How do you differentiate between Heparin-Induced Thrombocytopenia (HIT), Hemolytic Uremic Syndrome (HUS), Immune Thrombocytopenic Purpura/Thrombotic Thrombocytopenic Purpura (ITP/TTP), and Disseminated Intravascular Coagulation (DIC)?

Differentiating Between HIT, HUS, ITP/TTP, and DIC

The key to differentiating these thrombocytopenic disorders lies in combining platelet count severity, coagulation parameters (PT/aPTT), presence of schistocytes, and clinical context—with HIT showing moderate thrombocytopenia and normal PT, TTP/HUS showing severe thrombocytopenia with schistocytes and normal PT, ITP showing isolated thrombocytopenia with normal coagulation, and DIC showing prolonged PT/aPTT with elevated D-dimer and low fibrinogen. 1

Clinical and Laboratory Algorithm

Heparin-Induced Thrombocytopenia (HIT)

Key Distinguishing Features:

• Platelet count: Typically 30-70 × 10⁹/L, rarely falls below 20 × 10⁹/L 2
• Timing: Occurs 5-15 days after heparin exposure (or within 24 hours if recent prior exposure) 2, 3
• Coagulation studies: PT and aPTT are normal 1
• Hemolysis markers: Absent—no schistocytes, normal LDH, normal indirect bilirubin 2
• Clinical context: Recent heparin exposure (UFH > LMWH), thrombosis occurs in 33-55% of untreated patients 2, 4
• Bleeding: Rare despite thrombocytopenia; this is a prothrombotic condition 2, 4

Diagnostic Approach:

• Calculate 4T score (thrombocytopenia, timing, thrombosis, other causes) 5, 6
• Score ≥4 (intermediate/high probability): immediately discontinue all heparin and start non-heparin anticoagulant 5
• Confirm with anti-PF4/heparin antibody testing (immunoassay), followed by functional assay if positive 2, 6

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

Key Distinguishing Features:

• Platelet count: Typically <20 × 10⁹/L (profound thrombocytopenia) 1
• Coagulation studies: PT and aPTT are normal (PT within 5 seconds of upper limit of normal has 92% specificity for TTP-HUS vs DIC) 1
• Hemolysis markers: Schistocytes present, elevated LDH, elevated indirect bilirubin, low haptoglobin 1, 7
• Renal involvement: More prominent in HUS; variable in TTP 8
• Neurologic symptoms: More common in TTP (confusion, focal deficits, seizures) 8
• D-dimer and fibrinogen: Normal or mildly elevated D-dimer, normal fibrinogen 7

Pathophysiologic Distinction:

• TTP: Deficiency of ADAMTS13 protease (acquired or congenital) 8, 7
• HUS: Often associated with Shiga toxin-producing E. coli or complement dysregulation 7

Immune Thrombocytopenic Purpura (ITP)

Key Distinguishing Features:

• Platelet count: Variable, can be severe
• Coagulation studies: PT, aPTT, fibrinogen all normal
• Hemolysis markers: Absent—no schistocytes, normal LDH, normal bilirubin
• Clinical context: Isolated thrombocytopenia without systemic illness, no organ dysfunction
• Bleeding manifestations: Petechiae, purpura, mucosal bleeding proportionate to platelet count

Critical Distinction: ITP is a diagnosis of exclusion with isolated thrombocytopenia and no evidence of microangiopathic hemolytic anemia, coagulopathy, or thrombosis.

Disseminated Intravascular Coagulation (DIC)

Key Distinguishing Features:

• Platelet count: Variable thrombocytopenia, but typically not as profound as TTP/HUS 1
• Coagulation studies: Prolonged PT and aPTT, elevated D-dimer (often >5 μg/mL), low or normal fibrinogen 9, 1
• Hemolysis markers: Schistocytes may be present but less prominent than TTP/HUS 7
• Clinical context: Underlying trigger (sepsis, malignancy, trauma, obstetric complications) 9
• Bleeding tendency: Prominent due to consumption of clotting factors 7

Pathophysiologic Distinction:

• DIC involves activation of all coagulation, fibrinolysis, and platelet systems 7
• Hyperfibrinolysis observed in most DIC patients 7
• Chronic DIC (compensated): Normal or near-normal PT/aPTT with elevated D-dimer and normal fibrinogen 9

Practical Differentiation Matrix

When PT is Normal:

• Profound thrombocytopenia (<20 × 10⁹/L) + schistocytes → TTP/HUS 1
• Moderate thrombocytopenia (30-70 × 10⁹/L) + heparin exposure + thrombosis → HIT 2, 1
• Isolated thrombocytopenia, no hemolysis, no thrombosis → ITP

When PT is Prolonged:

• Elevated D-dimer + low/normal fibrinogen + underlying trigger → DIC 9, 1
• If PT prolonged >5 seconds beyond upper limit of normal, DIC is more likely than TTP-HUS 1

Critical Pitfalls to Avoid

Do not delay treatment for HIT while awaiting laboratory confirmation—if 4T score ≥4, immediately stop heparin and start alternative anticoagulation (argatroban, bivalirudin, fondaparinux) 2, 5, 10

Do not confuse chronic compensated DIC with TTP/HUS—chronic DIC may have normal PT/aPTT with only elevated D-dimer and normal fibrinogen, mimicking TTP/HUS, but reticulocyte count is typically normal in chronic DIC versus elevated in TTP/HUS 9

Do not start warfarin in acute HIT without bridging anticoagulation—this increases risk of venous limb gangrene 4, 3

In HIT, up to 25% of patients develop thrombosis before thrombocytopenia develops, so maintain high clinical suspicion in heparin-exposed patients with new thrombosis even if platelet count is normal 4

Bleeding is rare in HIT despite thrombocytopenia—if significant bleeding is present, consider alternative diagnoses like DIC or TTP/HUS 2, 4