What is the pathophysiology and management of hematological and immunological disorders?

Pathophysiology and Management of Hematological and Immunological Disorders

Overview of Immune-Mediated Hematologic Pathophysiology

Hematologic and immunologic disorders share a common pathophysiologic mechanism: autoimmune destruction of normal blood cells through autoantibody formation and dysregulated immune responses. 1

Key Pathophysiologic Mechanisms

• Autoantibody-mediated destruction: The immune system generates antibodies against self-antigens on blood cells, leading to accelerated clearance and destruction 1, 2
• Immune dysregulation: Persistent antigen stimulation from defective pathogen clearance drives chronic immune activation and autoimmunity 3
• Lymphocyte dysfunction: Abnormal B-cell and T-cell signaling results in loss of self-tolerance and production of autoreactive clones 2
• Cytokine-mediated effects: Inflammatory cytokines enhance autoimmune responses and can directly suppress hematopoiesis 4

Specific Hematologic Autoimmune Disorders

Immune Thrombocytopenia (ITP)

ITP results from immunologic destruction of otherwise normal platelets, typically presenting with isolated thrombocytopenia in the absence of other identifiable causes. 1

Clinical Presentation

• Easy or excessive bruising, petechiae (particularly lower legs), bleeding from gums or nose, blood in urine or stool 1
• Median time to onset: 40 days when associated with immune checkpoint inhibitors 1

Diagnostic Workup

• Complete blood count with peripheral blood smear and reticulocyte count 1
• Test for HIV, hepatitis C virus, hepatitis B virus, and Helicobacter pylori in newly diagnosed cases 1
• Direct antiglobulin test to rule out concurrent Evans syndrome 1
• Bone marrow evaluation only if other cell lines affected or abnormalities suggest alternative diagnosis 1

Management by Severity

Grade 1 (platelet count <100,000/μL): Continue monitoring with close clinical follow-up and laboratory evaluation 1

Grade 2 (platelet count <75,000/μL): Hold offending agents and monitor; if not resolved, interrupt treatment until improvement to Grade 1 1

Grade 3 (platelet count <50,000/μL):

• Administer prednisone 1 mg/kg/day (range 0.5-2 mg/kg/day) orally for 2-4 weeks, then taper over 4-6 weeks 1, 5
• IVIG 1 g/kg as one-time dose may be used with corticosteroids when rapid platelet increase required 1

Grade 4 (platelet count <25,000/μL):

• Hematology consultation mandatory 1
• Prednisone 1-2 mg/kg/day with IVIG 1
• If corticosteroids/IVIG unsuccessful, consider rituximab, thrombopoietin receptor agonists, or more potent immunosuppression 1

Autoimmune Hemolytic Anemia

Hemolytic anemia develops through autoantibody formation against red blood cells, leading to enhanced destruction of antibody-coated erythrocytes. 1, 4

Clinical Presentation

• Weakness, pallor, jaundice, dark-colored urine, fever, heart murmur 1
• Pooled incidence: 9.8% all grades, 5% grade 3-5 when associated with immune checkpoint inhibitors 1

Management Approach

• Hold offending agents immediately 1
• Corticosteroids as primary therapy 1
• IVIG for additional support 1
• Direct antiglobulin test confirms diagnosis 1

Acquired Hemophilia A

This disorder results from autoantibodies (inhibitors) directed against factor VIII, presenting with spontaneous bleeding without prior bleeding history. 1

Clinical Presentation

• Subcutaneous bleeding, muscle hematomas, GI/genitourinary/retroperitoneal bleeding 1
• Prolonged activated PTT with normal PT 1

Management by Bethesda Unit Level

Low titer (<5 Bethesda units):

• Hold immune checkpoint inhibitors; discuss resumption considering risks/benefits 1
• Prednisone 0.5-1 mg/kg/day 1
• Simple factor replacement with transfusion support 1
• Hematology consultation for bleeding management 1

High titer (>5 Bethesda units):

• Permanently discontinue offending agents 1
• Admit patient with immediate hematology consultation 1
• Bypassing agents (factor VII, factor VIII inhibitor bypass activity) 1
• Prednisone 1-2 mg/kg/day ± rituximab (375 mg/m² weekly for 4 weeks) and/or cyclophosphamide (1-2 mg/kg/day) for minimum 5 weeks 1
• If no improvement, add cyclosporine or immunoadsorption 1

Aplastic Anemia

Multiple cell line involvement requires evaluation for pure red cell aplasia, autoantibodies, aplastic anemia, and myelodysplasia. 1

Clinical Presentation

• Fatigue, shortness of breath, rapid/irregular heart rate, pallor, unexplained bruising/bleeding, skin rash, dizziness, headache, fever 1

Management Strategy

• Hold immune checkpoint inhibitors 1
• Corticosteroids as primary therapy 1
• IVIG for immune-mediated components 1
• Growth factor support (G-CSF, erythropoietin) 1
• Bone marrow evaluation mandatory when multiple cell lines affected 1

Primary Immunodeficiency Disorders

Combined Immunodeficiencies

Severe Combined Immunodeficiency (SCID) represents complete absence of specific immunity with extreme susceptibility to all pathogens including opportunistic organisms. 1

Clinical Presentation

• Chronic diarrhea, failure to thrive, recurrent severe infections 1
• Panhypogammaglobulinemia, lymphopenia or alymphocytosis, absent cellular immune function 1

Management Algorithm

1. Immediate supportive care: Antimicrobials and IgG replacement 1
2. Urgent hematopoietic stem cell transplantation: Seek as quickly as possible; outcomes greatly improved by earliest intervention 1
3. Infection prophylaxis: Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole 1

Humoral Immunodeficiencies

Agammaglobulinemia and common variable immunodeficiency manifest as recurrent bacterial infections of upper and lower respiratory tract due to extremely low or absent B cells. 1

Management Approach

• Agammaglobulinemia/Common Variable Immunodeficiency: IgG replacement therapy and/or antibiotic prophylaxis 1
• Milder antibody deficiencies (selective IgA deficiency, IgG subclass deficiency): Antibiotic prophylaxis primarily; IgG therapy in select cases 1

Critical Management Pitfalls

Common Errors to Avoid

• Do not perform plasmapheresis immediately after IVIG: This removes the administered immunoglobulin 1
• Avoid high-dose steroids in myasthenia gravis: Use 0.5-1 mg/kg instead of standard 1 mg/kg due to potential short-term exacerbation 1
• Do not delay HSCT in SCID: This is an urgent medical condition; infants can succumb to severe infection at any time 1
• Evaluate for multiple causes of thrombocytopenia: Must rule out TTP, disseminated intravascular coagulation, myelodysplastic syndrome before attributing to immune-mediated causes 1
• Consider autoimmune etiology early: Particularly when hematologic abnormalities present 1-2 weeks after initial infection symptoms 6

Monitoring Requirements

• Patients on interferon therapy: Monitor for autoimmune phenomena including thyroid disorders, hematologic disorders, connective tissue disorders 4
• Pre-existing autoantibodies: These patients have higher susceptibility to exacerbation of autoimmunity and should be monitored closely 4
• Corticosteroid-induced PCP risk: Consider prophylaxis when receiving prednisone equivalent ≥20 mg/day for ≥4 weeks 1