Vaso-Occlusion in Sickle Cell Anemia

Red cell disease Vaso-occlusion in sickle cell anemia R.E. Ware Introduction with other genotypes, such as HbSC and Professor and Vice-Chairman HbS/thalassemia, also have vaso-occlusive of Pediatrics, Director, Texas Sickle cell anemia (SCA) is a common events, their pathophysiology is different Children’s Center for Global Health, inherited congenital hemolytic anemia and less studied and will not be emphasized Director, International Hematology affecting millions of persons worldwide. further in this review. Center of Excellence, Baylor College SCA is characterized by a predominance of of Medicine and Texas Children’s abnormal sickle hemoglobin (HbS) within Hospital, Houston TX, USA the erythrocytes, which polymerizes under Nomenclature deoxygenating conditions, leading to deformed (sickled) cells with increased adhe- The nomenclature surrounding the pain Hematology Education: siveness, aberrant membrane composition, that is so characteristic of SCA has recently the education program for the and cellular dehydration. These intrinsic been called into question regarding cultural annual congress of the European defects, coupled with abnormal flow charac- sensitivity and appropriateness. Although Hematology Association teristics of sickled erythrocytes, lead to ery- the origin and first use of “crisis” for SCA throcyte fragility and pathological interac- patients is unknown, this word is quite use- 2011;5:323-329 tions with the endothelium and reticuloen- ful and has long been accepted, since it dothelial system; hence, the SCA is a encompasses both the suddenness and hemolytic anemia with both an intravascular severity of the pain. Particularly in discus- and extravascular component. sions involving the lay community, the word SCA is also a chronic inflammatory condi- is common but can be preceded by descrip- tion featuring widespread endothelial dam- tors such as “pain” or “painful” or even age, dysfunction, and activation. The vascu- “acute” to accentuate the symptoms. Among lopathy of SCA is now well-characterized healthcare providers, the word “vaso-occlu- but still not completely understood. The sive” is added to emphasize the pathophysi- intravascular milieu features sickled erythro- ology of the pain and to distinguish it from cytes, adhesive circulating blood cells, hyper - other etiologies, and “vaso-occlusive crisis” coagulability, plasma mediators of inflamma- has become the recognized VOC acronym. tion, and products of hemolysis. Together, Subsequently, however, the terms “event” these factors promote abnormal cellular and “episode” have been advocated over attachments and interactions with the “crisis”, since these are potentially less pejo- endothelium, which then alter normal vessel rative and remove any suggestion of psycho- integrity and lead to pathological responses. logical overlay or origin. Phrases like “vaso- The processes by which circulating leuko- occlusive event (VOE)” or “painful event” cytes, reticulocytes, and sickled erythrocytes have thus become commonly used to adhere to vascular endothelium and the describe SCA pain that requires medication effects of these interactions are increasingly or medical evaluation. The fact that a 2011 understood using in vitro and animal models, sickle cell conference had a highlighted topic which provide an opportunity to discover titled “Don’t take away my Crisis” that fea- and test therapeutic interventions. tures a debate on the merits and sanctity of Clinically, patients with SCA have period- the word “crisis” in SCA indicates that the ic acute events that reflect abrupt blockage issue is still far from resolved. In an attempt of blood flow within small vessels, leading to remain neutral yet informative, the cur- to distal tissue hypoxia and infarction; this rent text will simply use the descriptive but process is usually referred to as “vaso-occlu- admittedly rather bland term “vaso-occlusion”, since normal blood flow is impaired. sive event” to describe these sickle-related These sporadic events are typically painful pain and other acute processes. and often require medical attention, while some present mainly with respiratory or neu- rological symptoms. This sickle cell crisis is Pathophysiology among the more perplexing aspects of SCA, and its optimal clinical management is the The topic of sickle cell vaso-occlusion has subject of numerous current clinical trials. been extensively studied over the past 40 This review focuses on vaso-occlusion in years, and our understanding of the process SCA, which refers predominantly to patients has evolved considerably since the original with homozygous HbSS. Although patients simplistic concept of misshapen sickled ery- Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 