• Overall incidence: varies significantly depending on the type of heparin and patient population
  • Unfractionated heparin (UFH): 1–5% develop HIT antibodies; clinically significant HIT in 1–3% ^[1][2]
  • Low-molecular-weight heparin (LMWH): < 0.1–1% — substantially lower risk because LMWH binds PF4 less avidly (shorter chains form smaller complexes that are less immunogenic)
  • Fondaparinux (synthetic pentasaccharide): extremely rare (too small to form multimolecular complexes with PF4)

In Hong Kong, both UFH and LMWH (particularly enoxaparin) are widely used:

• UFH: commonly administered in CCU/ICU settings for acute coronary syndromes, cardiopulmonary bypass, and haemodialysis circuits
• LMWH: the standard for VTE prophylaxis and treatment in surgical and medical wards
• HIT incidence in the Chinese population appears similar to Western cohorts, although some data suggest slightly lower rates, possibly reflecting genetic variation in FcγRIIa polymorphisms
• Awareness is critical because Hong Kong has a high volume of cardiac surgeries (particularly at Queen Mary Hospital and Grantham Hospital) where post-cardiopulmonary bypass HIT is a recognised complication

• Small anucleate cell fragments derived from megakaryocytes in bone marrow
• Normal count: 150–400 × 10⁹/L
• Lifespan: ~7–10 days
• Contain α-granules (which store platelet factor 4 / PF4, vWF, fibrinogen, thrombospondin, PDGF) and dense (δ) granules (ADP, serotonin, calcium)
• Surface receptors include:
  • FcγRIIa (CD32): the only Fc receptor on platelets — this is the receptor that HIT antibodies use to activate platelets
  • GPIb/IX/V complex: for adhesion (binds vWF)
  • GPIIb/IIIa: for aggregation (binds fibrinogen)

• A small, positively charged (cationic) chemokine stored in platelet α-granules
• Released upon platelet activation
• Normal function: PF4 neutralises heparan sulphate (a natural anticoagulant on endothelial surfaces) → promotes local coagulation at sites of vascular injury
• PF4 has a very high affinity for heparin because heparin is strongly negatively charged (anionic) → PF4 binds heparin in a charge-dependent manner

• A highly sulphated, negatively charged glycosaminoglycan (GAG)
• Mechanism of anticoagulant action: binds antithrombin III (AT-III) via a specific pentasaccharide sequence → conformational change in AT-III → 1000-fold acceleration of AT-III's ability to inactivate thrombin (factor IIa) and factor Xa
• UFH: large heterogeneous molecules (MW 5,000–30,000 Da) — can form large multimolecular complexes with PF4
• LMWH: smaller molecules (MW 2,000–9,000 Da) — form smaller, less immunogenic complexes with PF4
• Fondaparinux: synthetic pentasaccharide (MW ~1,700 Da) — too small to bridge PF4 into multimolecular complexes

This is a classic exam question. In most thrombocytopenic conditions, you worry about bleeding. In HIT, you worry about clotting. Why?

• In ITP, platelets are passively destroyed by antibodies → they don't get activated → no prothrombotic state
• In HIT, the antibody-PF4-heparin immune complex ACTIVATES platelets (via FcγRIIa) before they are consumed → the activation process generates enormous amounts of thrombin → the platelets are "used up" in forming clots, not simply destroyed
• Additionally, monocyte tissue factor expression and endothelial injury contribute to the hypercoagulable state independently of platelet count

• Patients who have been exposed to heparin within the preceding 1–3 months may have pre-formed circulating anti-PF4/heparin antibodies
• On re-exposure to heparin, these antibodies can immediately bind to newly formed heparin-PF4 complexes → rapid-onset HIT within hours (< 24 hours) rather than the typical 5–14 days ^[2]

• Rarely, HIT can present days to weeks after heparin cessation
• The antibodies persist and can activate platelets even with minimal ongoing PF4-heparin complex formation
• This is an important diagnostic pitfall — always consider HIT even after heparin has been stopped

• A rare variant where anti-PF4 antibodies activate platelets independently of heparin (i.e., they bind PF4 alone without requiring heparin as a co-factor)
• Can present without any heparin exposure or persist after heparin cessation
• Clinically resembles severe HIT with very low platelet counts and extensive thrombosis
• Important to recognise as it will not respond to simply stopping heparin — requires immunosuppression and alternative anticoagulation

