Sickle Cell Disease

Authors: Amanda Saunders BS MBA & John Walsh MD*

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Background

Sickle Cell Disease (SCD) is the most common inherited blood disease in the United States and is frequently encountered at autopsy. It occurs when a child inherits two copies of a mutated hemoglobin gene and leads to a misfolded protein which leads to sickling of red blood cells in vessels. It is estimated that 70,000-100,000 Americans are affected with SCD and it occurs in 1/365 African American births. There are 3 main types of SCD which are the HbSS, HbSC and HbS-beta thalassaemia genotypes with SS being most prevalent. Sickle Cell Trait occurs when there is only 1 mutated copy of the gene and patients are typically asymptomatic. This occurs in 1/13 African American births.

The cause of death in patients with sickle cell disease can often be tied back to the pathophysiology of the sickle cells:

• Bacterial sepsis: leads to autosplenectomy caused by repeated infections and vasoocclusion. Moreover, the alternative complement pathway is affected in those with SCD which leads to reduced recruitment of neutrophils and puts these individuals at higher risk of disease from encapsulated organisms. (See the sepsis article for additional information).
• Acute chest syndrome (ACS) due to pulmonary arteriolar obstruction by sickled red blood cells or bone marrow embolism with thrombotic microangiopathy
• Chronic pulmonary vascular arteriopathy, pulmonary artery hypertension and cor pulmonale
• Cerebrovascular accident – infarction, intracerebral hemorrhage and subarachnoid hemorrhage
• Acute hepatic-splenic sequestration
• Acute and chronic renal failure
• Multi-organ failure following pan-body sickle crisis
• Deep vein thrombosis and pulmonary thromboembolism
• Dural venous sinus thrombosis and brain hemorrhage
• Aplastic marrow crisis from parvovirus B19 infection

Despite most individuals with sickle cell trait remaining asymptomatic, the incidence of cardio-respiratory arrest is over 20 times higher than the general public. Most of these instances occur during times of intense exertion or dehydration and it often is accompanied by rhabdomyolysis (Scheinin 2009).

Quick Tips at Time of Autopsy

Clinical History

• Patient’s may not know their sickle cell status due to an absence of standardized/mandatory universal testing. Thus, it is important to consider this in high-risk populations.
• Acute Chest Syndrome is a common cause of death if the episode progresses to respiratory failure and is most common in patients 1-3 days after hospitalization (most commonly vaso-occlusive crisis).
• Sickle disease can complicate and or compound other disease processes like ASCVD, or diabetes which need to be considered as a contributing factor.
• Depending on the circumstances, sickle cell disease may be of significant medicolegal importance, and consultation with the medical examiner’s office should be considered in some cases.

External examination

• Due to the high frequency of sepsis in sickle cell patients, a blood culture should always be taken from neck veins or heart prior to incisions being made. Both aerobic and anaerobic cultures should be taken. (See “Ancillary Testing” below for additional information).
• Many sickle cell patients are underweight due to the increased metabolic demands from increased body protein turnover and resting metabolic rate.
• Leg ulcers may also be seen secondary to local thrombi, mechanical obstruction, or bacterial infection.

Image: Example of bilateral, synchronous ulcers in a patient with SCD. Notice the thin extremities, the darkening of the skin around the ulcer, the lack of hair and the dryness of the skin. (Image credit: Minniti 2016).

Internal examination

• While all organ systems should be examined in SCD, the ones with the most common sickle cell related morbidity are the lungs, liver and spleen, brain, heart, kidneys and bone marrow.

Lungs

• Look for evidence of pulmonary artery hypertension, thrombotic obstruction of arteries, thromboembolism, infection/pneumonia, and/or generalized congestion.
• Fat emboli are also more common in patients with SCD than the general population as vaso occlusive crisis in the long bones can lead to infarction of the marrow.

Heart

• Examine the coronary arteries and check for left and right ventricular hypertrophy; high cardiac output due to chronic anemia can lead to significant dilatation of left ventricle.
• Some SCD patients may die of acute MI yet have patent coronary arteries indicating the MI likely resulted from abnormal cardiac microcirculation.

