Signs of Hemolysis
Hemolysis is characterized by a constellation of laboratory findings including elevated reticulocyte count, increased lactate dehydrogenase (LDH), reduced or absent haptoglobin, elevated unconjugated (indirect) bilirubin, and the presence of anemia, with peripheral blood smear examination revealing characteristic red cell morphology changes. 1, 2
Laboratory Markers of Hemolysis
Core Diagnostic Tests
The essential laboratory findings that establish hemolysis include:
- Elevated reticulocyte count - indicates active bone marrow compensatory response to red cell destruction 1, 2, 3
- Increased lactate dehydrogenase (LDH) - a sensitive marker of red cell breakdown, particularly elevated in intravascular hemolysis 1, 2, 3
- Decreased or absent haptoglobin - consumed by binding free hemoglobin released from lysed red cells 1, 2, 3
- Elevated unconjugated (indirect) bilirubin - typically increased but usually <5 mg/dL in chronic hemolysis 1, 2, 3
- Anemia - documented by complete blood count, often normocytic or macrocytic 2, 4
Additional Laboratory Findings
- Elevated free hemoglobin - particularly in intravascular hemolysis 2, 3
- Hemoglobinuria - dark-colored urine occurs only with severe, rapid intravascular hemolysis 5, 6
- Hemosiderinuria - indicates chronic intravascular hemolysis 6, 7
- Increased iron status parameters (serum ferritin, transferrin saturation) - may be disproportionately elevated even without transfusion history 1
Clinical Presentation
Symptoms
Patients may present with:
- Jaundice - from elevated unconjugated bilirubin 1, 3
- Dark-colored urine - from hemoglobinuria or bilirubinuria 5, 4
- Weakness and fatigue - from anemia 5, 4
- Dyspnea and tachycardia - compensatory responses to anemia 4
- Pallor - from reduced hemoglobin 5
Physical Examination Findings
- Splenomegaly - from extravascular hemolysis and sequestration 1
- Hepatomegaly - may be present in chronic hemolysis 1
- Heart murmur - from high-output state 5
Peripheral Blood Smear Findings
Blood smear examination is fundamental for diagnosis and should always be performed when hemolysis is suspected. 2, 4, 7
- Schistocytes - fragmented red cells indicating microangiopathic hemolysis, though their absence does not exclude thrombotic microangiopathy due to low sensitivity 1, 2, 7
- Spherocytes - suggest hereditary spherocytosis or immune-mediated hemolysis 3
- Echinocytes - variable proportion (3-30%) may be observed, particularly after splenectomy 1
- Anisocytosis and poikilocytosis - general red cell size and shape variation 1
- Polychromasia - reflects reticulocytosis 4
- Nucleated red blood cells (erythroblasts) - may appear in severe cases with ineffective erythropoiesis 1
Distinguishing Intravascular vs. Extravascular Hemolysis
Intravascular Hemolysis
- Marked elevation of LDH - more pronounced than in extravascular hemolysis 7
- Hemoglobinemia - free hemoglobin in plasma 6
- Hemoglobinuria - occurs only with severe, rapid intravascular lysis 6
- Hemosiderinuria - pathognomonic for chronic intravascular hemolysis 7
Extravascular Hemolysis
- Predominant elevation of unconjugated bilirubin - from red cell processing by reticuloendothelial system 3, 4
- Splenomegaly - from sequestration and destruction of red cells 1
- Less dramatic LDH elevation - compared to intravascular hemolysis 7
Important Caveats
Reticulocytosis may be inadequate or absent despite active hemolysis in 20-40% of cases, particularly when there is:
- Bone marrow involvement 7
- Iron, folate, or B12 deficiency 7
- Concurrent infections 7
- Autoimmune reaction against bone marrow precursors 7
- Reticulocytopenia in autoimmune hemolytic anemia is a poor prognostic factor 7
In pyruvate kinase deficiency, reticulocytosis is not proportional to hemolysis severity due to decreased erythropoietic drive and splenic sequestration of younger red cells 1
Red cell osmotic fragility is not informative as it can be normal or altered in hemolytic conditions 1
Confirmatory Testing
After establishing hemolysis, proceed with: