Sickle Cell Anemia Case study

Patient Introduction

I.T. an 18-year-old African American male with the chief complaint of increased localized pain of the upper and lower extremities one day prior to visit

History of Present Illness

• Onset approximately 36 hours following a gym workout of greater intensity than usual, preformed without hydration

• Pain severity rated 8/10

• No relief with 400mg ibuprofen every 6 hours over the past 24 hours

• Has baseline chronic pain in the arms, legs, and back

Past Medical History

• Age 10 ½ months severe dactylitis with significant swelling and pain in both hands and feet

• Age 11 months diagnoses with homozygous HbS disease

• Age 16 months hospitalized with acute sequestration syndrome and splenomegaly treated and released

• Age 30 & 34 months hospitalized for streptococcus pneumoniae

• Age 13 years acute staphylococcal osteomyelitis of left knee

• Since 3 years of age average of three painful crises per year with reports of up to 10

• Since becoming a teenager chronic low-grade pain in arms, legs, and back

Family History

• African American descent

• Both parents are carriers of the sickle cell trait

• One sibling (brother age 17) carrier of sickle cell trait

Social History

• Single male lives at home with brother and mother during summer in college dormitory during next academic year

• Does not smoke, drink alcohol, or use illicit drugs (except once 2 years ago)

• Previous sexual activity with one parter last year not currently active

• Gets as much exercise daily as he can tolerate

• Tries to maintain a healthy and balanced diet

• No coffee but 2-3 caffeinated soft drinks daily

Review of Systems

• Persistent fatigue that is generally tolerable

• Denies headache, cough, fever, chills, dizziness, lightheadedness, nausea, vomiting, diarrhea, shortness of breath, blurred vision, chest pain, blood in urine, abdominal pain, and painful urination

Clinical Manifestations/Signs/Symptoms

Primary Symptoms

• Chronic hemolytic anemia

• Vaso-occlusive episodes

• Jaundice

• Delayed growth

• Dactylitis

Secondary Symptoms

• Acute and chronic pain

• Priapism

• Fatigue

• Acute chest syndrome

• Splenic sequestration

• Organ dysfunction

Tertiary Symptoms

• Frequent infections

• Strokes

• Avascular necrosis

• Pulmonary hypertension

Chronic Hemolytic Anemia

• HbS polymerization

• RBC sickling

• RBC hemolysis

• Reduced RBC lifespan

Fatigue

• Decreased hemoglobin

• Reduced oxygen delivery to tissues

• Impaired ATP production

Vaso-occlusive Episodes

• Sickled RBCs death

• Endothelial activation

• Cell adhesion

• Multicellular aggregation

• Tissue ischemia

• Inflammation amplifies

Acute Pain

• Sickled RBCs block micro vessels

• Tissue ischemia

• Nociceptor activation

Chronic Pain

• Tissue damage

• Neuropathic changes

• Consistent nociceptor sensitized

Dactylitis

• Vaso-occlusion in blood vessels in hands and feet

• Tissue ischemia

• Bone marrow infarction

Acute Splenic sequestration

• Sudden trapping of RBC in spleen

• Blood pooling

• Rapid splenic enlargement (splenomegaly)

• Sudden drop in circulating hemoglobin

Organ Dysfunction

• Repeated Vaso-occlusion

• Chronic ischemia-reperfusion injury

• Progressive damage to organs

Frequent Infections

• Repeated splenic infarction

• Functional asplenia

• Decreased clearance of encapsulated bacteria

• Increased susceptibility to severe infection

Normal Lab Values

• Hb- 13.6 - 17.5 g/dL

• Hct- 39 – 49%

• Retic: 0.5 - 2.5%

• Bilirubin - total -0.1 - 1.2 mg/dL

• Bilirubin - indirect- 0.1 - 0.7 mg/dL

Lab Values in Sicle Cell Anemia

• Hb- Lowered

• Hct- Lowered

• Retic- Increased

• Bilirubin - total- increased

• Bilirubin - indirect- increased

Hemolysis Pathophysiology

Hyperhemolysis is the root cause of all abnormal lab values

• Point mutation beta gene chromosome 11

• Glutamic acid to valine

• HbS production

• Hydrophobic region promote polymerization in

deoxygenated state

• Sickling and increased rigidity

• Increased hemolysis

• Shortened RBC lifespan (10-20 days)