Liver

• Patients with sickle cell disease may develop liver disease as a result of intrahepatic sickling of erythrocytes, viral hepatitis, iron overload from repeated transfusions, and pigmented gallstones secondary to chronic hemolysis.
• As in other organs, the risk of thrombosis (e.g. a portal vein thrombosis) is increased.

Spleen

• The spleen has typically auto infarcted by adulthood and only a small remnant remains, however acute, massive sequestration may also cause enlargement (especially in younger patients who have not lost their spleen).
  • Auto-splenectomy is caused by micro vascular occlusion and may be seen as early as age 5. Splenic sequestration typically occur from age six months to 5 years and it is due to sickled RBCs getting trapped in the red pulp causing an obstruction a larger draining vein.

Image: The small (~4 cm), fibrotic residual spleen of an adult with sickle cell disease. (Image Credit: Utah Digital Pathology).

Kidneys

• Examine for pyelonephritis, papillary necrosis, cortical necrosis. Pyelonephritis and urinary tract infections are more common in SCD patients because of the functional asplenia and increased susceptibility to bacterial infections.
• Although very uncommon, sickle cell trait is associated with medullary carcinoma of the kidney.

Bone marrow

• Check for old and new vertebral/long bone infarcts, extent of hematopoietic marrow (hyperplasia), osteomyelitis.
  • If a long bone sickle crisis has been diagnosed clinically, it may be useful to remove 1 femur and split it longitudinally.

Ancillary Testing

• A blood smear on a glass slide can be done at the time of autopsy to demonstrate the presence of sickled cells. Of note, sickling can be seen as a postmortem artifact in non-sickle cell patients, but the extent of sickling is usually amplified in cases of true sickle cell disease. (Thogmartin 2011)
• Blood may be necessary for a variety of tests including: bacterial cultures (both aerobic and anaerobic) and spun blood for serology such as parvovirus B19 virus.
• Whole blood can be taken if the red cell sickle status had not been evaluated prior to autopsy. Similarly, some patients that are labeled as having sickle trait may actually have the HbSC genotype that was not identified because the laboratory tests were incomplete. If there is uncertainty about the patient’s genotype, autopsy blood can be tested to reevaluate.

Quick Tips at Time of Histology Evaluation

Lungs

• Acute chest syndrome
  • This diagnosis is made mostly based on clinical findings, but histology can help support the diagnosis.
  • Two variations:
    • Type A: severe distension of arterioles, capillaries and venules with sickled RBCs and signs of local infarction
    • Type B: Emboli of necrotic bone marrow to small pulmonary artery leading to thrombosis and acute cor pulmonale
  • Chronic sickle cell pulmonary arteriopathy
    • Common cause of pulmonary artery hypertension in patients with SCD

Image: Alveolar air spaces in the lung with abundant sickled red blood cells from an autopsy with a fatal sickle cell crisis. (Image credit: Meagan Chambers, University of Washington).

Spleen

• Histologic findings in splenic sequestration include expansion of the red pulp, with tightly packed sickled RBCs.
• Histologic findings in older patients with a small spleen include progressive changes secondary to vascular damage, including
  • Decreased white pulp including lower lymphoid follicle density and fewer marginal zones. (This finding is in keeping with the clinical observation of impaired immunologic functions against blood-borne bacteria).
  • Increased microvessel density (which can be demonstrated with CD34 and/or SMA staining).
  • Fibrosis (especially in the red pulp) and Gamma-Gandy Bodies: foci of hemorrhage/hemosiderin, fibrosis, and calcium. (They are caused by portal hypertension).
  • Red pulp macrophages are not increased.

Image: Example of a Gamma-Gandy nodule. (Image credit: Duy Doan/Temple University Hospital).

Image: Two low power (2x) views of the spleen. The left  is from a healthy/non-sickle cell patient, and the right is from a sickle cell autopsy patient. The sickle cell spleen on the right demonstrates decreased white pulp. (Image credit: Meagan Chambers/University of Washington).

