John Kark, M.D. (formerly of the Uniformed Services University of the Health Sciences, Bethesda, MD.) Howard Universty School of Medicine Center for Sickle Cell Disease 2121 Georgia Avenue Washington, D.C. 20059 revised December 20, 2000 Introduction Sickle cell trait usually is not regarded as a disease state because it has complications that are either uncommon or mild. Nevertheless, under unusual circumstances serious morbidity or mortality can result from complications related to polymerization of deoxy-hemoglobin S. Such problems include increased urinary tract infection in women, gross hematuria, complications of hyphema, splenic infarction with altitude hypoxia or exercise, and life-threatening complications of exercise, exertional heat illness (exertional rhabdomyolysis, heat stroke, or renal failure) or idiopathic sudden death (1-4). Pathologic processes that cause hypoxia, acidosis, dehydration, hyperosmolality, hypothermia, or elevated erythrocyte 2,3-DPG can transform silent sickle cell trait into a syndrome resembling sickle cell disease with vaso-occlusion due to rigid erythrocytes. Compound heterozygous sickle cell disease can be mistaken as uncomplicated sickle cell trait, particularly when an unusual globin variant is involved.

In addition some disease associations have been noted with sickle cell trait which might not result from polymerization of hemoglobin S but from linkage to a different gene mutation. The association of hemoglobin S with cases of renal medullary carcinoma, early end stage renal failure in autosomal dominant polycystic kidney disease, and surrogate end points for pulmonary embolism are not necessarily the result of hemoglobin S polymerization. Complications from sickle cell trait are important because about three million people in the United States have this genotype, about 40 to 50 times the number with sickle cell disease.

People with uncomplicated sickle cell trait have a normal blood examination as assessed by conventional clinical methods, including normal red cell morphology, indices, reticulocyte counts, and red blood cell survival by chromium labeling. Conventional methods of detecting hemolysis are negative, such as measurements of serum haptoglobin, bilirubin, and LDH. Erythrocyte density distribution is normal, adherence to endothelium is not increased, altered membrane lipids and proteins are not detectable, cytoplasmic inside-out vesicles with high calcium content are absent, and permanently distorted erythrocytes are not observed.

When blood is drawn with anaerobic technique into a syringe with dilute buffered glutaraldehyde one obtains an accurate picture of circulating erythrocytes in vivo (the Sherman test). No sickled cells are observed at rest, but exercise to exhaustion at sea level regularly induces mild levels of reversible sickling in peripheral venous blood (less than 1%). Exposure to altitude hypoxia will progressively increase the extent of sickling observed with sickle cell trait from 2% at 4,050 ft. to 8.5% at 13,123 ft. Hypobaric chamber exposures used for military aviation training, involving hypoxic exposures simulating 10,000 to 25,000 ft from ninety to six minutes, did not cause hemolysis in subjects with uncomplicated sickle cell trait (3).

Determination that a clinical syndrome is due to sickle cell trait rather than a subtle form of sickle cell disease is difficult. Reversible sickling and unsickling of erythrocytes (reflecting the rapid formation and dissolution of deoxy-hemoglobin S polymers) takes place in seconds. Hence, the presence or absence of intravascular sickled erythrocytes in tissue specimens depends upon the degree of oxygenation of the sample just before fixation and only has clinical relevance if fixation occurred at oxygen tensions identical to those extant during generation of primary lesions. Agonal hypoxemia causes artifactual intravascular sickling. Conversely, blood samples smeared in room air and then fixed will show artifactual unsickling. One cannot determine the role of hemoglobin S in clinical events from the presence or absence of intravascular sickling in blood samples, biopsy specimens, or autopsy specimens unless these were rapidly fixed at physiologic oxygen tension.

While fatal intravascular sickling with extensive microvascular obstruction could theoretical result from sickle cell trait, such an event cannot be demonstrated by histologic examination at autopsy. If a clinical event is not specific for hemoglobin S, one may need to show that the complication occurs significantly more often in people with sickle cell trait relative to a control group. Such an association does not prove cause. Stronger evidence that polymerization of hemoglobin S causes a problem is demonstration of relative protection by alpha thalassemia.

The common African polymorphism causing alpha thalassemia is the product of a prior mismatched cross over event which creates chromosome 16 expressing only one of the two alpha globins and a chromosome 16 carrying three alpha globin exons. Loss of one or two alpha globin genes decreases the fraction of hemoglobin S and produces obvious microcytosis. Anemia is absent or mild.

Examination of maximal urinary concentrating ability in people with sickle cell trait relative to alpha globin gene number demonstrated that one or two alpha globin gene deletions were associated with better preserved renal function (5). In other words the less hemoglobin S that was present, the less renal function that was lost. This implied a significant role of polymerized hemoglobin S in the pathogenesis of renal isosthenuria (see below). In some instances the anatomic lesions due to sickle cell trait are so distinct that a relationship to polymerization of Hb S can be reasonably inferred. Such complications of sickle cell trait include glaucoma or recurrence after treatment for hyphema and splenic infarction in the absence of primary trauma, infection, inflammation or tumor in the spleen.

People with sickle cell trait often experience subclinical tissue infarction from microvascular obstruction by rigid erythrocytes. Most people with sickle cell trait develop microscopic infarction of the renal medulla because the extreme hypoxemia, hypertonicity, acidosis, and hyperthermia of arterial blood passing through the long vasa recta of the renal medulla promote polymerization of deoxy-hemoglobin S (6). Flow through these vessels requires more than ten seconds, providing an unusually long exposure time for polymerization of hemoglobin S. Cumulative focal lesions result in loss of maximal urine concentrating ability which is progressive with age and develops in most adults with sickle cell trait (3, 6). The functional defect limits urine concentration to approximately the osmolality of serum, causing isosthenuria rather than hyposthenuria. In people with sickle cell trait urine osmolality can usually reach values higher than plasma during overnight dehydration (400 to 800 mOsmol). Although one may speculate that this lesion might predispose to development of mild exertional heat illness (EHI) during exercise in hot weather, clinically significant problems related to this deficit have not been demonstrated. Necrosis of the renal papillae can result in hematuria, which is usually microscopic. Gross hematuria is occasionally provoked by heavy exercise or occurs spontaneously.

An important potential complication of sickle cell trait is unexpected exercise-related death (ERD). The validity of this association aroused heated controversy (4). The possibility that previously healthy young people with sickle cell trait might suffer increased mortality from exercise was first suggested by observations of enlisted recruits in US Armed Forces basic training. A military trainee with Hb AS suffered exercise related hypernatremia during physical training in the field. He only survived a critical illness that included acute renal failure because of dialysis (8). During a single summer, there were four exercise-related deaths among recruits at Fort Bliss, all of whom were black and had sickle cell trait, while no recruits with normal hemoglobin died. Only 1.5% of these recruits had sickle cell trait. The authors suggested a significant risk association with sickle cell trait (8).

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