What is heparin-induced thrombocytopenia (HIT) syndrome, its risk factors, and treatment options for an adult patient with a history of cardiovascular disease, surgery, or other conditions requiring anticoagulation therapy?

Heparin-Induced Thrombocytopenia (HIT) Syndrome

HIT is a life-threatening immune-mediated disorder where IgG antibodies against platelet factor 4 (PF4)-heparin complexes cause paradoxical thrombosis despite thrombocytopenia, requiring immediate heparin cessation and alternative anticoagulation to prevent death, limb loss, and devastating thrombotic complications. 1

Pathophysiology

The core mechanism involves IgG antibodies recognizing PF4-heparin complexes on platelet surfaces, triggering massive platelet activation, thrombin generation, and release of procoagulant microparticles. 2 This cascade activates not only platelets but also monocytes, neutrophils, and endothelial cells, with tissue factor expression driving the hypercoagulable state. 1

• Thrombocytopenia results from two processes: platelet consumption in developing thrombi and clearance of antibody-coated platelets by the mononuclear phagocyte system. 2
• A minimum of 12-14 saccharides (molecular weight >4000 Da) are required to form the antigenic complex, explaining why unfractionated heparin (UFH) carries 10-fold higher risk than low-molecular-weight heparin (LMWH). 1, 2
• Despite the name, platelet counts often remain above 50,000/mm³, with typical decreases of ≥50% from baseline rather than absolute thrombocytopenia. 2

Clinical Features and Timing

The characteristic platelet count fall occurs 5-10 days after heparin initiation (typical-onset HIT), but three atypical patterns exist that clinicians must recognize. 1

Timing Patterns:

• Typical-onset HIT: Platelet drop 5-10 days post-heparin exposure 1
• Rapid-onset HIT: Abrupt fall within 24 hours in patients with circulating antibodies from recent heparin exposure (within past month, occasionally up to 100 days) 1
• Delayed-onset HIT: Thrombocytopenia occurring up to 3 weeks after heparin cessation 1, 3

Critical Diagnostic Features:

• Thrombocytopenia (platelet count <150 × 10⁹/L) occurs in 85-90% of patients 1
• In 25% of HIT cases, thrombosis precedes thrombocytopenia—do not wait for platelet drop to suspect HIT 1
• Median platelet nadir is approximately 50-60 × 10⁹/L 4

Post-Cardiac Surgery Pitfall:

After cardiopulmonary bypass, platelet counts normally fall by 38% and continue declining for 1-2 postoperative days. 1 Two patterns should trigger HIT suspicion: (1) platelet fall beginning ≥4 days postoperatively (day of surgery = day 0), and (2) thrombocytopenia persisting ≥4 days after surgery. 1

Risk Factors

Unfractionated heparin in cardiac or orthopedic surgery patients represents the highest risk scenario (1-5% incidence), while medical patients on LMWH have substantially lower risk (0.1-1%). 1

Stratified Risk:

• Type of heparin: UFH > LMWH (10-fold difference) > fondaparinux 1, 2
• Patient population: Cardiac/orthopedic surgery (1-5%) > medical/obstetric (0.1-1%) 1
• Gender: Women have approximately twice the risk of men 1, 2
• Duration of exposure: Longer heparin courses increase risk 1

Thrombotic Complications: The True Danger

Venous thrombosis occurs in 17-55% of untreated HIT patients, with arterial thrombosis in 3-10%, making thrombosis—not bleeding—the primary cause of morbidity and mortality. 2

Thrombotic Manifestations:

• Venous: Deep vein thrombosis, pulmonary embolism, cerebral venous thrombosis 3
• Arterial: Limb ischemia, stroke, myocardial infarction 3
• Microvascular: Skin necrosis, venous limb gangrene (especially if warfarin started before platelet recovery) 1
• Mortality: 5-10% death rate; 1-3% amputation rate 1

Diagnostic Approach

Calculate the 4T score immediately when HIT is suspected—this clinical prediction tool guides whether to stop heparin and start alternative anticoagulation before laboratory confirmation. 1

Laboratory Testing Strategy:

Two complementary assay types exist: immunoassays (high sensitivity, lower specificity) and functional assays (lower sensitivity, high specificity). 1

• Immunoassays (PF4/heparin ELISA): Detect anti-PF4/heparin antibodies; positive in many patients who never develop clinical HIT 1
• Functional assays (serotonin release assay, heparin-induced platelet activation): Detect platelet-activating antibodies; most accurate for clinical HIT 1
• Use washed platelets rather than platelet-rich plasma for optimal reliability 1