323 | 16th Congress of the European Hematology Association throcytes forming a transient log-jam within small vessels, thereby impeding local blood flow until released. One major advance came 30 years ago when several investigators identified abnormal adhesion between sickle erythrocytes and vascular endothelium,1-2 indicat- ing that deoxygenation and HbS polymerization had effects beyond changing erythrocyte shape. Elucidation of the critical role of circulating leukocytes in triggering this contact was another major step forward.3-4 Several recent reviews have highlighted the numerous advances and refinements of the current state of knowledge about vaso-occlusion in SCA since that time.5-6 Vaso-occlusion still begins with sickled erythrocytes but is now known to be a highly complex process involving frequent abnormal interactions among a wide variety of circulating blood cells, plasma factors, and vascular endotheli- Figure 1. Main blood components participating in the complex interactions of vaso-occlusion in SCA. Although um. Each major component of this triad contributes to the sickling process begins within erythrocytes, many other the vaso-occlusive process and the interactions are cir- circulating blood cells become involved as primary and cular, highly interactive, and often amplifying (Figure 1). secondary participants. Plasma factors promote vaso- occlusive and reflect cellular damage and vascular inflam- Proper understanding of vaso-occlusion, with conse- mation. The vascular endothelium is progressively dam- quent blockage of blood flow and distal tissue hypoxia, aged and its inflammation and dysfunction leads to addi- requires recognition and discussion of all aspects of the tional vaso-occlusion and vasculopathy. These interactions pathophysiology within this triad. are circular and amplifying. First and foremost, it should be emphasized that the vaso-occlusion event observed in SCA is unique and does not have another medical equivalent; this fact with an abnormal surface marker profile reflecting mandates that the pathophysiology begins and hinges widespread vascular damage. Levels of CEC are elevat- upon the presence of HbS and the sickled erythrocyte. ed in steady-state SCA but further increase during acute Abundant HbS within the erythrocytes, which leads to vaso-occlusion and may reflect disease severity.19 intracellular polymerization, morphological shape Microparticles derived from endothelium also circulate changes, and abnormal cell-vessel interactions, cannot in SCA.20 Activation markers can be detected on these be overlooked as the principal culprit of the vaso-occlu- circulating cells and microparticles, including intercellu- sive process. Newborn infants with SCA have low lar adhesion molecule-1 (ICAM-1), vascular cell adhe- amounts of HbS (typically 5-25%) and appear to be pro- sion molecule-1 (VCAM-1), E-selectin, P-selectin, and tected in the early neonatal period due to high amounts tissue factor.21-24 Not all endothelium is identical, howev- of intracellular fetal hemoglobin (HbF). Vaso-occlusive er, and it is likely that intrinsic differences in the vascu- events do not develop clinically until the protective lar endothelial beds themselves are important determi- effects of HbF begin to wane, usually in the first few nants of the cerebrovascular and pulmonary damage in years of life.7 Conversely, hereditary persistence of HbF SCA that begins early in life and could perhaps be as provides lifelong protection against clinical events,8 important as physiological fluctuations such as blood which further emphasizes the critical importance of the flow and oxygenation. This is an area that has not been erythrocyte (and its HbS concentration) in the genesis fully explored but could reveal insights into the patho- and development of vaso-occlusive events. The sickle physiology of vaso-occlusion and help explain the erythrocyte is not simply an inert carrier of HbS, how- propensity for damage within certain organs. ever, because the erythrocyte membrane itself is abnor- Another critical consequence of these abnormal ery- mal9 and coated with adhesive molecules that promote throcyte-endothelial interactions is the progressive adhesion to the endothelium. Reticulocytes are especial- development of a generalized inflammatory process. As ly adherent,10 perhaps because they are less dense and previously mentioned, circulating erythrocytes, and retain surface markers from the marrow that are not especially younger reticulocytes, have increased levels removed or “polished” in the absence of a healthy of adhesion and activation molecules. The total white spleen. Sickle erythrocytes express a wide variety of blood cell (WBC) count becomes elevated early

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