# Clinical Cases: Hemoglobinopathies

## Case 1: Sickle Cell Disease with Acute Vaso-Occlusive Crisis

### Patient Presentation
**Demographics:** 24-year-old African American male

**Chief Complaint:** Severe pain in lower back, legs, and chest for 12 hours

**History of Present Illness:**
The patient has known sickle cell disease (HbSS) diagnosed at birth through newborn screening. He reports sudden onset of severe pain starting in his lower back and spreading to his thighs and chest. He rates the pain 10/10, describing it as similar to previous vaso-occlusive crises. He reports mild shortness of breath. He was recently non-compliant with hydroxyurea. He denies fever initially but developed low-grade temperature overnight. He has had 4 hospitalizations for pain crises in the past year.

**Physical Examination:**
- Vital signs: BP 125/80, HR 110, RR 24, Temp 38.1C, SpO2 94% on room air
- General: Young man in obvious distress, writhing in pain
- HEENT: Scleral icterus, conjunctival pallor
- Cardiac: Tachycardic, III/VI systolic murmur
- Lungs: Decreased breath sounds at right base, no crackles
- Abdomen: Mild splenomegaly (auto-infarcted but not completely absent)
- Extremities: Tender to palpation over femurs bilaterally
- Skin: Chronic leg ulcer over left medial malleolus

### Workup and Results

**Complete Blood Count:**
- WBC: 18,500/uL (elevated from baseline 12,000)
- Hemoglobin: 7.2 g/dL (baseline 8.5)
- MCV: 85 fL
- Platelets: 425,000/uL
- Reticulocyte count: 12%

**Hemoglobin Electrophoresis (prior):**
- HbS: 92%
- HbF: 5%
- HbA2: 3%
- HbA: 0% (confirms HbSS disease)

**Chemistry:**
- LDH: 580 U/L (elevated)
- Total bilirubin: 4.2 mg/dL (elevated)
- Creatinine: 1.4 mg/dL (elevated from baseline 1.0)

**Chest X-ray:**
- New infiltrate in right lower lobe

**Arterial Blood Gas:**
- pH 7.38, pCO2 32, pO2 65 on room air

### Clinical Image

![Sickle Cell Disease Blood Smear](case_01_image.jpg)

*Peripheral blood smear in sickle cell disease showing characteristic sickle-shaped red blood cells (drepanocytes), target cells, and polychromasia reflecting ongoing hemolysis and reticulocytosis.*

### Diagnosis
**Sickle Cell Vaso-Occlusive Crisis complicated by Acute Chest Syndrome**

Acute chest syndrome criteria met:
- New pulmonary infiltrate on chest X-ray
- Respiratory symptoms (dyspnea, hypoxia)
- In setting of sickle cell disease

### Treatment Plan
1. **Pain management (priority):**
   - IV morphine or hydromorphone patient-controlled analgesia
   - Scheduled NSAIDs (ketorolac) if no renal contraindication
   - Avoid meperidine (seizure risk with metabolite accumulation)

2. **Acute chest syndrome management:**
   - Supplemental oxygen to maintain SpO2 > 92%
   - Incentive spirometry every 2 hours while awake
   - Empiric antibiotics (ceftriaxone + azithromycin) for atypical coverage
   - Simple transfusion to raise hemoglobin to 10 g/dL
   - Consider exchange transfusion if worsening

3. **Supportive care:**
   - IV fluids (avoid over-hydration which worsens ACS)
   - DVT prophylaxis
   - Monitor for multiorgan failure

4. **Long-term management:**
   - Restart hydroxyurea and emphasize compliance
   - Consider chronic transfusion program if frequent ACS
   - Evaluate for curative options (stem cell transplant, gene therapy)

### Teaching Points
1. Acute chest syndrome is the leading cause of death in adult sickle cell patients
2. The pathophysiology involves in situ sickling, fat embolism, and infection
3. Incentive spirometry prevents atelectasis that triggers sickling
4. Exchange transfusion rapidly reduces HbS percentage for severe cases
5. Hydroxyurea increases HbF, which does not participate in sickling
6. Pain management should be aggressive - undertreated pain is common
7. Fever in sickle cell disease requires evaluation for infection due to functional asplenia

---

## Case 2: Beta-Thalassemia Major

### Patient Presentation
**Demographics:** 8-year-old male of Mediterranean descent

**Chief Complaint:** Routine transfusion clinic visit

**History of Present Illness:**
The patient was diagnosed with beta-thalassemia major at 18 months of age when he presented with severe anemia and failure to thrive. He has been on a chronic transfusion program, receiving packed red blood cells every 3-4 weeks to maintain pre-transfusion hemoglobin above 9 g/dL. He is on deferasirox for iron chelation. His parents are concerned about his short stature compared to peers.

