What is heparin-induced thrombocytopenia (HIT), its signs and symptoms, diagnosis, and management in a cardiovascular intensive care unit (CVICU) setting?

Heparin-Induced Thrombocytopenia (HIT) in the CVICU

Definition

Heparin-induced thrombocytopenia (HIT) is a life-threatening immune-mediated prothrombotic disorder caused by IgG antibodies against platelet factor 4 (PF4)/heparin complexes, characterized by thrombocytopenia and paradoxical thrombosis despite low platelet counts. 1

HIT is distinct from benign Type I heparin-associated thrombocytopenia, which is non-immune, occurs early, and resolves despite continued heparin therapy. 1

Relevant Anatomy and Physiology

Platelet Factor 4 and Immune Complex Formation

• Platelet factor 4 (PF4) is a positively charged protein released from platelet alpha-granules that normally neutralizes heparin. 2
• When heparin binds to PF4, it forms multimolecular complexes that undergo conformational changes, creating immunogenic epitopes. 2
• A minimum of 12-14 saccharides (molecular weight >4000 Da) are required to form antigenic PF4/heparin complexes, explaining why unfractionated heparin (UFH) carries 10-fold higher risk than low molecular weight heparin (LMWH). 3, 2

Cellular Activation Cascade

• IgG antibodies develop against PF4/heparin complexes, typically 5-10 days after heparin exposure (or earlier with recent prior exposure within 30-100 days). 2
• Immune complexes bind to platelet Fcγ receptor IIA, triggering massive platelet activation and aggregation. 2, 4
• Activated platelets release procoagulant microparticles that amplify the coagulation cascade. 2
• Multi-cellular activation involves endothelial cells, neutrophils, and monocytes expressing tissue factor, contributing to explosive thrombin generation and hypercoagulability. 1

Etiology and Pathophysiology

Mechanism of Thrombocytopenia

• Thrombocytopenia results from two processes: massive platelet consumption in developing thrombi and clearance of antibody-coated platelets by the mononuclear phagocyte system. 2
• Despite the name, platelet counts often remain above 50,000/mm³, with typical decrease of ≥50% from baseline rather than absolute severe thrombocytopenia. 2, 5

Thrombotic Complications

• The hallmark of HIT is paradoxical thrombosis despite thrombocytopenia. 1
• Venous thrombosis (DVT, PE, cerebral vein thrombosis) occurs in 17-55% of untreated patients. 2
• Arterial thrombosis (limb ischemia, stroke, myocardial infarction, mesenteric thrombosis) occurs in 3-10% of cases. 2, 6
• Skin necrosis, gangrene requiring amputation, and death can occur. 6

Risk Factors

• Unfractionated heparin (UFH) carries 10-fold higher risk than LMWH. 3, 2
• Women have approximately twice the risk compared to men. 3, 2
• Cardiac surgery patients receiving UFH have the highest risk (1-5%). 3
• Prophylactic UFH in surgery or renal replacement therapy carries >1% risk. 1
• Curative UFH treatment in any setting carries >1% risk. 1

Signs & Symptoms

Thrombocytopenia Pattern

• Platelet count fall >50% from baseline is the cardinal feature, even if absolute count remains >100,000/mm³. 1
• Platelet count typically begins dropping 5-10 days after heparin initiation (typical-onset HIT). 1, 5
• Rapid-onset HIT occurs within 24 hours in patients with heparin exposure in the previous 5-30 days due to preformed antibodies. 1, 5
• Delayed-onset HIT can occur days to weeks after heparin discontinuation. 6, 5

Thrombotic Manifestations

• New venous thromboembolism (DVT, PE) is the most common presentation. 2
• Arterial thrombosis: limb ischemia, stroke, myocardial infarction. 2, 6
• Skin lesions at heparin injection sites (erythematous plaques or necrosis). 1
• Acute systemic reactions after IV heparin bolus (fever, chills, dyspnea, chest pain, hypotension). 1
• Adrenal hemorrhage with acute adrenal insufficiency. 6

Severe Presentations

• Disseminated intravascular coagulation (DIC) with microvascular thrombosis occurs with very high antibody levels. 5
• Venous limb gangrene can occur if warfarin is started before platelet recovery. 3

Typical CVICU Presentation

High-Risk CVICU Scenarios

• Post-cardiac surgery patients receiving UFH for cardiopulmonary bypass have the highest HIT risk (1-5%). 3
• Patients on continuous renal replacement therapy with UFH anticoagulation. 1
• Post-operative thrombocytopenia developing 5-10 days after surgery in patients receiving UFH prophylaxis. 1
• Patients with intra-aortic balloon pumps or extracorporeal circuits causing consumption thrombocytopenia that can mask HIT. 3

