What is the recommended workup and treatment for a patient presenting with symptoms of hemolysis, such as jaundice, fatigue, or shortness of breath, with a history of autoimmune disorders, infections, or medications known to cause hemolysis?

Hemolysis Workup

Begin with a comprehensive laboratory panel including CBC with peripheral smear, reticulocyte count, LDH, haptoglobin, direct and indirect bilirubin, and direct antiglobulin test (DAT/Coombs), as these are essential for confirming hemolysis and determining its etiology. 1, 2

Initial Laboratory Evaluation

The diagnostic workup must include specific markers that confirm hemolysis and guide further investigation:

Core Hemolysis Markers

• Complete blood count (CBC) with evidence of anemia and macrocytosis 1, 3
• Peripheral blood smear to identify spherocytes, schistocytes, or other morphologic abnormalities that indicate specific hemolytic processes 1, 2
• Reticulocyte count (typically elevated, confirming active bone marrow response to hemolysis) 1, 2
• Lactate dehydrogenase (LDH) (elevated in hemolysis) 1, 2
• Haptoglobin (decreased or absent in hemolysis) 1, 2
• Direct and indirect bilirubin (elevated indirect/unconjugated bilirubin indicates hemolysis) 1, 3
• Free hemoglobin in serum 1

Immune-Mediated Hemolysis Assessment

• Direct antiglobulin test (DAT/Coombs test) with monospecific antisera is mandatory before initiating any treatment to distinguish immune from non-immune causes 1, 2, 4
• Autoimmune serology to evaluate for underlying autoimmune disorders 1

Secondary Causes and Differential Diagnosis

Medication and Toxin Exposure

Obtain detailed medication history evaluating for common drug causes including:

• Antibiotics: cephalosporins, penicillins, rifampin, ciprofloxacin 1, 3
• Antivirals: ribavirin, interferon 1, 3
• Other medications: dapsone, NSAIDs, quinine/quinidine, fludarabine, lorazepam, diclofenac 1, 3
• Recent insect, spider, or snake bites 1, 2

Infectious Etiologies

• Viral studies: HIV, hepatitis B and C, CMV, parvovirus, EBV 3, 5
• Bacterial causes: Mycoplasma and other bacterial infections 1
• Parasitic infections: Consider malaria and babesiosis in appropriate clinical contexts 6

Hematologic Disorders

• Disseminated intravascular coagulation (DIC) panel including PT/INR 1
• Paroxysmal nocturnal hemoglobinuria (PNH) screening via flow cytometry 1
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency testing 1, 3
• Protein electrophoresis and cryoglobulin analysis 1
• Bone marrow analysis with cytogenetic studies if no obvious cause identified, to evaluate for myelodysplastic syndromes 1

Nutritional and Metabolic Causes

• B12, folate, copper, and iron studies to exclude nutritional deficiencies 1, 3
• Thyroid function tests 1, 3
• Assessment for methemoglobinemia in appropriate clinical contexts 1, 3

Management Based on Severity

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

• Continue close clinical monitoring with regular laboratory evaluation 1, 2
• Identify and address underlying cause 2, 3
• Folic acid 1 mg once daily supplementation 1, 3

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

• Prednisone 0.5-1 mg/kg/day for immune-mediated hemolysis 1, 2, 7
• Consider hematology consultation 2, 8
• Hold any causative agents and strongly consider permanent discontinuation 1

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

• Mandatory hematology consultation 1, 2
• Prednisone 1-2 mg/kg/day (oral or IV depending on symptom severity and speed of development) 1, 3, 7
• Consider hospital admission based on clinical judgment 1
• RBC transfusion per existing guidelines targeting hemoglobin 7-8 g/dL in stable, noncardiac inpatients; transfuse only the minimum number of units necessary to relieve symptoms 1, 8
• Folic acid 1 mg once daily 1, 3
• Permanently discontinue causative agents 1

Grade 4 (Life-Threatening): Life-threatening consequences requiring urgent intervention

• Immediate hospital admission 1, 2
• Urgent hematology consultation 1, 2
• IV methylprednisolone 1-2 mg/kg/day 1, 3
• If no improvement or worsening on corticosteroids, initiate second-line immunosuppressive therapy: rituximab, IVIG, cyclosporine A, or mycophenolate mofetil 1, 3
• RBC transfusion per existing guidelines; discuss with blood bank team prior to transfusion 1
• Permanently discontinue causative agents 1

Critical Clinical Scenarios Requiring Immediate Action

Thrombotic Microangiopathy (TTP/HUS)

Immediate plasma exchange (PEX) should be initiated without waiting for ADAMTS13 results if TTP is suspected, as delay significantly increases mortality 8, 3. Key features include:

• Schistocytes on peripheral smear with thrombocytopenia 6
• Platelet transfusion is contraindicated except for life-threatening bleeding 8
• Eculizumab therapy for complement-mediated hemolytic uremic syndrome 8

DAT-Negative Autoimmune Hemolytic Anemia

• Diagnosis made after exclusion of other causes of hemolysis 3, 5
• Supported by response to corticosteroids 3, 5
• More frequently severe and may require multiple treatments 5

Common Pitfalls to Avoid

• Do not delay DAT/Coombs testing, as it must be performed before initiating corticosteroids or transfusions to ensure accurate diagnosis 3, 4
• Do not over-transfuse; target hemoglobin 7-8 g/dL in stable patients to avoid volume overload and unnecessary transfusion reactions 1, 8
• Do not miss secondary causes: Always investigate for underlying lymphoproliferative disorders, infections, drugs, immunodeficiencies, and systemic autoimmune diseases through careful history, physical examination, and targeted testing 3, 5
• Do not give platelets in suspected TTP except for life-threatening bleeding, as this may worsen thrombosis 8