What is thrombotic microangiopathy and what is the appropriate work‑up and management for a 48‑year‑old man with severe anemia, profound thrombocytopenia, low reticulocyte count, high ferritin, low serum iron, normal renal and hepatic function, chronic aspirin use, and prior intracerebral hemorrhage?

What is Thrombotic Microangiopathy (TMA)?

Thrombotic microangiopathy (TMA) is a life-threatening condition defined by the triad of non-immune microangiopathic hemolytic anemia (with schistocytes on blood smear), thrombocytopenia, and acute organ damage—most commonly affecting the kidneys, brain, or heart—caused by endothelial injury and platelet-rich microthrombi occluding arterioles and capillaries. 1, 2, 3

Core Pathophysiology

TMA results from endothelial damage leading to platelet aggregation and microvascular occlusion, causing mechanical destruction of red blood cells (producing schistocytes) and consumptive thrombocytopenia. 2, 4, 3 The resulting ischemia produces severe organ dysfunction that can be acutely life-threatening. 5, 4

Major TMA Subtypes

The differential diagnosis hinges on identifying the underlying mechanism:

Primary TMA Forms

• Thrombotic Thrombocytopenic Purpura (TTP): Characterized by ADAMTS13 activity <10% with or without inhibitor antibodies. Presents with fever, microangiopathic hemolytic anemia, renal dysfunction, and fluctuating neurological signs including confusion, coma, seizures, aphasia, hemiplegia, and papilledema. 6, 1

• Atypical Hemolytic Uremic Syndrome (aHUS): Complement-mediated TMA with ADAMTS13 activity >10%, often associated with mutations in complement regulatory proteins. 1, 7, 4

• Shiga toxin-associated HUS (STEC-HUS): Infection-triggered, classically in children with bloody diarrhea. 5, 4

Secondary TMA Forms

Secondary TMA occurs in association with:

• Malignant hypertension (severe BP >200/120 mmHg with advanced retinopathy) 6
• Autoimmune diseases (systemic lupus erythematosus, antiphospholipid syndrome) 6
• Pregnancy complications (eclampsia, HELLP syndrome) 6
• Malignancy and chemotherapy 6
• Drugs (calcineurin inhibitors, immune checkpoint inhibitors) 6
• Transplantation 5

Immediate Diagnostic Workup

Critical first-line tests must be ordered urgently and include: 6, 1

• ADAMTS13 activity level and inhibitor titer (distinguishes TTP from other TMAs)
• Complete blood count with platelet count
• Peripheral blood smear review for schistocytes
• Lactate dehydrogenase (LDH) and haptoglobin (hemolysis markers)
• Direct antiglobulin test (DAT) to exclude immune hemolysis
• Creatinine and urinalysis for hematuria/proteinuria (renal involvement)
• Prothrombin time, activated partial thromboplastin time, fibrinogen (exclude DIC)
• Blood group and antibody screen

Additional testing based on clinical context: 6, 1

• Complement levels (C3, C4, CH50) for suspected aHUS
• Blood pressure measurement and funduscopic examination for malignant hypertension 6
• Pregnancy test in women of childbearing age

Critical Diagnostic Pitfall

Do not dismiss TMA based on "rare" or absent schistocytes alone—schistocyte counts can be low in early or evolving TMA, and test sensitivity is limited. 1 The presence of hemolysis markers (elevated LDH, low haptoglobin, elevated indirect bilirubin) with thrombocytopenia and organ dysfunction should trigger immediate TMA evaluation even with few schistocytes. 1

Management Algorithm

TTP (ADAMTS13 <10%)

Do not delay plasma exchange while awaiting ADAMTS13 results if TTP is strongly suspected clinically, as mortality increases with delayed treatment. 6, 1

• Immediately initiate therapeutic plasma exchange (PEX) according to existing guidelines 6, 1
• Administer methylprednisolone 1g IV daily for 3 days, with first dose given immediately after first PEX 6, 1
• Continue daily PEX until platelet count exceeds 100-150 × 10⁹/L for 2 consecutive days 1
• Consider rituximab for refractory cases 6
• Consider caplacizumab if available 6

aHUS (ADAMTS13 >10%)

• Begin eculizumab therapy urgently with dosing: 900 mg weekly for 4 doses, then 1,200 mg at week 5, followed by 1,200 mg every 2 weeks 6, 1, 7
• Administer meningococcal vaccination and long-term penicillin prophylaxis (eculizumab increases meningococcal infection risk) 6, 7
• Review and discontinue all potentially causative medications 1

Malignant Hypertension-Associated TMA

• Initiate controlled blood pressure lowering with IV antihypertensive agents 6
• TMA should improve within 24-48 hours if hypertension is the primary cause 6, 1
• If no improvement, consider alternative TMA etiology 6

Graded Approach for Secondary TMA

Grade 1 (schistocytes without anemia/thrombocytopenia):

• Hold potentially causative medications 6, 1
• Hematology consultation 6
• Close monitoring 6

Grade 2 (anemia and thrombocytopenia without severe organ dysfunction):

• Administer prednisone 0.5-1 mg/kg/day 6, 1, 8
• Monitor hemoglobin weekly during steroid tapering 6, 1

Grade 3 (clinically significant organ dysfunction):

• Consider hospital admission based on clinical judgment 6, 1
• Hematology consultation 6
• Administer prednisone 1-2 mg/kg/day (oral or IV) 6, 1, 8
• Consider RBC transfusion per guidelines 6, 1

Grade 4 (life-threatening consequences):

• Admit patient 6
• Hematology consultation 6
• IV methylprednisolone 1-2 mg/kg/day 6, 8
• If no improvement or worsening on corticosteroids, initiate additional immunosuppression: rituximab, IVIG, cyclosporine, mycophenolate mofetil, or antithymocyte globulin 6, 1, 8

Transfusion Guidelines

RBC transfusion should only be administered to relieve symptoms of anemia or achieve hemoglobin 7-8 g/dL in stable, non-cardiac inpatients. 6, 1, 8 Do not transfuse more than the minimum number of units necessary, as excessive transfusion can worsen hemolysis. 6, 1, 8

Platelet transfusion is generally contraindicated in TTP unless life-threatening bleeding is present. 1 Discuss with blood bank team before any transfusions in suspected TMA. 6

Monitoring Requirements

During acute phase, monitor daily: 1, 8

• Complete blood count with differential
• LDH and haptoglobin
• Creatinine

Monitor hemoglobin levels weekly until steroid tapering is complete, then less frequently. 6, 1, 8

Application to Your Patient

For your 48-year-old man with severe anemia, profound thrombocytopenia, low reticulocyte count, high ferritin, low serum iron, normal renal/hepatic function, chronic aspirin use, and prior intracerebral hemorrhage:

The low reticulocyte count (suggesting hypoproliferative anemia rather than hemolysis) makes classic TMA less likely. 1 However, you must still:

1. Immediately check peripheral smear for schistocytes and order ADAMTS13, LDH, haptoglobin, and DAT 6, 1
2. If schistocytes are present with elevated LDH/low haptoglobin, proceed with TMA workup even with low reticulocyte count (early or evolving TMA) 1
3. Consider alternative diagnoses including immune-mediated hemolytic anemia, myelodysplastic syndrome, or medication-related cytopenias (aspirin rarely causes thrombocytopenia) 1
4. The prior intracerebral hemorrhage complicates management—avoid plasma exchange if possible due to bleeding risk, and platelet transfusion may be necessary despite TMA if active bleeding 6