This is the most clinically important classification ^[1][2]:

• Isolated HIT (thrombocytopenia without thrombosis): ~50% of cases — but these patients remain at very high risk of subsequent thrombosis (up to 50% within 30 days if untreated) → still requires therapeutic anticoagulation
• HITT (HIT with thrombosis): ~50% of cases at diagnosis
  • Venous: DVT, PE, cerebral venous sinus thrombosis, adrenal vein thrombosis (→ adrenal haemorrhagic infarction)
  • Arterial: stroke, acute limb ischaemia, MI, mesenteric ischaemia
  • Skin necrosis at heparin injection sites

• Typical-onset HIT: Day 5–14 after starting heparin (most common)
• Rapid-onset HIT: < 24 hours (prior heparin exposure within 1–3 months)
• Delayed-onset HIT: Days to weeks after heparin cessation (rare but important)

Clinical Vignette (High Yield for Exams) A 65-year-old woman is 7 days post-total hip replacement. She has been on subcutaneous UFH for DVT prophylaxis since surgery. Routine bloods show a platelet count of 80 × 10⁹/L (pre-operative baseline was 250 × 10⁹/L — a > 50% drop). She develops sudden onset right leg swelling and pain. Duplex ultrasound confirms extensive iliofemoral DVT.

This is classic HIT: surgical patient, UFH, day 5–14 onset, > 50% platelet drop, new thrombosis.

1. The platelet count in HIT rarely drops below 20 × 10⁹/L — if the platelet count is < 10–15 × 10⁹/L, consider other diagnoses (ITP, TTP/HUS, DIC, drug-induced thrombocytopenia from other drugs) ^[2]

2. The relative drop in platelet count is more important than the absolute nadir — a patient whose platelets drop from 400 to 150 × 10⁹/L (> 50% drop) may still have HIT even though the count is technically "normal"

3. "White clot syndrome": HIT thrombi are classically described as platelet-rich "white clots" (as opposed to the fibrin-rich "red clots" of typical venous thrombosis) — this reflects the pathogenesis of platelet activation and aggregation

4. Heparin flushes count! — Even small amounts of heparin used to flush IV lines or coat arterial line transducers can trigger or perpetuate HIT. All sources of heparin must be eliminated ^[2]

5. Heparin-coated devices (e.g., heparin-bonded catheters, cardiopulmonary bypass circuits) can also trigger HIT

Why it mimics HIT: It is literally heparin-associated thrombocytopenia, occurring on heparin. The critical distinguishing feature is the timing (early, days 1–4 vs. 5–14) and severity (mild vs. > 50% drop). HIT Type I is benign and self-limiting — the platelet count recovers even with continued heparin.

Why it happens: Heparin can directly interact with platelet surfaces at high concentrations, causing a mild, transient, non-immune-mediated aggregation. No antibody is involved, so there is no prothrombotic consequence.

From GC 027 lecture ^[4]: ITP is acquired immune-mediated thrombocytopenia — diagnosis of exclusion

Why it can be confused with HIT: Both cause isolated thrombocytopenia with relatively preserved other blood counts. A hospitalised patient on heparin who develops ITP could be misdiagnosed as HIT.

Key distinguishing point: ITP causes bleeding (platelet-type mucocutaneous), while HIT causes thrombosis. ITP platelets can drop to single digits; HIT platelets rarely < 20 × 10⁹/L. ITP has no temporal relationship to heparin initiation. In ITP, the platelet count remains fairly constant in the absence of therapy, in contrast to drug-induced thrombocytopenia which fluctuates with intermittent drug exposure ^[10].

From senior notes ^[1]: Drug-induced thrombocytopenia pathogenesis: IgG antibodies recognise a neo-epitope created by binding of drugs to platelet glycoprotein → form immune complex which binds to platelet Fc receptor

Why it can be confused: Any drug-induced thrombocytopenia in a hospitalised patient receiving multiple medications could overlap temporally with heparin initiation. The key is that non-heparin DITP causes platelet destruction (bleeding risk), not activation (thrombosis risk).

