Heparin Induced Thrombotic Thrombocytopaenia

Immune-mediated hypercoagulable state due to formation of auto-antibodies to a heparin-platelet complex characterised by:

Presentation 5-14 days after heparin exposure
Key exceptions:
- Major surgery “resets the clock”
  May precipitate HITT after the appropriate interval in a patient receiving long-term heparin.
- Re-commencing heparin in a patient who has been heparin exposed in the preceding 90 days
  Initial exposure leads to antibody formation, which causes rapid onset of HITT when heparin is recommenced.
Thrombocytopenia
- Usually to 30-50% of baseline
- Not <20×10⁹/L
- Occurs over 1-3 days
Thrombosis
- 30%
- May be arterial or venous
- May be in both large and small vessels

Various definitions and classifications are used interchangeably. This definition emphasises Type II HITT, which is the clinically significant form.

Some authorities distinguish between:

Type I, or HIT
Benign condition characterised by:
- Transient, mild thrombocytopaenia
  Platelets >100×10⁹/L.
- 10% of patients who receive heparin
- Resolves following heparin administration
- No thrombosis
- Occurs in first 2 days
- Probably non-immune in origin
Type II, or HITT
Clinically significant thrombocytopaenia with thrombosis.

Epidemiology and Risk Factors

Incidence:

Risk factors:

Highest risk in patients who received UFH for 7-10 days.

Platelet factor 4 protein is expressed on platelet cell surface
This binds heparin and activates lymphocytes and antibodies
Production of an IgG anti-PF4 antibody occurs
Binding of antibody results in:
- Platelet activation
- Platelet factor 4 release
  - Positive feedback
- Removal of IgG-coated platelets by reticuloendothelial system

Key factors:

Laboratory:

Imaging:

Diagnosis is challenging due to multiple potential causes of thrombocytopaenia and common use of heparins.

Risk may be calculated using the 4T score:

4T Score
Category	2 Points	1 Point	0 Points
Magnitude of thrombocytopaenia	↓ By >50% Nadir >20×10⁹/L	↓ By 30-50% Nadir 10-19×10⁹/L	↓ By <30% Nadir <10×10⁹/L
Timing of thrombocytopaenia	5-10 days <1 day following restarting heparin With previous heparin exposure in last 30 days.	>10 days <1 day following restarting heparin With previous heparin exposure in last 100 days.	<4 days
Thrombotic sequelae	Proven thrombosis Skin necrosis Acute systemic reaction following heparin bolus	Progressive thrombosis Recurrent thrombosis Silent thrombosis Erythematous lesions
Other causes of thrombocytopaenia	Non-evident	Possible	Definite

Differentials include:

Diagnostic process:

Calculate 4T score
If intermediate or high
- Cease heparin
- Immunoassay
- If positive, confirm with functional assay
- If strongly positive, commence therapeutic non-heparin anticoagulation

Specific therapy:

Pharmacological
- Cease heparin
  - UFH and LMWH
  - Heparin flushes in arterial lines
  - Heparin bonded:
    - Extracorporeal circuits
    - Lines
    - IDCs
- Transition to a non-heparinoid anticoagulant
  - Direct thrombin-inhibitor
    - Bivalirudin
      If impaired hepatic and renal function.
    - Argatroban
      If normal hepatic function.
  - Factor Xa inhibitor
    - Fondaparinux
  - Vitamin K antagonist
    Only when platelet count is >150×10⁹/L due to risk of worsening thrombosis.
  - DOAC
Procedural
- Plasmapheresis
  - If refractory to medical therapy
  - If requiring heparin/protamine for CPB in patients with previous HITT
Physical

Supportive care:

Recovery:

Platelet count improves usually within ~1/52 after cessation of heparin
May take weeks.
Antibody clearance takes 50-85 days
Future heparin exposure does not guarantee recurrence, but heparin exposure should be minimised in future

Greinacher A. Heparin-Induced Thrombocytopenia. Solomon CG, ed. N Engl J Med. 2015;373(3):252-261. doi:10.1056/NEJMcp1411910
Ivascu NS, Fitzgerald M, Ghadimi K, Patel P, Evans AS, Goeddel LA, et al. Heparin-Induced Thrombocytopenia: A Review for Cardiac Anesthesiologists and Intensivists. Journal of Cardiothoracic and Vascular Anesthesia. 2019 Feb;33(2):511–20.