.

Article Type: Research Article

Abstract: Sickle cell disease (SCD) is an inherited disorder of hemoglobin structure that has no established cure in adult patients. Cure has been achieved in selected children with sickle cell anemia (SCA) using allogeneic bone marrow transplantation or cord blood transplantation. SCD is essentially a triumvirate of (1) pain syndromes, (2) anemia and its sequelae and (3) organ failure, including infection. Pain, however, is the hallmark of SCD and dominates its clinical picture throughout the life of the patients. The prevalence of these complications varies with age from infancy through adult life. However, pain, infections and anemia requiring blood transfusion occur …throughout the life span of affected patients. The overall medical care of patients with SCD in developed countries has improved such that their life expectancy has almost doubled since 1951. Currently, there are at least five major approaches for the general management of SCD and its complications. These include (i) symptomatic management, (ii) supportive management, (iii) preventive management, (iv) abortive management, and (v) curative therapy. Show more

Keywords: Sickle cell disease, sickle cell anemia, complications, management

DOI: 10.3233/CH-189002

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 105-128, 2018

Authors: Ballas, Samir K.

Article Type: Research Article

Abstract: Sickle cell disease (SCD) in general and sickle cell anemia in particular is a highly complex disorder both at the molecular and clinical levels. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of the disease. Moreover, despite the fact that SCD is a chronic malady, its manifestations are both acute and chronic. The former include, among other things, the recurrent vaso-occlusive crises (its hallmark) and acute chest syndrome. The chronic complications include most commonly avascular necrosis and leg ulcers. Currently, survival of patients with …SCD has improved dramatically thanks to newborn screening, antibiotic prophylaxis, better vaccine, safer blood transfusion and the use of hydroxyurea. It is the advent of these therapies that improved the survival. This improvement, however, introduced a third dimension of the disease: comorbidities that occur in aging people in the general population. There is concern that the gain in survival may be offset by the comorbidities. Thus it is the purpose of this review to identify the comorbidities in the elderly with SCD and differentiate them from the basis disease to implement proper therapies so that better survival could be maintained. Show more

Keywords: Sickle cell disease, aging, comorbidities

DOI: 10.3233/CH-189003

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 129-145, 2018

Authors: Chang, Alicia K. | Ginter Summarell, Carly C. | Birdie, Parendi T. | Sheehan, Vivien A.

Article Type: Research Article

Abstract: Sickle cell disease (SCD) is one of the most common single disease disorders world-wide. It is remarkable for its clinical heterogeneity, even among individuals with identical genotypes. Some individuals experience morbidity and mortality in early childhood, while others have a relatively mild course, and normal or near normal life expectancy. Many clinical complications are associated with SCD; most notably frequent pain episodes, stroke, acute chest syndrome, avascular necrosis, nephropathy, retinopathy and pulmonary hypertension. While the effects of higher fetal hemoglobin (HbF) levels, UGTA1A polymorphisms, alpha-thalassemia and G6PD deficiency on SCD has been extensively studied, these variables do not explain all …of the clinical heterogeneity of SCD. It is not known why some patients develop certain complications, and it is difficult to predict which complications a particular patient will experience. Much work has been done to identify genetic variants associated with these disease complications; many associations remain unvalidated. As the field continues to move beyond small sample collections and candidate gene approaches into whole genome sequencing and merging of samples from all over the world, we will identify more genetic variants associated with development of specific SCD related complications, and hopefully leverage this knowledge into targeted therapies. Show more

Keywords: Sickle cell disease, alpha-thalassemia, viscosity

DOI: 10.3233/CH-189004

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 147-164, 2018

Authors: Connes, Philippe | Renoux, Céline | Romana, Marc | Abkarian, Manouk | Joly, Philippe | Martin, Cyril | Hardy-Dessources, Marie-Dominique | Ballas, Samir K.

Article Type: Research Article

Abstract: This review focuses on the contribution of abnormal blood rheology in the pathophysiology of sickle cell anemia (SCA). SCA is characterized by a reduction of red blood cell (RBC) deformability but this reduction is very heterogeneous among patients. Recent works have shown that patients with the lowest RBC deformability (measured by ektacytometry) have enhanced hemolysis and would be more prone to develop several complications such as priapism, leg ulcers and glomerulopathy. In contrast, patients with the highest deformability, and not under hydroxyurea therapy, seem to develop more frequently vaso-occlusive like events. Although less studied, RBC aggregation properties are very different …between SCA and healthy individuals and it was demonstrated that increased RBC aggregates strength could be involved in some complications. Finally, several studies have established that the vascular system of SCA patients could not fully compensate any increase in blood viscosity because of the loss of vascular reactivity, which may result in vaso-occlusive crises. Show more

Keywords: Sickle cell anemia, blood viscosity, red blood cell deformability, red blood cell aggregation

DOI: 10.3233/CH-189005

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 165-172, 2018

Authors: Detterich, Jon A.