Biphasic Platelet Pattern in Cardiac Surgery

• In post-cardiac surgery patients, a "biphasic" platelet count evolution is equivalent to a high-probability 4T score. 1
• Initial expected post-operative drop followed by recovery, then a second unexpected drop 5-10 days post-surgery. 1

Diagnostic Challenges in CVICU

• Multiple competing causes of thrombocytopenia: sepsis, DIC, massive transfusion, hemodilution, extracorporeal circuits. 1, 3
• Post-operative bleeding risk makes anticoagulation decisions particularly challenging. 1
• Antiphospholipid syndrome can mimic HIT with both thrombocytopenia and thrombosis. 3

Diagnosis & Evaluation

Clinical Probability Assessment: The 4Ts Score

Calculate the 4Ts score immediately when thrombocytopenia develops in any heparinized patient. 1, 3, 7

4Ts Scoring System 1

Thrombocytopenia (T1):

• 2 points: Platelet fall >50% AND nadir ≥20 × 10⁹/L
• 1 point: Platelet fall 30-50% OR nadir 10-19 × 10⁹/L
• 0 points: Platelet fall <30% OR nadir <10 × 10⁹/L

Timing of platelet fall (T2):

• 2 points: Day 5-10 after heparin start OR ≤1 day with heparin exposure in previous 5-30 days
• 1 point: >10 days OR timing unclear OR ≤1 day with heparin exposure in previous 30-100 days
• 0 points: <4 days without recent heparin exposure

Thrombosis or other sequelae (T3):

• 2 points: New thrombosis, skin necrosis, or acute systemic reaction after IV heparin bolus
• 1 point: Progressive or recurrent thrombosis, erythematous skin lesions, suspected thrombosis
• 0 points: None

Other causes of thrombocytopenia (T4):

• 2 points: No other evident cause
• 1 point: Possible other cause
• 0 points: Definite other cause

Score Interpretation:

• 0-3 points: Low probability (<1% risk of HIT)
• 4-5 points: Intermediate probability (10-30% risk)
• 6-8 points: High probability (>80% risk)

Laboratory Testing

Immunological Assays

• Order anti-PF4 antibody testing immediately for intermediate or high 4Ts scores. 1
• ELISA or chemiluminescent tests detect IgG, IgM, IgA antibodies against PF4/heparin complexes. 1
• Excellent negative predictive value (>99%) - negative test essentially rules out HIT. 1
• Specificity improves when testing specifically for IgG antibodies and reporting quantitative results (optical density). 1
• Common pitfall: Anti-PF4 antibodies are present in nearly 50% of post-cardiac surgery patients without HIT, limiting positive predictive value. 1

Functional Assays

• Serotonin release assay (SRA) or heparin-induced platelet activation (HIPA) assay detect platelet-activating antibodies. 1
• Higher specificity than immunoassays but less widely available and take longer. 1
• Confirm positive immunoassays when clinical probability is low-intermediate. 1

Baseline Laboratory Tests

• Immediately check: PT, aPTT, fibrinogen, D-dimers to evaluate for DIC. 1
• Examine blood smear to exclude pseudothrombocytopenia from EDTA-induced platelet clumping. 1
• Repeat platelet count in citrate tube if EDTA pseudothrombocytopenia suspected. 1

Imaging Studies

• Perform bilateral lower extremity Doppler ultrasound in all suspected HIT cases to screen for asymptomatic DVT. 1
• Upper extremity ultrasound if central venous catheters present. 1
• CT angiography for suspected PE. 1

Critical Diagnostic Principle

Never delay stopping heparin and starting alternative anticoagulation while awaiting laboratory confirmation. 1

Interventions/Treatments: Medical and Nursing Management

Immediate Actions for Suspected HIT

Stop ALL heparin immediately (including heparin flushes, heparin-coated catheters, LMWH) when 4Ts score is ≥4. 1, 3, 6

Initiate therapeutic-dose alternative anticoagulation immediately, even without confirmed thrombosis. 1, 3

Alternative Anticoagulants for Acute HIT

First-Line Options Based on Organ Function 1, 3

Normal renal and hepatic function:

• Argatroban (direct thrombin inhibitor)
• Bivalirudin (direct thrombin inhibitor)
• Fondaparinux (factor Xa inhibitor)
• DOACs (rivaroxaban, apixaban) - increasingly used off-label

Severe renal impairment (CrCl <30 mL/min):

• Argatroban is the only recommended agent 3

Severe hepatic impairment (Child-Pugh C):

• Argatroban is contraindicated 3
• Consider bivalirudin or fondaparinux

Argatroban Dosing and Monitoring 3

• Initial dose: 2 mcg/kg/min IV infusion (reduce to 0.5-1.2 mcg/kg/min in hepatic impairment or post-cardiac surgery)
• Target aPTT 1.5-3 times baseline
• Check aPTT 2 hours after initiation or dose adjustment
• Common pitfall: Argatroban prolongs INR, complicating transition to warfarin

