7.3 Hemoglobinopathies, Thalassemias & Paroxysmal Nocturnal Hemoglobinuria
Key Takeaways
- Thalassemias and hemoglobinopathies are the two enumerated topics within the hemoglobinopathy blueprint subsection.
- Thalassemia trait shows microcytosis with a normal or elevated red blood cell count and a normal red cell distribution width, unlike iron deficiency.
- Acute chest syndrome in sickle cell disease requires prompt transfusion, antibiotics and respiratory support and is a leading cause of death.
- Hydroxyurea reduces vaso-occlusive crises, acute chest syndrome and mortality by raising fetal hemoglobin.
- Paroxysmal nocturnal hemoglobinuria produces complement-mediated intravascular hemolysis with thrombosis at unusual sites and is diagnosed by flow cytometry rather than by the historical sucrose or acid hemolysis tests.
Last updated: August 2026
1. Microangiopathic Hemolytic Anemia (MAHA) & PNH
Microangiopathic Hemolytic Anemia (MAHA)
MAHA results from mechanical fragmentation of erythrocytes passing through microvascular thrombi or fibrin networks in arterioles and capillaries. Peripheral blood smear demonstrates schistocytes (helmet cells, fragmented erythrocytes) comprising > 1.0% of total RBCs. Primary causes include Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS), Disseminated Intravascular Coagulation (DIC), malignant hypertension, and scleroderma renal crisis.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Pathophysiology: Acquired somatic mutation in the X-linked PIGA gene within hematopoietic stem cells, resulting in deficient synthesis of the glycosylphosphatidylinositol (GPI) anchor. Without GPI anchors, erythrocytes lack membrane-bound complement regulatory proteins CD55 (Decay-Accelerating Factor) and CD59 (Membrane Attack Complex Inhibitor / MIRL), leading to uncontrolled, chronic alternative complement-mediated intravascular lysis.
- Classic Clinical Triad:
- Coombs-Negative Intravascular Hemolytic Anemia: Episodic dark/cola-colored morning urine (hemoglobinuria), fatigue, chronic renal hemosiderosis.
- Severe Thrombophilia at Atypical Venous Sites: Intra-abdominal veins (Budd-Chiari syndrome / hepatic vein thrombosis, portal/mesenteric vein thrombosis), cerebral sagittal sinus thrombosis, and dermal veins.
- Pancytopenia / Bone Marrow Failure: Aplastic anemia-PNH overlap syndrome, smooth muscle dystonias (esophageal spasms, severe abdominal pain, erectile dysfunction) due to free hemoglobin scavenging nitric oxide (NO).
- Diagnostic Gold Standard: High-sensitivity multi-parameter flow cytometry on peripheral blood granulocytes and erythrocytes demonstrating absence or reduction of CD55, CD59, and GPI-anchored protein marker FLAER (fluorescently labeled aerolysin).
- Management:
- Terminal Complement C5 Inhibitors: Eculizumab (IV every 2 weeks) or long-acting Ravulizumab (IV every 8 weeks) blocks cleavage of C5 to C5a/C5b, preventing MAC formation, dramatically reducing intravascular hemolysis, transfusion dependence, and thrombotic events.
- Mandatory Prophylaxis: All patients must receive Meningococcal vaccinations (MenACWY and MenB) at least 2 weeks prior to starting C5 inhibitors due to increased risk of invasive Neisseria meningitidis infections (supplement with oral penicillin/ciprofloxacin prophylaxis if urgent treatment is required before vaccine takes effect).
2. Hemoglobinopathies: Sickle Cell Disease (SCD)
Sickle cell disease (HbSS) results from a homozygous missense mutation (Glu6Val substitution on codon 6 of the $\beta$-globin gene), causing polymerization of deoxygenated HbS, erythrocyte sickling, chronic extravascular/intravascular hemolysis, and microvascular vaso-occlusion.
Major Acute Complications and Management
| Complication | Pathophysiology & Presentation | Diagnostic Findings | Evidence-Based Management |
|---|---|---|---|
| Vaso-Occlusive Pain Crisis (VOC) | Microvascular occlusion by sickled RBCs and leukocyte adhesion; severe bone, back, chest, or joint pain | Normal imaging, clinical diagnosis of exclusion | Rapid, individualized IV opioids (Morphine, Hydromorphone), oral/IV hydration (avoid fluid overload), maintain oxygenation |
| Acute Chest Syndrome (ACS) | Pulmonary vaso-occlusion, fat embolism, or infection (Mycoplasma, Chlamydia, S. pneumoniae); fever, chest pain, tachypnea, hypoxemia, cough | New pulmonary infiltrate on chest radiograph | Empiric IV Ceftriaxone + oral Azithromycin, supplemental O2, incentive spirometry q2h; Simple transfusion for mild-moderate ACS; Automated Red Cell Exchange Transfusion (Erythrocytapheresis) for severe hypoxemia (PaO2 < 60 mmHg or SpO2 < 90% on high-flow O2), neurological deficits, or rapid progression to target HbS < 30% and Hb ~10 g/dL |
| Aplastic Crisis | Transient cessation of erythropoiesis caused by Parvovirus B19 infection of erythroid precursors | Severe acute drop in Hb with profound reticulocytopenia (RI < 0.5%, retics near 0%) | Supportive RBC transfusions until marrow recovers (usually 7–14 days); droplet isolation in hospital |
| Splenic Sequestration Crisis | Massive pooling of RBCs within the red pulp of the spleen; presents with sudden pallor, tachycardia, left upper quadrant pain, and acute splenomegaly | Severe anemia, marked reticulocytosis, rapid splenic enlargement, hypovolemic shock | Emergent crystalloid resuscitation, careful simple RBC transfusion (avoid over-transfusion as trapped RBCs can re-enter circulation); splenectomy after stabilization |
| Acute Ischemic Stroke | Large-vessel intracranial occlusion (internal carotid, middle cerebral) | Brain MRI / MRA | Emergent automated exchange transfusion to lower HbS < 30%; long-term chronic transfusion therapy to maintain HbS < 30% |
Disease-Modifying Therapies in Sickle Cell Disease
- Hydroxyurea (First-line): Ribonucleotide reductase inhibitor that stimulates HbF (Fetal Hemoglobin) synthesis, reduces intracellular HbS concentration, lowers leukocyte/platelet counts, and decreases VOC frequency, ACS episodes, and all-cause mortality. Indicated for all patients with HbSS aged ≥ 9 months or adults with ≥ 3 VOCs/year, history of ACS, or severe chronic anemia. Titrate to maximum tolerated dose based on ANC (target ANC 1,500–3,000/mcL; hold if ANC < 1,000 or platelets < 80,000). Teratogenic (hold 3 months prior to conception).
- L-Glutamine: Reduces oxidative stress in RBCs; reduces frequency of VOC and hospitalizations.
- Voxelotor: HbS oxygen affinity modulator; binds HbS and stabilizes the oxygenated state, inhibiting deoxygenation-induced polymerization and reducing hemolysis.
- Crizanlizumab: Monoclonal antibody targeting P-selectin on activated vascular endothelial cells and platelets; blocks multicellular adhesion and reduces pain crisis frequency.
- Infection Prophylaxis: Functional asplenia (Howell-Jolly bodies on smear) begins in infancy due to recurrent splenic infarctions. Mandates: Daily oral Penicillin VK prophylaxis until age 5, comprehensive vaccination against encapsulated organisms (PCV20 / PPSV23 pneumococcal, MenACWY, MenB, and H. influenzae type b), and immediate empiric IV Ceftriaxone for any temperature ≥ 38.5°C.