ÎÚÑ»´«Ã½

ASH Position

Listing "sickle cell crisis" or "sickle cell trait" as a cause of death on an autopsy report for an individual with sickle cell trait is medically inaccurate and without medical evidence of causation. Sickle cell trait occurs when an individual has one sickle cell gene and one normal gene, which is common in individuals of African descent, occurring in approximately 8-10% of these individuals in the United States. Among individuals with sickle cell trait, post-mortem sickling is frequently likely to be observed on autopsy because lack of obligatory oxygen after death. Therefore, post-mortem sickling and sickled red blood cells seen after death are not medical evidence of a sickle cell crisis as a primary or secondary cause of death. Further, a 2024 ÎÚÑ»´«Ã½ (ASH) expert panel of hematologists, forensic pathologists, and evidence-based methodologists found no high-level evidence that individuals with sickle cell trait have acute pain crises. The panel that any listing on the death certificate of either sickle cell crisis or sickle trait contributing to death is erroneous and must be re-examined for the underlying cause of death.¹ Listing sickle cell trait as a cause of sudden death is without any medical evidence. In instances when “Sudden death” is listed as a cause of death, the etiology refers to the concept of sudden cardiac death or arrhythmia and not sickle cell trait. To list sickle cell trait as a cause of sudden death is medically inaccurate and without medical evidence of causation.

Among individuals with sickle cell trait, rhabdomyolysis (the rapid breakdown of skeletal muscle), can occur for at least two reasons and may occur in individuals with or without sickle cell trait. The first is exertion-related rhabdomyolysis. Exertion-related rhabdomyolysis in those with sickle cell trait with or without death has been documented in extreme circumstances, including high-intensity military training and elite college-level football training, commonly in combination with severe environmental conditions, including extreme heat and dehydration. The second cause of rhabdomyolysis is trauma or crush injury, which may occur in individuals with sickle cell trait and cause death. Trauma-related rhabdomyolysis may be temporally associated with death in an individual with the sickle cell trait, but the sickle cell trait is not the cause of death; the cause of death is the muscle injury leading to rhabdomyolysis and the sequelae.

Background

Sickle cell disease is an inherited blood disorder that affects approximately 100,000 Americans primarily but not exclusively of African ancestry. Sickle cell disease is common in India, the Middle East, Mediterranean countries, South America, the Caribbean, and Africa. Given the global trend of migration from one country to another and genetic admixture that makes an assignment of racial or ethnic background fraught with error, any individuals with exertion-related rhabdomyolysis and rhabdomyolysis-related death should be evaluated for sickle cell trait or sickle cell disease. Sickle cell disease requires the inheritance of two variants of the HBB gene, which produces abnormal hemoglobin, the majority of which is hemoglobin S. When two variant copies are inherited, it causes severe anemia, pain, and other devastating disabilities and, in some cases, premature death.

In contrast to sickle cell disease, patients with sickle cell trait inherit one variant of the HBB gene and one normal copy. Sickle cell trait affects hundreds of millions of people worldwide and millions of Americans – including 8 to 10 percent of all African Americans. Individuals with sickle cell trait do not have sickle cell disease at birth, nor will they develop sickle cell disease later in life. Their hemoglobin is predominantly hemoglobin A, the normal hemoglobin. Individuals with sickle cell trait do not have uncomplicated acute vaso-occlusive pain, the most common clinical manifestation of sickle cell disease. However, they may have acute vaso-occlusive-like pain associated with splenic infarction, pulmonary emboli, or other co-morbidities that may cause pain. In individuals with sickle cell trait, the acute pain events are not similar to acute vaso-occlusive pain in individuals with sickle cell disease.

The presence of sickle cell trait rarely manifests clinical disease. Established co-morbidities associated with sickle cell trait include exertional rhabdomyolysis, pulmonary emboli, splenic infarction with high altitude, and renal diseaseⁱⁱ and renal medullary cancer of the kidney.ⁱⁱⁱ Most individuals with sickle cell trait will have an average life span without serious health consequences. In the 1960s, increased mortality rates among athletes and military recruits with sickle cell trait were reported before understanding the connection between strenuous exercise, heat-related illness, and sickle cell trait.^iv Further evidence demonstrated that these deaths occurred in conjunction with dehydration, rhabdomyolysis, renal failure, disseminated intravascular coagulation, and cardiac arrhythmia.^{v vi vii} After implementing universal precautions to prevent exertional rhabdomyolyses for all soldiers, among 47,944 black soldiers who had received testing for sickle cell trait, the rate of death was no different among those with and without the sickle trait. However, the rate of exertional rhabdomyolysis remained higher in those with sickle cell trait than those without sickle cell trait.^viii

Millions of American men, women, and children with sickle cell trait lead normal, healthy lives. In deceased individuals with sickle cell trait, a cause of death listing “sickle cell crisis,” “sickle cell disease with acute pain,” or any similar terminology is without medical evidence, and the cause of death other than sickle cell trait should be re-considered.

The ÎÚÑ»´«Ã½ (ASH) represents approximately 18,000 physicians, scientists, and trainees committed to studying and treating blood and blood-related diseases. ASH members include clinicians specializing in treating children and adults with sickle cell disease (SCD) and researchers investigating the biological basis, management, prevention, and treatment of medical complications of children and adults with SCD.

References:

ⁱ Weeks LD, Wilson AM, Naik RP, et al. Sickle Cell Trait Does Not Cause “Sickle Cell Crisis” Leading to Exertion-Related Death: A Systematic Review [published online ahead of print 30 January 2025]. Blood. doi: 10.1182/blood.2024026899.

ⁱⁱ Naik, Rakhi P et al. “Clinical Outcomes Associated With Sickle Cell Trait: A Systematic Review.” Annals of internal medicine vol. 169,9 (2018): 619-627. doi:10.7326/M18-1161

ⁱⁱⁱ Kathryn E. Beckermann et al., Renal Medullary Carcinoma: Establishing Standards in Practice. JOP 13, 414-421(2017). DOI:10.1200/JOP.2017.020909

^iv Jones SR, Binder RA, Donowho EM, Jr. Sudden death in sickle-cell trait. N Engl J Med. 1970;282(6):323-325.

^v Kark JA, Posey DM, Schumacher HR, Ruehle CJ. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med. 1987;317(13):781-787

^vi Mitchell, Bruce L. “Sickle cell trait and sudden death--bringing it home.” Journal of the National Medical Association vol. 99,3 (2007): 300-5

^vii Thogmartin JR et al. J Forensic Sci. 20111 Sep; 56(5):1352

^viii Nelson DA, Deuster PA, Carter R, 3rd, Hill OT, Wolcott VL, Kurina LM. Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers. N Engl J Med. 2016;375(5):435-442