Phases of HIT (Critical for Management):

The American Society of Hematology 2018 guidelines conceptualize HIT in five sequential phases, each requiring different management: 1

1. Suspected HIT: Clinical suspicion, awaiting laboratory confirmation
2. Acute HIT: Confirmed diagnosis, highly prothrombotic phase until platelet recovery
3. Subacute HIT A: After platelet recovery but functional assay still positive
4. Subacute HIT B: Functional assay negative but immunoassay still positive
5. Remote HIT: All antibodies undetectable

Management: Immediate Actions

When HIT is strongly suspected (intermediate or high 4T score), immediately discontinue ALL heparin products—including heparin flushes and heparin-coated catheters—and start therapeutic-dose non-heparin anticoagulation without waiting for laboratory confirmation. 1, 3

Critical Management Principles:

• Never give platelet transfusions in HIT unless life-threatening bleeding occurs—platelets fuel the thrombotic process 1
• Do not start warfarin until platelet count recovers to >150 × 10⁹/L—starting warfarin during acute HIT causes venous limb gangrene 1, 4
• If patient already on warfarin when HIT diagnosed, give vitamin K to reverse it 4
• Continue non-heparin anticoagulant for minimum 5 days AND until platelet count recovers before transitioning to warfarin 1

Non-Heparin Anticoagulant Options:

The 2018 American Society of Hematology guidelines and 2012 ACCP guidelines recommend direct thrombin inhibitors or factor Xa inhibitors as first-line alternatives. 1

Parenteral Options:

• Argatroban (direct thrombin inhibitor): 0.5-1.2 µg/kg/min IV continuous infusion; adjust to aPTT 1.5-3.0 times baseline 1
• Bivalirudin (direct thrombin inhibitor): 0.15 mg/kg/h IV continuous infusion; adjust to aPTT 1.5-2.5 times baseline 1
• Danaparoid (indirect factor Xa inhibitor): 150 mg SC twice daily until platelet recovery 1
• Fondaparinux (indirect factor Xa inhibitor): 5-10 mg SC once daily (off-label but increasingly used) 1, 4

Oral Options (Increasingly Used Off-Label for Acute HIT):

• Rivaroxaban: 15 mg twice daily 1, 5
• Apixaban: 10 mg twice daily 1, 5
• Dabigatran: 150 mg twice daily 1

Direct oral anticoagulants (DOACs) are increasingly used in appropriate acute HIT cases because they are easier to administer, more cost-effective, and eliminate the need for transition to oral anticoagulation after platelet recovery. 5

Special Clinical Situations

Urgent Cardiac Surgery in HIT Patient:

For patients requiring urgent cardiac surgery with acute or subacute HIT, use bivalirudin as the procedural anticoagulant rather than heparin. 1 If surgery can be delayed 3 months until antibodies clear, UFH can be safely used. 1

Renal Replacement Therapy:

Argatroban is preferred over lepirudin in patients requiring dialysis, as lepirudin is renally cleared and accumulates dangerously. 1

Pregnancy:

Fondaparinux or danaparoid are preferred in pregnant patients with HIT, as direct thrombin inhibitors have limited safety data in pregnancy. 1

Isolated HIT (HIT Without Thrombosis):

Even without thrombosis at presentation, patients with confirmed HIT require therapeutic-dose anticoagulation for minimum 4 weeks because thrombosis risk remains 30-50% without treatment. 1

Common Pitfalls to Avoid

• Do not use aPTT to monitor LMWH—it does not prolong aPTT; use anti-Xa levels instead 6
• Do not assume all thrombocytopenia on heparin is HIT—calculate the 4T score to avoid unnecessary cessation in low-probability cases 1
• Do not restart any heparin product if HIT is confirmed—even LMWH or fondaparinux can cross-react in some patients 6, 3
• Do not stop alternative anticoagulation when platelets recover—continue for minimum 4 weeks total to prevent late thrombosis 1
• Do not overlook HIT in patients presenting with thrombosis weeks after heparin discontinuation—delayed-onset HIT occurs 1, 3

Spontaneous HIT Syndrome

A HIT-mimicking disorder can occur without any heparin exposure, typically after orthopedic surgery (especially total knee arthroplasty) or severe infections, featuring the same platelet-activating anti-PF4 antibodies and thrombotic complications. 7 Treatment includes non-heparin anticoagulation (direct oral factor Xa inhibitors preferred) and high-dose immunoglobulin. 7