From the lecture ^[8]: DIC: excessive activation of coagulation cascade → (1) too much fibrin → clots block blood vessels, (2) excessive consumption of coagulation factors → bleeding tendency, (3) excess fibrin clots trap and overconsume platelets → thrombocytopenia, (4) fibrin strands shear RBCs → MAHA

Why it's the most important differential: DIC and HIT can coexist in critically ill patients (e.g., a septic post-surgical patient on heparin). Both cause thrombocytopenia with possible thrombotic events. The key differentiator is the clotting profile: DIC causes a "full-house" coagulopathy (↑PT, ↑APTT, ↓fibrinogen, ↑D-dimer, schistocytes on PBS) ^[11], while HIT has a normal clotting profile because the coagulation cascade factors are not consumed — the pathology is primarily platelet-driven.

From senior notes ^[13]: TTP: thrombotic microangiopathy caused by severely reduced activity of ADAMTS13 (vWF-cleaving protease) → characterised by small-vessel platelet-rich thrombi → thrombocytopenia, MAHA, and widespread multiorgan thrombosis

Why it can be confused with HIT: Both cause thrombocytopenia with thrombotic events. However, TTP causes microvascular thrombosis (microangiopathy with MAHA — schistocytes, organ ischaemia) while HIT causes predominantly macrovascular thrombosis (DVT, PE, large vessel arterial occlusion). The presence of MAHA features (schistocytes, elevated LDH, low haptoglobin) strongly favours TTP over HIT.

Why it can be confused: Both cause thrombocytopenia with thrombotic events. HUS has prominent renal failure with MAHA, which is absent in HIT.

Why it's critical to distinguish: Septic patients are frequently on heparin for DVT prophylaxis. Their platelet count may drop from sepsis itself, from DIC, or from HIT — or from a combination. The temporal relationship to heparin and the clotting profile are the key discriminators. Sepsis-induced thrombocytopenia usually has an identifiable infectious source and abnormal coagulation parameters.

Why mentioned: Hospitalised patients with chronic liver disease (common in HK — hepatitis B) may be on heparin for various indications. Their thrombocytopenia may be from hypersplenism rather than HIT.

Why mentioned: The timing overlaps with HIT. However, PTP is associated with transfusion (not heparin), causes more severe thrombocytopenia, and presents with bleeding rather than thrombosis.

From senior notes ^[1][10]: EDTA can cause platelet clumping → falsely low platelet count on automated analyser

Why it's important: This is the first thing to rule out in any patient with an unexpected low platelet count. Peripheral blood smear is required to confirm that thrombocytopenia is not artifactual due to platelet clumping ^[10]. A simple repeat in a citrate tube resolves the issue.

From senior notes ^[7][9]: All causes of bone marrow failure: acute leukaemia, aplastic anaemia, MDS, bone marrow infiltration by neoplastic disease

Why it matters: If the patient has pancytopenia, HIT is very unlikely — look for bone marrow pathology instead. ITP (and by extension HIT) is characterised by isolated thrombocytopenia WITHOUT anaemia or leukopenia ^[7].

Why it can be confused: APS causes thrombocytopenia + thrombosis — the same combination as HIT. However, APS is chronic/recurrent, not acutely related to heparin exposure, and often has a prolonged APTT (paradoxically — "lupus anticoagulant" is a misnomer; it causes thrombosis in vivo despite prolonging the APTT in vitro).

This is the cornerstone of HIT diagnosis. From senior notes ^[1][2]: the 4T scoring system assigns 0, 1, or 2 points for each of 4 components, giving a total score of 0–8.

Scoring interpretation ^[1]:

• 6–8: HIGH probability → start treatment immediately; send anti-PF4/heparin antibody but do NOT wait for result
• 4–5: INTERMEDIATE probability → send anti-PF4/heparin antibody; consider empirical treatment (stop heparin and start alternative anticoagulant) while awaiting result
• ≤ 3: LOW probability → HIT very unlikely (negative predictive value > 99%); look for other causes of thrombocytopenia; can generally continue heparin

The 4T score is excellent for ruling OUT HIT (high NPV when score ≤ 3), but its positive predictive value for intermediate and high scores is moderate (~10–15% for intermediate, ~50–65% for high). This means many patients with 4T scores of 4–5 do NOT actually have HIT — they have other causes of thrombocytopenia. This is why laboratory confirmation is needed.