Liver

• Severe congestion and expansion of the sinusoids can be seen due to hepatic sequestration.

Image: Intermediate magnification micrograph of cirrhosis due to sickle cell disease. The red blood cells show sickling (arrow). (Image Credit: Colli 2018).

Image: Sickled red blood cells can be found in multiple additional organs. The above photo demonstrates sickled RBCs in expressed bone marrow at autopsy. (Image credit: Meagan Chambers, University of Washington).

Quick Tips at Time of Reporting

• Simply because the patient has SCD does not mean this contributed to their death. It is critical to distinguish whether SCD is the cause of death, played a contributory role or was irrelevant to the cause of death.
• Typically sickle cell trait is not fatal. However there are exceptions such as cardio-pulmonary collapse from a sickle cell chest crisis secondary to stress.
• Death in sickle cell patients is frequently unexpected (about 40% of cases) and a large number of deaths occur within 24 hours of presentation of acute disease (about 28% of deaths).
• Example Cause of Death Statements:
  • Anemia due to hepatosplenic-sequestration due to sickle cell disease.
  • Sepsis due to bacterial sequestration due to sickle cell disease.
  • Cor pulmonale due to chronic sickle pulmonary arteriopathy due to sickle cell disease.

Recommended References

• Bailey D, Swift B, Lucas S, Herlihy N. Autopsy in Sickle Cell Disease and Sickle Trait. Royal College of Pathologists. August 2023. Available here.
• Pizzi M, Fuligni F, Santoro L, Sabattini E, Ichino M, De Vito R, Zucchetta P, Colombatti R, Sainati L, Gamba P, Alaggio R. Spleen histology in children with sickle cell disease and hereditary spherocytosis: hints on the disease pathophysiology. Hum Pathol. 2017 Feb;60:95-103. doi: 10.1016/j.humpath.2016.09.028. Epub 2016 Oct 19. PMID: 27771375.
• Scheinin L, Wetli CV. Sudden death and sickle cell trait: medicolegal considerations and implications. Am J Forensic Med Pathol. 2009 Jun;30(2):204-8. doi: 10.1097/PAF.0b013e318187dfcd. PMID: 19465821.

Additional References

• Brousse, Valentine, Pierre Buffet, and David Rees. “The spleen and sickle cell disease: the sick (led) spleen.” British journal of haematology 166.2 (2014): 165-176.
• Gladwin, Mark T., and Elliott Vichinsky. “Pulmonary complications of sickle cell disease.” New England journal of medicine 359.21 (2008): 2254-2265.
• Manci, Elizabeth A., et al. “Causes of death in sickle cell disease: an autopsy study.” British journal of haematology 123.2 (2003): 359-365.
• Ogun, Gabriel Olabiyi, Henry Ebili, and Taiwo Racheal Kotila. “Autopsy findings and pattern of mortality in Nigerian sickle cell disease patients.” Pan African Medical Journal 18.1 (2014).
• Piubelli, Mario Luiz Marques, Leticia Campos Clemente, and Amaro Nunes Duarte-Neto. “Gamna-Gandy bodies of the spleen in sickle cell disease.” Autopsy & Case Reports 9.2 (2019).
• Theocharidou, Eleni, and Abid R. Suddle. “The liver in sickle cell disease.” Clinics in liver disease 23.2 (2019): 177-189.
• Thogmartin JR, Wilson CI, Palma NA, Ignacio SS, Shuman MJ, Flannagan LM. Sickle cell trait-associated deaths: a case series with a review of the literature. J Forensic Sci. 2011 Sep;56(5):1352-60. doi: 10.1111/j.1556-4029.2011.01774.x. Epub 2011 Apr 11. PMID: 21480898.

*The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of the Department of Navy, Armed Forces Medical Examiner System, Uniformed Services University of Health Science, DHA, Department of Defense, or the US Government. The authors report no conflict of interest or sources of funding.