What is the cause of schistocytes on a peripheral blood smear?

Causes of Schistocytes on Peripheral Blood Smear

Schistocytes on peripheral blood smear indicate microangiopathic hemolytic anemia (MAHA), most commonly caused by thrombotic microangiopathies (TMA) including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), but can also result from disseminated intravascular coagulation (DIC), malignant hypertension, metastatic carcinoma, mechanical heart valves, and decompensated chronic liver disease. 1, 2

Primary Thrombotic Microangiopathies

The presence of schistocytes defines the hallmark of TMA, which consists of the triad of non-immune microangiopathic hemolysis, thrombocytopenia, and organ involvement (typically renal). 1, 3

TTP and HUS

• TTP occurs when ADAMTS13 activity is <10%, often accompanied by neurological symptoms and more severe thrombocytopenia. 1
• HUS presents with ADAMTS13 activity >10% and predominantly renal involvement with evidence of complement activation. 1
• The absence of abundant schistocytes does not exclude TMA due to low test sensitivity, and even "rare" schistocyte counts can occur in early or evolving disease. 1

Critical Diagnostic Pitfall

• Do not dismiss TMA based on low schistocyte counts alone - schistocytes above 1% can be clinically significant, and moderate thrombocytopenia with few schistocytes may still represent TMA, particularly in malignant hypertension-associated cases. 1

Malignancy-Associated MAHA

• Metastatic carcinoma, particularly gastric, breast, prostate, lung adenocarcinoma, and signet-ring cell carcinoma of the colon can cause MAHA with schistocytes. 1, 4
• Cancer-associated MAHA may present as the initial manifestation of occult malignancy before other symptoms develop. 4

Cardiovascular and Mechanical Causes

• Mechanical heart valves cause chronic low-grade hemolysis with schistocyte formation due to shear stress on red blood cells. 1
• Malignant hypertension with severe blood pressure elevation and advanced retinopathy produces TMA, typically showing only moderate thrombocytopenia and fewer schistocytes compared to TTP/HUS, with normal or slightly reduced ADAMTS13 activity. 1

Hepatic Causes

• Decompensated chronic liver disease causes MAHA through multiple mechanisms: elevated bilirubin directly triggering eryptosis, microangiopathic changes in hepatic vasculature causing mechanical RBC damage, and indirect hyperbilirubinemia indicating ongoing hemolysis. 2
• The presence of schistocytes in liver disease is pathognomonic for microangiopathic hemolytic anemia. 2

Other Causes

• Chronic renal failure can produce schistocytes through uremic toxin effects on red blood cell membranes. 1
• DIC should be differentiated from primary TMA by checking PT, PTT, fibrinogen, and D-dimer - DIC shows more pronounced coagulopathy and elevated fibrin degradation products. 2
• Solid organ transplantation can cause transplant-associated TMA. 5

Conditions Where Schistocytes Are NOT Expected

According to the American Society of Hematology guidelines, schistocytes are explicitly NOT consistent with idiopathic thrombocytopenic purpura (ITP) - their presence should prompt evaluation for alternative diagnoses. 6

Essential Immediate Workup

When schistocytes are identified, urgently order:

• ADAMTS13 activity level and inhibitor titer (distinguishes TTP from other TMAs) 1
• Complete blood count with platelet count 1
• Lactate dehydrogenase (LDH) and haptoglobin (markers of hemolysis) 1
• Direct antiglobulin test (DAT) to exclude immune-mediated hemolysis 1
• Creatinine and urinalysis for hematuria/proteinuria (assess renal involvement) 1
• Peripheral blood smear review by expert hematopathologist 1
• PT, PTT, fibrinogen to exclude DIC 1
• Blood pressure measurement and funduscopic examination to evaluate for malignant hypertension 1