**Physical Examination:**
- Vital signs: BP 100/65, HR 90, RR 18, Temp 36.8C
- General: Small for age, appears younger than stated age
- HEENT: Frontal bossing, prominent maxillary bones (chipmunk facies)
- Cardiac: Grade II/VI systolic murmur
- Abdomen: Hepatomegaly (4 cm below costal margin), splenomegaly (6 cm below costal margin)
- Growth: Height and weight below 5th percentile

### Workup and Results

**Complete Blood Count (pre-transfusion):**
- Hemoglobin: 8.8 g/dL
- MCV: 68 fL
- RDW: 22%
- Reticulocyte count: 4%

**Hemoglobin Electrophoresis:**
- HbF: 95%
- HbA2: 5%
- HbA: 0%

**Iron Studies:**
- Ferritin: 2,400 ng/mL (elevated despite chelation)
- Transferrin saturation: 85%

**Monitoring Labs:**
- Cardiac MRI T2*: 15 ms (borderline cardiac iron loading)
- Liver iron concentration: 8 mg/g dry weight (elevated)

**Genetic Testing:**
- Homozygous for beta-zero thalassemia mutation

### Diagnosis
**Beta-Thalassemia Major (Cooley's Anemia) with Iron Overload**

Key features:
- Absent beta-globin production (beta-zero/beta-zero)
- Transfusion-dependent anemia
- Iron overload requiring chelation
- Classic skeletal changes from marrow expansion
- Growth delay from chronic anemia and iron overload endocrinopathy

### Treatment Plan
1. **Transfusion therapy:**
   - Continue regular transfusions every 3-4 weeks
   - Target pre-transfusion Hgb 9-10.5 g/dL
   - Use leukoreduced, phenotypically matched blood

2. **Iron chelation intensification:**
   - Increase deferasirox dose
   - Consider combination therapy (deferasirox + deferoxamine) for cardiac iron
   - Target ferritin < 1,000 ng/mL, cardiac T2* > 20 ms

3. **Monitoring:**
   - Annual cardiac MRI T2* for cardiac iron
   - Annual liver MRI for hepatic iron
   - Endocrine evaluation (growth hormone, thyroid, glucose)
   - DEXA scan for bone density

4. **Curative options:**
   - HLA typing for potential matched sibling donor transplant
   - Discuss gene therapy clinical trials

### Teaching Points
1. Beta-thalassemia major presents in infancy as HbF declines and beta-chain deficiency manifests
2. Without transfusion, severe anemia triggers massive marrow expansion causing skeletal deformities
3. Chronic transfusion leads to iron overload - the major cause of morbidity without chelation
4. Cardiac iron (measured by T2* MRI) is the critical determinant of survival
5. Allogeneic stem cell transplant is curative in young patients with matched donors
6. Gene therapy (betibeglogene autotemcel) now FDA-approved as curative option

---

## Case 3: Beta-Thalassemia Trait Misdiagnosed as Iron Deficiency

### Patient Presentation
**Demographics:** 32-year-old female of Greek ancestry

**Chief Complaint:** Referred for persistent microcytic anemia despite iron supplementation

**History of Present Illness:**
The patient was found to have microcytic anemia during routine prenatal labs for her first pregnancy. Her primary care physician prescribed ferrous sulfate 325 mg three times daily for presumed iron deficiency. After 3 months of treatment, her MCV remains low and she was referred to hematology. She denies fatigue, bleeding, or GI symptoms. Her mother and sister were told they have "mild anemia."

**Physical Examination:**
- Vital signs: Normal
- General: Well-appearing woman, not pale
- HEENT: No pallor, no jaundice
- Cardiac: Regular rate, no murmurs
- Abdomen: Gravid uterus, no hepatosplenomegaly
- Extremities: No edema

### Workup and Results

**Complete Blood Count:**
- WBC: 7,200/uL
- Hemoglobin: 10.8 g/dL (mildly low)
- MCV: 64 fL (markedly low)
- MCH: 22 pg
- RBC count: 5.8 million/uL (elevated)
- RDW: 14% (normal)

**Iron Studies:**
- Serum iron: 95 mcg/dL (normal)
- TIBC: 320 mcg/dL (normal)
- Ferritin: 180 ng/mL (normal, likely elevated from iron supplementation)
- Transferrin saturation: 30% (normal)

**Hemoglobin Electrophoresis:**
- HbA: 94.5%
- HbA2: 5.8% (elevated, normal < 3.5%)
- HbF: 0.7%

**Calculations:**
- Mentzer index (MCV/RBC): 64/5.8 = 11 (< 13 suggests thalassemia)

### Diagnosis
**Beta-Thalassemia Trait (Beta-Thalassemia Minor)**

Distinguishing from iron deficiency:
| Feature | Iron Deficiency | Thalassemia Trait |
|---------|-----------------|-------------------|
| Ferritin | Low | Normal/High |
| TIBC | High | Normal |
| RBC count | Low/Normal | High |
| RDW | High | Normal |
| HbA2 | Normal | Elevated (> 3.5%) |
| Mentzer index | > 13 | < 13 |

### Treatment Plan
1. **Stop iron supplementation:**
   - No iron deficiency present
   - Continued iron may cause iron overload

2. **Prenatal counseling:**
   - Test father for thalassemia trait
   - If both parents are carriers: 25% risk of thalassemia major in offspring
   - Offer genetic counseling and prenatal diagnosis

3. **No treatment needed for thalassemia trait:**
   - Mild anemia does not require treatment
   - Patient should understand this is inherited, not nutritional
   - Provide documentation to prevent future inappropriate iron therapy

4. **Family screening:**
   - Offer testing to siblings and other family members
   - Important for reproductive counseling

### Teaching Points
1. Thalassemia trait causes microcytosis disproportionate to the degree of anemia
2. The RBC count is elevated (producing more small cells to compensate)
3. RDW is normal (uniform population of small cells) vs. elevated in iron deficiency
4. HbA2 > 3.5% is diagnostic of beta-thalassemia trait
5. The Mentzer index (MCV/RBC) < 13 suggests thalassemia; > 13 suggests iron deficiency
6. Iron supplementation is not indicated and may be harmful
7. Genetic counseling is essential for reproductive decision-making