Hematology Sickle Cell Disease Overview

Hematology Lecture Notes

• Sickle cell disease (SCD) is a group of hemoglobin disorders.
• It results from inheriting the sickle β-globin gene, with a specific abnormality.
• The abnormality is caused by substituting valine for glutamic acid in position 6 of the β chain.
• The homozygous state (HbSS or sickle cell anemia) is the most prevalent form of sickle cell disease.
• Interactions between HbS and thalassemia or certain variant hemoglobins can also lead to sickling.
• The term sickle cell disease (SCD) encompasses all conditions associated with hemoglobin sickling in red blood cells.

Pathophysiology

• Deoxygenation of HbS triggers the formation of large polymers.
• This change in shape causes the red blood cell to become rigid and distorted, characteristically forming a sickle shape.
• Sickling leads to membrane fragmentation and complement-mediated lysis, causing intravascular red blood cell destruction.
• Red blood cell membrane damage also triggers extravascular hemolysis due to trapped abnormal cells or phagocytosis by macrophages.
• Intracellular polymers cause red blood cell membrane changes, oxidant substance generation, and abnormal adherence to vascular endothelium.
• Deformed blood and increased blood viscosity contribute to vascular occlusion.

Factors Affecting Hb Polymerization

• The oxygenation status of the circulating red blood cells influences Hb polymerization.
• The intracellular hemoglobin S concentration plays a role.
• The presence of non-sickle hemoglobins (HbF) can also affect polymerization.

Clinical Features

• Hemolytic anemia: A hallmark of the condition.
• Crises: Severe episodes including vaso-occlusive, aplastic, or hemolytic crisis.
• Mulitple Organ Damage: Microinfarcts in the heart, skeleton, spleen, and central nervous system.
• Symptoms of Anemia: Symptoms may be mild relative to the severity of anemia. Hb S releases oxygen to tissues more readily than Hb A.
• Clinical Expression: Clinical expression is quite variable among patients. Some have almost normal lifespans, while others experience severe crises even as infants, with potentially fatal outcomes in early childhood or young adulthood.
• Effects of Chronic Hemolysis: Anemia in severe cases results in a higher probability of stroke and renal dysfunction. Conversely, higher hemoglobin levels correlate with higher incidences of painful episodes, avascular necrosis, and acute chest syndrome. Jaundice arises from rapid heme turnover and bilirubin generation. Cholelithiasis (gallstones) results from red blood cell destruction and excess bilirubin in the hepatobiliary system.
• Painful Crises: Common, sporadic, and influenced by infection, acidosis, dehydration, or deoxygenation.
• Visceral Crises: Acute sickle chest syndrome (most common cause of death), splenic or hepatic sequestration. Priapism (prolonged painful erection), and liver/kidney damage are also potential complications.
• Hand-foot syndrome: Painful dactylitis, a frequent initial manifestation, causing swelling and pain in the hands and feet.
• Aplastic Crisis: Usually due to parvovirus B19 infection, causing a sudden and potentially life-threatening decrease in red blood cell production.
• Hemolytic Crisis: A catastrophic decrease in hematocrit, with increased jaundice and reticulocyte count, from unknown reasons.

Other Organ Damage

• Brain/spinal cord: Stroke may occur in 7% of patients, sometimes silently.
• Leg ulcers: Deep, non-healing skin ulcers, often on the medial malleolus.
• Autosplenectomy: Gradual destruction of the spleen due to repeated infarcts in childhood.
• Pulmonary hypertension: A potential complication.

Infections

• Early loss of splenic function, coupled with the inability of the body to produce specific IgG antibodies to polysaccharide antigens, increases the risk of severe sepsis (gram-negative septicaemia).
• Pneumonia, urinary tract infections, and osteomyelitis are relatively common. Infections are often serious.

Pregnancy

• Hemoglobin levels tend to decrease in pregnancy.
• Painful crises may be more frequent in the last trimester.
• Increased risk of preeclampsia.
• Risk to the fetus.

Growth and Development

• Children with SCD may have normal birth weights but experience delayed developmental milestones.

Lab Findings

• Hemoglobin levels are typically low (6-9 g/dL).
• Sickle cells and target cells are often present in the blood.
• Splenic atrophy may cause Howell-Jolly bodies in blood.
• Blood screening tests for sickling are positive when deoxygenated.
• Hemoglobin electrophoresis shows absence of Hb A in Hb SS. Hb F amounts vary, often lower in severe cases.

Therapy

• Routine health care (avoid precipitation factors, folic acid, hydration and nutrition).
• Transfusion therapy.
• Hydroxyurea to increase HbF.
• Pain management.
• Bone marrow transplantation.
• Gene therapy.

Sickle Cell Trait

• Benign condition with no anemia and normal blood cell appearance.
• Hematuria (blood in the urine) is a common symptom, thought to be related to minor renal papillary infarcts.
• Hb S levels are between 25-45% of total hemoglobin.
• Require careful monitoring during anesthesia, pregnancy, and high altitude.

Hemolytic Anemias

• Classified as hereditary and acquired.
• Hereditary: Membrane defects (e.g. HS, PNH), metabolic defects (e.g. G6PD), defective hemoglobin synthesis (e.g. HbS, thalassemias).
• Acquired: Immune or non-immune causes.

Acquired Hemolytic Anemias

• Immune-mediated: Antibodies against red blood cells, classified as warm or cold.
  • Warm: IgG antibodies, more commonly seen. Usually associated with spherocytosis, elevated bilirubin, elevated LDH, and positive direct Coomb's test. Common clinical presentations include fatigue, jaundice, and splenomegaly.
  • Cold: IgM antibodies, typically associated with agglutination/rouleaux formation and cold temperature-dependence.
• Non-Immune-mediated: Red cell fragmentation syndromes (e.g. mechanical trauma from artificial heart valves or DIC)

Direct Coombs Test (DAT)

• Used to detect antibodies or complement proteins attached to red blood cells which helps classify hemolytic anemia as acquired or hereditary.
• Negative result suggests hereditary hemolytic anemia while a positive result suggests acquired hemolytic anemia.

Autoimmune Hemolytic Anemias (AIHAs)

• Antibodies produced by the body targeting its own red blood cells.
• Classified into warm (IgG mediated) and cold (IgM mediated).
• Positive DAT indicative of disease.
• Clinical features will vary depending on causes.

Alloimmune Haemolytic Anaemias

• Antibodies from one individual react against red blood cells of another.
• ABO incompatibility in transfusions and Rh disease of the newborn are notable examples.

Non-Immune Haemolytic Anemias

• Physical damage to red blood cells leads to fragmentation syndromes.
• This can happen due to various factors like artificial heart valves, mechanical heart valves, or arteriovenous malformations.
• DIC implicated as a cause for microangiopathic hemolytic anemia associated with abnormal small vessels.

Aplastic Anemia

• Characterized by pancytopenia (low red blood cells, white blood cells, and platelets).
• Caused by bone marrow aplasia.
• Etiology includes primary (congenital) or secondary factors (e.g. radiation, chemicals, and certain drugs, and viral hepatitis).
• Clinical features include anemia, infections, bleeding manifestations. Key lab findings are reduced reticulocytes, selective neutropenia, and thrombocytopenia. Bone marrow shows hypoplasia with significant fat replacement.