Article Type: Research Article

Abstract: Sickle cell anemia is characterized by a mutation resulting in the formation of an abnormal beta-hemoglobin called hemoglobin S. Hemoglobin S polymerizes upon deoxygenation, causing impaired red blood cell deformability and increased blood viscosity at equivalent hematocrits. Thus, sickle cell disease is a hemorheologic disease that results in various pathologic processes involving multiple organ systems including the lungs, heart, kidneys and brain. Red blood cell mechanics and the perturbations on blood flow-endothelial interaction underlie much of the pathology found in sickle cell disease. Transfusion therapy is one of the few therapeutic options available to patients, acting as both primary and …secondary prevention of stroke. Transfusion therapy, both simple and exchange, is also used for unremitting and frequent pain crises and pulmonary hypertension. Therefore, understanding basic rheologic changes following transfusion inform other therapeutic options that aim to mitigate this diffuse pathologic process. This review will aim to highlight transfusion effects on blood rheology. Show more

DOI: 10.3233/CH-189006

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 173-186, 2018

Authors: Brugnara, Carlo

Article Type: Research Article

Abstract: Cell dehydration is a distinguishing characteristic of sickle cell disease and an important contributor to disease pathophysiology. Due to the unique dependence of Hb S polymerization on cellular Hb S concentration, cell dehydration promotes polymerization and sickling. In double heterozygosis for Hb S and C (SC disease) dehydration is the determining factor in disease pathophysiology. Three major ion transport pathways are involved in sickle cell dehydration: the K-Cl cotransport (KCC), the Gardos channel (KCNN4) and Psickle , the polymerization induced membrane permeability, most likely mediated by the mechano-sensitive ion channel PIEZO1. Each of these pathways exhibit unique characteristics in regulation …by oxygen tension, intracellular and extracellular environment, and functional expression in reticulocytes and mature red cells. The unique dependence of K-Cl cotransport on intracellular Mg and the abnormal reduction of erythrocyte Mg content in SS and SC cells had led to clinical studies assessing the effect of oral Mg supplementation. Inhibition of Gardos channel by clotrimazole and senicapoc has led to Phase 1,2,3 trials in patients with sickle cell disease. While none of these studies has resulted in the approval of a novel therapy for SS disease, they have highlighted the key role played by these pathways in disease pathophysiology. Show more

Keywords: Membrane transport, KCNN4, Gardos channel, KCC, K-Cl cotransport, Piezo-1, deoxygenation, sickling

DOI: 10.3233/CH-189007

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 187-204, 2018

Authors: Usmani, Ashar | Machado, Roberto F.

Article Type: Research Article

Abstract: Sickle cell disease (SCD) is a monogenetic disorder caused by a mutation in the β-globin gene HBB leading to polymerization of red blood cells causing damage to cell membranes, increasing its rigidity and intravascular hemolysis. Multiple lines of evidence suggest that SCD can be viewed as pan-vasculopathy associated with multiple mechanisms but driven by hemoglobin S polymerization. Here we review the pathophysiology, clinical manifestations and management strategies for cerebrovascular disease, pulmonary hypertension and renal disease associated with SCD. These “vascular phenotypes” reflect the systemic nature of the complications of SCD and are a major threat to the well-being of patients …with the disorder. Show more

Keywords: Sickle cell disease, cerebral vasculopathy, pulmonary hypertension, renal disease, nitric oxide

DOI: 10.3233/CH-189008

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 205-221, 2018

Authors: Kim-Shapiro, Daniel B. | Gladwin, Mark T.

Article Type: Research Article

Abstract: Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions which leads to red blood cell (RBC) distortion, calcium-influx mediated RBC dehydration, increased RBC adhesivity, reduced RBC deformability, increased RBC fragility, and hemolysis. These impairments in RBC structure and function result in multifaceted downstream pathology including inflammation, endothelial cell activation, platelet and leukocyte activation and adhesion, and thrombosis, all of which contribute vascular occlusion and substantial morbidity and mortality. Hemoglobin released upon RBC hemolysis scavenges nitric oxide (NO) and generates reactive oxygen species (ROS) and thereby decreases bioavailability of this important signaling molecule. As …the endothelium-derived relaxing factor, NO acts as a vasodilator and also decreases platelet, leukocyte, and endothelial cell activation. Thus, low NO bioavailability contributes to pathology in sickle cell disease and its restoration could serve as an effective treatment. Despite its promise, clinical trials based on restoring NO bioavailability have so far been mainly disappointing. However, particular “NO donating” agents such as nitrite, which unlike some other NO donors can improve sickle RBC properties, may yet prove effective. Show more

Keywords: Nitric oxide, sickle cell disease, hemolysis, red blood cell, hemoglobin