• Leads directly to; decreased Hb and Hct, increased reticulocytosis, and hyperbilirubinemia

Decreased Hemoglobin and Hematocrit Pathophysiology

Measured Hb – in vitro after lysing RBC's

Hematocrit – percentage of blood volume that is RBC's

• Uncompensated hemolytic anemia

• Rate of erythropoiesis insufficient to compensate for

increased hemolysis

• Net loss of RBC's

• Decreased RBC count accounts for low Hct

• Low RBC count indicative of low Hb levels

• Free Hb is rapidly cleared and does not show up in significant amounts in blood tests

Increased Reticulocytosis Pathophysiology

Increased reticulocyte percentage is caused by stress erythropoiesis.

• Increased hemolysis leads to lower blood-oxygen levels

• Chronic anemia stimulates EPO release from kidneys

• EPO stimulates bone marrow, increased erythropoiesis

• Chronic stimulation leads to "stress erythropoiesis"

• Reticulocytosis is significantly increased

Total/Indirect Hyperbilirubinemia Pathophysiology

Chronic hemolysis and conjugation limits are the root causes of hyperbilirubinemia.

• Hemolysis leads to metabolism of Hb

• Free heme released into the blood stream

• Enzymatically processed into unconjugated bilirubin (Indirect)

• Chronic hemolysis produces excess heme

• Overwhelms liver hepatocytes ability to conjugate bilirubin for excretion

• Increased reabsorption of conjugated bilirubin

• Increased total bilirubin concentration

Pharmacological Interventions

Acute Vaso-occlusive Pain Crisis

• Opioids

- Morphine

- Hydromorphone

- Diamorphine

• Non-opioid

- Ketamine

-Lidocaine

Disease Modifying Therapies (DMT)

• Antimetabolites

- Hydroxyurea

• Amino Acids

- L-Glutamine

• Monoclonal Antibodies

- Crizanlizumab

Non-Pharmacological Interventions

Preventative & Emerging Therapies

• Blood Transfusions

• Gene Therapy

- Casgevy-editing

- Lyfgenia-addition

• Hematopoietic Stem Cell Transplant

Symptom Control

• Hydration

• Warm compress

• Cognitive Behavioral Therapy

• Relaxation Techniques

Hydroxyurea

Molecular Target

• Small molecule antimetabolite

• Inhibits ribonucleotide reductase (M2 subunit)

• S-phase-specific suppression of DNA synthesis

Induction of Fetal Hemoglobin (HbF)

• Induces stress erythropoiesis

• Induces y-globin gene expression

• Elevates HbF concentration in erythrocytes

Inhibition of S Polymerization

• HbF interferes with deoxygenated HbS fiber formation

• Reduces intracellular polymerization

• Decreases erythrocyte sickling

Pathophysiological Impact

• Decreased hemolysis

• Reduces endothelial activation and leukocyte adhesion

• Lowers microvascular vaso-occulusion

L-glutamine

Molecular Target

• Oral amino acid therapy

• Modulates intracellular redox metabolism within erythrocytes

Enhancement of NAD-Dependent Redox Balance

• Increases availability of reduced nicotinamide adenine dinucleotide (NADH)

• Improves intracellular NAD+/NADH ration within erythrocytes

• Decreases accumulation of reactive oxygen species (ROS)

Stabilization of Erythrocyte Membrane Integrity

• Decreases oxidative damage to membrane proteins and lipids

• Reduces erythrocyte fragility and hemolysis

Pathophysiological Impact

• Limits endothelial activation

• Reduces vaso-occlusive crisis frequency

Crizanlizumab

Molecular Target

• Humanized IgG2 monoclonal antibody

• Binds P-selectin on activated endothelial cells and platelets

Inhibition of P-Selectin-Mediated Adhesion

• Blocks interaction between P-selectin and glycoprotein ligand-1 (PSGL-1)

• Prevents leukocyte and sickled erythrocyte tethering to activated endothelium

Reduction of Multicellular Aggregate Formation

• Reduces erythrocyte-leukocyte-platelet interactions

• Limits propagation of microvascular vaso-occlusion

Pathophysiological Impact

• Decreases frequency of vaso-occlusive crisis