How do you differentiate between heparin-induced thrombocytopenia (HIT), hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC)?

Differentiating Between HIT, HUS, TTP, and DIC

The key to differentiating between heparin-induced thrombocytopenia (HIT), hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and disseminated intravascular coagulation (DIC) lies in the clinical presentation, laboratory findings, and specific diagnostic tests, with platelet count and coagulation profiles being the most critical differentiating factors.

Clinical and Laboratory Differentiation

Heparin-Induced Thrombocytopenia (HIT)

• Timing: Typically occurs 5-10 days after heparin exposure (or within 24 hours with recent exposure in past 30-100 days) 1
• Key features:
  • Moderate thrombocytopenia (platelet count rarely <20×10^9/L)
  • Paradoxical thrombosis despite thrombocytopenia
  • Normal coagulation studies (PT, aPTT, fibrinogen)
  • Normal or slightly elevated D-dimers
  • History of heparin exposure is essential
• Diagnostic approach:
  • Apply 4T score to determine pretest probability 2
  • Anti-PF4/heparin antibody testing (immunoassay) for intermediate/high probability cases 1
  • Functional assay (serotonin release assay or HIPA) to confirm diagnosis if immunoassay positive 1

Thrombotic Thrombocytopenic Purpura (TTP)

• Key features:
  • Severe thrombocytopenia (often <20×10^9/L)
  • Microangiopathic hemolytic anemia
  • Neurological symptoms (fluctuating)
  • Fever
  • Renal dysfunction (less prominent than in HUS)
  • Normal PT/INR (critical differentiating feature from DIC) 3
  • ADAMTS13 activity severely decreased (<10%)
• Diagnostic approach:
  • CBC with peripheral smear showing schistocytes
  • LDH markedly elevated
  • Indirect hyperbilirubinemia
  • Negative direct Coombs test
  • ADAMTS13 activity and inhibitor testing

Hemolytic Uremic Syndrome (HUS)

• Key features:
  • Moderate thrombocytopenia (usually not as severe as TTP)
  • Microangiopathic hemolytic anemia
  • Prominent renal failure
  • Often preceded by diarrheal illness (STEC-HUS)
  • Normal PT/INR
  • Normal ADAMTS13 activity
• Diagnostic approach:
  • CBC with peripheral smear showing schistocytes
  • Elevated creatinine and BUN
  • Stool culture for E. coli O157:H7 (in diarrheal HUS)
  • Shiga toxin testing

Disseminated Intravascular Coagulation (DIC)

• Key features:
  • Thrombocytopenia (variable severity)
  • Prolonged PT/INR and aPTT (key differentiating feature) 3
  • Low fibrinogen (unlike other conditions)
  • Markedly elevated D-dimers
  • Associated with underlying condition (sepsis, trauma, malignancy)
• Diagnostic approach:
  • Complete coagulation profile (PT, aPTT, fibrinogen, D-dimer)
  • Peripheral smear for schistocytes (may be present but less prominent)
  • Assess for underlying cause
  • Apply SIC (sepsis-induced coagulopathy) criteria for early detection 1

Critical Differentiating Laboratory Tests

Condition	Platelets	PT/INR	aPTT	Fibrinogen	D-dimer	Specific Tests
HIT	Moderate ↓ (rarely <20×10^9/L)	Normal	Normal	Normal	Normal/↑	Anti-PF4/heparin antibodies
TTP	Severe ↓ (<20×10^9/L)	Normal	Normal	Normal	Normal/↑	ADAMTS13 activity <10%
HUS	Moderate ↓	Normal	Normal	Normal	Normal/↑	Stool STEC testing (if diarrheal)
DIC	Variable ↓	Prolonged	Prolonged	↓↓	↑↑↑	Underlying condition

Diagnostic Algorithm

1. Assess for heparin exposure:

   • If recent heparin exposure AND thrombocytopenia, calculate 4T score 2
   • If 4T score intermediate/high, order anti-PF4/heparin antibody testing 1

2. Evaluate coagulation profile:

   • If PT/INR and aPTT prolonged with low fibrinogen and high D-dimers → suspect DIC 1
   • If normal coagulation tests → proceed to step 3

3. Assess for microangiopathic hemolytic anemia:

   • If schistocytes present on peripheral smear with elevated LDH and indirect bilirubin:
     • If severe thrombocytopenia (<20×10^9/L) and neurological symptoms → suspect TTP 3
     • If prominent renal failure and history of diarrhea → suspect HUS 4

4. Order specific confirmatory tests:

   • For suspected HIT: Functional assay if immunoassay positive 1
   • For suspected TTP: ADAMTS13 activity and inhibitor
   • For suspected HUS: Stool culture and Shiga toxin testing (if diarrheal)
   • For suspected DIC: Serial monitoring of coagulation parameters and treat underlying cause 1

Important Clinical Pitfalls

1. Misdiagnosing HIT: Many patients develop anti-PF4/heparin antibodies without clinical HIT, leading to overdiagnosis. Functional assays help confirm true HIT 5.

2. Confusing DIC with HIT: Both can cause thrombosis and thrombocytopenia, but DIC typically has abnormal coagulation studies while HIT does not 5.

3. Delayed diagnosis of TTP: TTP is 90% fatal without prompt plasma exchange. A platelet count <20×10^9/L with PT within 5 seconds of normal range has 92% specificity for TTP-HUS over DIC 3.

4. Overlooking "shock liver": DIC with cardiogenic or septic shock can cause ischemic limb gangrene with pulses, mimicking HIT 5.

5. Failure to recognize autoimmune HIT variants: Spontaneous HIT can occur without heparin exposure and persistent HIT can continue despite heparin discontinuation 1.

By systematically evaluating clinical presentation, timing, laboratory findings, and specific diagnostic tests, clinicians can accurately differentiate between these potentially life-threatening conditions and initiate appropriate treatment promptly.