What are the signs and management of hemolysis?

Signs and Management of Hemolysis

Clinical Signs of Hemolysis

Hemolysis presents with a characteristic constellation of clinical and laboratory findings that reflect premature red blood cell destruction. 1, 2

Clinical Manifestations

• Weakness, fatigue, and inability to perform physical activity due to anemia 1
• Jaundice (yellowing of skin and eyes) from elevated unconjugated bilirubin 1, 2
• Dark-colored urine (hemoglobinuria in severe intravascular hemolysis) 1
• Pallor from reduced hemoglobin 1
• Fever may accompany acute hemolytic episodes 1
• Heart murmur from increased cardiac output compensating for anemia 1
• Tachycardia and dyspnea in acute presentations 3

Laboratory Hallmarks

The diagnosis is definitively established by demonstrating both red cell destruction and compensatory bone marrow response. 2, 3

Evidence of Red Cell Destruction:

• Elevated LDH (lactate dehydrogenase) from intracellular enzyme release 1, 2
• Decreased or absent haptoglobin (binds free hemoglobin) 1, 2
• Elevated unconjugated (indirect) bilirubin from heme breakdown 1, 2
• Schistocytes on peripheral blood smear (fragmented RBCs, particularly in microangiopathic hemolysis) 1, 4
• Free hemoglobin in plasma (hemoglobinemia) in severe intravascular hemolysis 1, 5
• Hemoglobinuria and hemosiderinuria in severe intravascular cases 5

Evidence of Bone Marrow Response:

• Reticulocytosis (elevated reticulocyte count indicating increased RBC production) 1, 2
• Macrocytosis (elevated MCV) from young, larger reticulocytes 1

Diagnostic Work-Up

A systematic approach must differentiate immune from non-immune causes and identify the specific etiology. 1, 4

Initial Laboratory Evaluation:

• Complete blood count (CBC) with peripheral blood smear to assess anemia severity, identify schistocytes, spherocytes, or other morphologic abnormalities 1, 4
• Reticulocyte count to confirm bone marrow response 1, 2
• LDH, haptoglobin, total and indirect bilirubin to confirm hemolysis 1, 4
• Direct antiglobulin test (DAT/Coombs test) to distinguish immune-mediated from non-immune hemolysis 1, 3

Specialized Testing Based on Clinical Context:

For Suspected Autoimmune Hemolytic Anemia:

• Autoimmune serology 1
• Protein electrophoresis and cryoglobulin analysis 1

For Suspected Thrombotic Microangiopathy (TTP/HUS):

• ADAMTS13 activity and inhibitor levels (severely deficient <10% indicates TTP) 4, 6
• Serum creatinine to assess renal involvement 1, 4
• Complement testing (C3, C4, CH50) for atypical HUS 1
• Stool studies for Shiga toxin/E. coli O157:H7 if diarrhea present 4

For Other Etiologies:

• Glucose-6-phosphate dehydrogenase (G6PD) level for enzyme deficiency 1
• Paroxysmal nocturnal hemoglobinuria (PNH) screening by flow cytometry for GPI-anchored proteins 1
• Viral studies (EBV, CMV, HHV6, parvovirus, mycoplasma) for infectious causes 1
• Medication review for drug-induced hemolysis (common culprits: cephalosporins, penicillins, NSAIDs, quinine, ribavirin, rifampin, dapsone, interferon) 1
• Bone marrow biopsy if no obvious cause identified or concern for myelodysplastic syndrome 1

Management Algorithm

Grade 1 (Mild): Hemoglobin <LLN to 10.0 g/dL

Continue monitoring with close clinical follow-up and serial laboratory evaluation. 1

• No immediate intervention required for stable patients 1
• Address underlying cause if identified 1

Grade 2 (Moderate): Hemoglobin <10.0 to 8.0 g/dL

Hold any potentially causative agents and initiate corticosteroid therapy. 1

• Prednisone 0.5-1 mg/kg/day for autoimmune hemolytic anemia 1, 4
• Strongly consider permanent discontinuation of immune checkpoint inhibitors if applicable 1
• Hematology consultation recommended 1

Grade 3 (Severe): Hemoglobin <8.0 g/dL, Transfusion Indicated

Permanently discontinue causative agents, admit for monitoring, and initiate aggressive immunosuppression. 1

• Mandatory hematology consultation 1
• Prednisone 1-2 mg/kg/day (oral or IV depending on acuity) 1
• RBC transfusion per existing guidelines: transfuse only the minimum necessary to relieve symptoms or achieve safe hemoglobin (7-8 g/dL in stable, non-cardiac patients) 1, 6
• Folic acid 1 mg daily supplementation to support erythropoiesis 1, 6
• Consider hospital admission based on clinical judgment 1

Grade 4 (Life-Threatening): Urgent Intervention Required

Immediate hospitalization with aggressive immunosuppression and consideration of additional therapies. 1

• Admit patient immediately 1
• IV methylprednisolone 1-2 mg/kg/day 1
• If no improvement or worsening on corticosteroids, initiate second-line agents: rituximab, IVIG, cyclosporine A, or mycophenolate mofetil 1
• Coordinate with blood bank prior to transfusions 1

Special Considerations for Thrombotic Microangiopathy

TTP (Thrombotic Thrombocytopenic Purpura)

TTP requires immediate plasma exchange as delay significantly increases mortality. 4, 6

• Do not wait for ADAMTS13 results if clinical suspicion is high 6
• Initiate plasma exchange immediately per existing protocols 1, 6
• Methylprednisolone 1 g IV daily for 3 days, with first dose after first plasma exchange 1, 6
• Add rituximab early to reduce relapse risk 6
• CRITICAL PITFALL: Platelet transfusion is contraindicated unless life-threatening bleeding, as it may worsen thrombosis 4

Atypical HUS (Hemolytic Uremic Syndrome)

Complement-mediated HUS requires eculizumab therapy. 1, 4

• Eculizumab dosing: 900 mg weekly for 4 doses, then 1,200 mg at week 5, followed by 1,200 mg every 2 weeks 1, 4, 6
• Permanently discontinue immune checkpoint inhibitors if applicable 1

Monitoring During Treatment

Weekly hemoglobin levels during active treatment and steroid taper, then less frequently once stable. 4

• Monitor platelet counts, LDH, and haptoglobin to assess treatment response 4, 6
• Watch for iron overload in patients requiring multiple transfusions 6
• Maintain high index of suspicion for complications, particularly in TTP where delayed recognition increases mortality 6

Critical Pitfalls to Avoid

• Never delay plasma exchange in suspected TTP while awaiting ADAMTS13 results—this is life-saving therapy 6
• Avoid platelet transfusion in TTP except for life-threatening bleeding 4
• Always review medication history thoroughly as drug-induced hemolysis is common and reversible 1, 4
• Do not over-transfuse: target hemoglobin 7-8 g/dL in stable patients to minimize transfusion-related complications 1, 6
• Coordinate with blood bank in autoimmune hemolytic anemia as crossmatching may be difficult 1