Bivalirudin

• Initial dose: 0.15-0.2 mg/kg/h IV infusion
• Monitor aPTT (target 1.5-2.5 times baseline)
• Requires dose reduction in renal impairment

Fondaparinux

• Dose based on weight: <50 kg: 5 mg SC daily; 50-100 kg: 7.5 mg SC daily; >100 kg: 10 mg SC daily
• No monitoring required
• Contraindicated if CrCl <30 mL/min

Direct Oral Anticoagulants (DOACs) 8

• Increasingly used off-label for acute HIT due to ease of administration and cost-effectiveness
• Rivaroxaban 15 mg PO twice daily for 21 days, then 20 mg daily
• Apixaban 10 mg PO twice daily for 7 days, then 5 mg twice daily
• Only use when platelet count >50,000/mm³ to minimize bleeding risk
• Avoid if severe renal impairment

Warfarin Management

Do NOT initiate warfarin until:

• Platelet count recovers to >150 × 10⁹/L 3
• Patient is therapeutically anticoagulated with alternative agent for at least 5 days 1

If patient already on warfarin when HIT diagnosed:

• Administer vitamin K to reverse warfarin 5
• Start alternative anticoagulant immediately

Rationale: Early warfarin causes protein C depletion before protein S and factors II, IX, X, leading to transient hypercoagulability and venous limb gangrene. 3

Duration of Anticoagulation

• Isolated HIT (no thrombosis): Anticoagulate for minimum 4 weeks 1
• HIT with thrombosis: Anticoagulate for 3-6 months (treat as standard VTE) 1

Platelet Transfusions

Avoid platelet transfusions in HIT unless life-threatening bleeding. 1

• Platelet transfusions can worsen thrombosis by providing substrate for antibody-mediated activation. 1

Immediate Nursing Priorities

Medication Safety

• Remove ALL heparin products from patient's medication administration record immediately. 6
• Check all IV flushes - replace heparin flushes with normal saline. 6
• Remove heparin-coated central venous catheters if feasible. 1
• Critical error prevention: Carefully examine all vials to avoid confusion between heparin concentrations and catheter lock flush products. 6

Monitoring

• Platelet count monitoring:

  • Daily platelet counts until recovery to >150 × 10⁹/L 1
  • Continue monitoring for 2 weeks after heparin discontinuation (delayed HIT risk) 6

• Anticoagulation monitoring:

  • aPTT every 2 hours initially when using argatroban or bivalirudin until stable 3
  • Daily aPTT once therapeutic range achieved
  • No monitoring required for fondaparinux or DOACs

• Bleeding assessment:

  • Monitor for signs of hemorrhage (unexplained hypotension, tachycardia, falling hematocrit, occult blood) 6
  • Neurological checks if intracranial hemorrhage risk

Thrombosis Surveillance

• Daily assessment for new thrombotic symptoms: leg swelling/pain, chest pain, dyspnea, neurological changes, limb ischemia. 1
• Measure bilateral leg circumferences daily. 1
• Assess peripheral pulses and skin perfusion. 1

Patient/Family Education

• Explain HIT diagnosis and lifelong heparin avoidance. 1
• Provide written documentation of HIT diagnosis for future medical care. 1
• Ensure medical alert bracelet/card documenting heparin allergy. 1

Potential Complications

Thrombotic Complications

• 30-50% of untreated HIT patients develop thrombosis within 30 days. 3
• Venous thromboembolism (DVT, PE) is most common. 2
• Limb-threatening arterial thrombosis requiring amputation. 6
• Stroke, myocardial infarction, mesenteric ischemia. 2, 6

Hemorrhagic Complications

• Alternative anticoagulants carry considerable bleeding risk, especially in thrombocytopenic patients. 4
• Adrenal hemorrhage with acute adrenal insufficiency. 6
• Retroperitoneal hemorrhage, ovarian hemorrhage. 6
• Intracranial hemorrhage. 6

Warfarin-Related Complications

• Venous limb gangrene from early warfarin initiation before platelet recovery. 3
• Skin necrosis from protein C depletion. 3

Delayed Complications

• Delayed-onset HIT occurring days to weeks after heparin discontinuation. 6, 5
• Recurrent HIT with re-exposure to heparin. 1

Relevant Red Flags & CVICU Tips

Red Flags Requiring Immediate Action

• Platelet count drop >50% from baseline in any heparinized patient. 1, 7
• New thrombosis in a patient receiving heparin with any degree of thrombocytopenia. 1
• Skin necrosis at heparin injection sites. 1
• Acute systemic reaction (fever, chills, dyspnea, hypotension) within 30 minutes of IV heparin bolus. 1
• Unexplained fall in hematocrit or blood pressure in heparinized patient. 6