DOI: 10.3233/CH-189009

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 223-237, 2018

Authors: van Beers, Eduard J. | van Wijk, Richard

Article Type: Research Article

Abstract: Sickle cell disease (SCD) is a monogenetic disorder marked by hemolytic anemia and vaso-occlusive complications. The hallmark of SCD is the intracellular polymerization of sickle hemoglobin (HbS) after deoxygenation, and the subsequent characteristic shape change (sickling) of red cells. Vaso-occlusion occurs after endothelial activation, expression of adhesion molecules and subsequent adhesion of leucocytes and sickle erythrocytes to the vascular wall. Here we review how oxidative stress from various sources influences this process. Emerging evidence points towards a dominant mechanism in which innate immune receptors, such as Toll like receptor 4, activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidases to produce reactive …oxygen species (ROS) which in turn enables downstream pro-inflammatory signaling and subsequent endothelial activation. By serving as an iron donor for the Fenton reaction, heme radically increases the amount of ROS further, thereby increasing the signal originating from the innate immune receptor and downstream effects of innate immune receptor activation. In SCD this results in the production of pro-inflammatory cytokines, endothelial activation and leucocyte adhesion, and eventually vaso-occlusion. Any intervention to stop this cascade, including Toll like receptor blockade, NADPH oxidase inhibition, ROS reduction, heme scavenging, iron chelation, or anti-adhesion molecule antibodies has been successfully used in pre-clinical studies and holds promise for patients with SCD. Show more

Keywords: Sickle cell disease, heme, reactive oxygen species

DOI: 10.3233/CH-189010

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 239-250, 2018

Authors: Coates, Thomas D. | Chalacheva, Patjanaporn | Zeltzer, Lonnie | Khoo, Michael C.K.

Article Type: Research Article

Abstract: Sickle cell disease (SCD) is a genetic disorder of hemoglobin producing hemoglobin-S (HbS) and resulting in recurrent severe episodes of pain, organ damage and premature death due to vaso- occlusion. Deoxy HbS polymerizes, causing red cells to become rigid and lodge in the microvasculature if they do not escape into larger vessels before this transformation occurs. The mechanism that triggers this transition from steady state to vaso-occlusive crisis (VOC) is not known. Patients state that cold, emotional stress, and pain itself can trigger these events. In spite of the connection between these symptoms and the autonomic nervous system (ANS), and …the fact that the ANS regulates regional microvascular blood flow, the role of the ANS in sickle pathophysiology has not been significantly investigated. We will briefly review the mechanism of SCD vaso-occlusion, the dysautonomia associated with SCD and sickle trait, and the role that the ANS may play in the genesis of sickle vaso-occlusive crisis. Show more

DOI: 10.3233/CH-189011

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 251-262, 2018

Authors: Conran, Nicola | Belcher, John D.

Article Type: Research Article

Abstract: The primary β-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these …inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option. Show more

Keywords: Cytokine, endothelium, hemolysis, hydroxyurea, vaso-occlusion

DOI: 10.3233/CH-189012

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 263-299, 2018

Authors: Faes, Camille | Sparkenbaugh, Erica M. | Pawlinski, Rafal

Article Type: Research Article

Abstract: Chronic activation of coagulation is one of the features of sickle cell disease (SCD). Increased tissue factor expression, phosphatidylserine exposure, thrombin generation and fibrinolysis, as well as decreased levels of natural anticoagulants have been reported in SCD patients and in the mouse models of SCD. Consistent with this, patients with SCD are prone to develop thrombotic complications. In addition, the altered morphology of sickle red blood cells (RBC) may also alter the properties and dynamics of clot formation in SCD patients. Clinical data and results from animal models have revealed complex interactions between coagulation, chronic hemolysis, and inflammation suggesting that …activation of coagulation may contribute to the pathophysiology of SCD. Show more

Keywords: Sickle cell anaemia, procoagulant state, haemolysis, clot, microparticles

DOI: 10.3233/CH-189013

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 301-318, 2018

Authors: Romana, Marc | Connes, Philippe | Key, Nigel S.

Article Type: Research Article

Abstract: Several pathophysiological pathways in sickle cell disease (SCD), the most prevalent hemoglobinopathy worldwide, result in activation of circulating blood cells and the release of submicron vesicles, so-called microparticles (MPs). MPs are candidate biomarkers in vascular disease that exhibit functional biological properties. Compared to healthy individuals, higher level of plasma MPs, mostly derived from platelets and red blood cells (RBC), has been repeatedly observed in SCD patients in their steady-state condition. In contrast, conflicting results have been obtained on the impact of SCD complications and hydroxyurea treatment on circulating MP concentrations, largely due to non-standardized pre- and analytical procedures. Several factors …responsible for the increased release of MPs by RBC have been identified in SCD such as sickling/unsickling, oxidative stress and abnormal activity of RBC acid sphingomyelinase. Besides their well-known pro-coagulant effect, sickle RBC-derived MPs produced ex vivo can induce ROS production by endothelial cells and promote a pro-inflammatory and pro-adhesive phenotype that may lead to renal occlusion in SCD mice. However, the functional properties of circulating MPs in human sickle cell disease remain to be studied and fully characterized. Show more

Keywords: Sickle cell disease, microparticles, physiopathology

DOI: 10.3233/CH-189014

Citation: Clinical Hemorheology and Microcirculation, vol. 68, no. 2-3, pp. 319-329, 2018