CVICU-Specific Tips

Post-Cardiac Surgery Patients:

• Look for biphasic platelet pattern - initial expected drop, recovery, then second unexpected drop. 1
• 4Ts score is less reliable; biphasic pattern is more specific. 1
• Anti-PF4 antibodies are present in 50% post-cardiac surgery without HIT - interpret positive immunoassays cautiously. 1

Renal Replacement Therapy:

• Argatroban is the preferred alternative anticoagulant for CRRT in HIT patients with renal failure. 3
• Regional citrate anticoagulation is an alternative for CRRT. 1

Extracorporeal Circuits:

• Consumption thrombocytopenia from circuits can mask HIT. 3
• Consider HIT if thrombocytopenia persists beyond expected timeframe. 3

Common Pitfalls to Avoid

Diagnostic Pitfalls:

• Do NOT use gestalt approach - always calculate 4Ts score. 1
• Do NOT order HIT testing in low-probability patients (4Ts 0-3) - wastes resources and leads to false positives. 1
• Do NOT assume thrombocytopenia is from other causes in ICU patients without calculating 4Ts score. 1
• Do NOT wait for laboratory confirmation before stopping heparin and starting alternative anticoagulation. 1

Treatment Pitfalls:

• Do NOT use prophylactic doses of alternative anticoagulants - therapeutic doses are mandatory even without documented thrombosis. 3
• Do NOT start warfarin before platelet count >150,000/mm³. 3
• Do NOT give platelet transfusions unless life-threatening bleeding. 1
• Do NOT use LMWH as alternative anticoagulant - high cross-reactivity with HIT antibodies. 1
• Do NOT overlook heparin flushes and heparin-coated catheters as ongoing heparin sources. 6

Monitoring Pitfalls:

• Do NOT stop platelet monitoring after heparin discontinuation - delayed HIT can occur. 6
• Do NOT assume negative anti-PF4 antibody rules out HIT if tested too early (<5 days of heparin exposure). 1

Special Situations in CVICU

Urgent Cardiac Surgery in Patient with HIT History:

• Bivalirudin is preferred for cardiopulmonary bypass anticoagulation. 1
• If bivalirudin unavailable and HIT antibodies negative (>100 days since acute HIT), UFH can be used intraoperatively only with immediate post-operative alternative anticoagulant. 1

Percutaneous Cardiovascular Intervention:

• Bivalirudin is preferred anticoagulant for PCI in acute or recent HIT. 1

Massive Bleeding on Alternative Anticoagulant:

• No specific reversal agents for argatroban or bivalirudin. 3
• Supportive care with blood products. 3
• Consider recombinant factor VIIa in life-threatening hemorrhage (off-label). 3

Expected Course and Prognostic Clues

Typical Clinical Course

Acute Phase (Days 0-7 after diagnosis):

• Platelet count typically begins recovering 1-3 days after heparin discontinuation and alternative anticoagulation initiation. 8
• Platelet count usually normalizes within 4-10 days. 8
• Thrombosis risk remains elevated during acute phase despite rising platelet count. 8

Subacute Phase A (Platelet recovery but antibodies still present):

• Platelet count >150 × 10⁹/L but immunoassay still positive. 8
• Transition to warfarin or continue DOAC. 8
• Lower thrombosis risk than acute phase. 8

Subacute Phase B (Platelet recovery and antibodies cleared):

• Platelet count >150 × 10⁹/L and immunoassay negative. 8
• Continue anticoagulation for appropriate duration based on thrombosis presence. 8
• Very low thrombosis risk. 8

Remote Phase (>100 days after acute HIT):

• HIT antibodies typically disappear within weeks to months. 2
• Heparin can potentially be used for brief procedures if antibodies confirmed negative, though avoidance is preferred. 1

Prognostic Factors

Good Prognosis:

• Early recognition and prompt heparin discontinuation with alternative anticoagulation. 1
• Isolated HIT without thrombosis. 1
• Rapid platelet recovery (within 5-7 days). 8

Poor Prognosis:

• Delayed diagnosis with continued heparin exposure. 1
• Mortality rate 10-20% in HIT with thrombosis if untreated. 7
• Severe thrombocytopenia (platelet nadir <20 × 10⁹/L) associated with DIC and worse outcomes. 5
• Bilateral lower extremity DVT or extensive thrombosis. 1
• Limb gangrene requiring amputation. 6
• Development of venous limb gangrene from early warfarin use. 3

Long-Term Considerations

• Lifelong heparin avoidance is mandatory. 1
• Document HIT diagnosis prominently in medical record. 1
• Provide patient with written documentation and medical alert identification. 1
• For future surgeries, use alternative anticoagulants (bivalirudin, fondaparinux). 1
• Recurrent HIT can occur with heparin re-exposure even years later. 1