A practical working definition used in most centres:

HIT is diagnosed when ALL of the following are present:

1. Clinical scenario consistent with HIT (4T score ≥ 4)
2. Positive immunoassay for anti-PF4/heparin antibodies (usually ELISA)
3. ± Positive functional assay (serotonin release assay or heparin-induced platelet activation assay) — considered confirmatory/gold standard
4. Exclusion of other causes of thrombocytopenia

However, in practice, treatment is initiated based on clinical suspicion alone (high 4T score) before lab confirmation returns. You treat first, confirm later.

Remember: up to 50% of HIT patients have thrombosis at diagnosis. Therefore, once HIT is suspected, actively screen for thrombosis even if not clinically apparent:

1. Residual heparin effect on APTT: If the patient is still on heparin when bloods are drawn, the APTT will be elevated from the heparin itself, not from any coagulopathy. From GC 027 ^[4]: Patient on unfractionated heparin: no change in PT, increase in APTT — this is the drug effect, not a pathological finding.

2. False-positive ELISA: Up to 50% of cardiac surgery patients develop anti-PF4/heparin antibodies without clinical HIT. Always interpret the ELISA in the context of the 4T score. A positive ELISA with a low 4T score is almost certainly a false positive.

3. False-negative ELISA: Rarely, HIT antibodies are present but the ELISA is negative (e.g., if the antibody recognises PF4 in a different conformation). If clinical suspicion remains very high despite a negative ELISA, a functional assay should be sent.

4. Timing of testing: Anti-PF4/heparin antibodies are transient — they typically decline over weeks to months. Testing should be done at the time of clinical suspicion, not weeks later (may be falsely negative by then).

5. From the haematology investigations lecture ^[8]: D-dimer is a fibrin degradation product; it is not very specific (cannot rule in) but quite sensitive (can rule out if negative). In HIT, D-dimer may be mildly elevated from thrombosis but will not reach the dramatically high levels seen in DIC.

From senior notes ^[1][2]: STOP heparin and switch to non-heparin anticoagulant

This is the single most important action. It must be absolute — every source of heparin must be eliminated:

Why stopping heparin alone is NOT sufficient: Heparin removal stops new PF4-heparin complex formation, but circulating HIT antibodies persist for weeks. The prothrombotic state (activated platelets, monocyte tissue factor, endothelial injury) continues to generate thrombin. Without therapeutic anticoagulation, up to 50% of patients with isolated HIT develop thrombosis within 30 days after heparin cessation alone.

From senior notes ^[2]: Hold and reverse warfarin: initial phase of warfarin administration can result in depletion of functional protein C ± S → transient hypercoagulable state

This is counterintuitive — warfarin is an anticoagulant, so why would it make things worse?

The mechanism:

• Warfarin inhibits vitamin K epoxide reductase → reduces production of factors II, VII, IX, X (procoagulant) AND Protein C and Protein S (natural anticoagulants)
• Protein C has the shortest half-life (~6 hours) of all vitamin K-dependent factors
• Factor II (prothrombin) has the longest half-life (~60 hours)
• Therefore, in the first few days of warfarin therapy, Protein C drops much faster than procoagulant factors → creating a transient hypercoagulable state
• In the context of HIT's already massively prothrombotic state, this Protein C depletion can precipitate:
  • Warfarin-induced skin necrosis — microvascular thrombosis in subcutaneous venules → purpura fulminans
  • Venous limb gangrene — extensive venous thrombosis of extremities → ischaemic necrosis requiring amputation

From Maksim's notes ^[15]: Warfarin side effects: Skin necrosis (0.02%): local thrombosis due to Protein C/S deficiency

Action: If the patient is already on warfarin when HIT is diagnosed:

1. Stop warfarin immediately
2. Give Vitamin K 10 mg IV to replenish Protein C/S levels and reverse the warfarin effect
3. Warfarin should only be restarted once:
   • Platelets have recovered to ≥ 150 × 10⁹/L ^[2]
   • The patient is stably anticoagulated on an alternative agent
   • Warfarin is started at a LOW dose (e.g., 5 mg/day, not loading doses) and overlapped with the alternative anticoagulant for ≥ 5 days until INR is 2–3 for at least 2 consecutive days

From senior notes ^[2]: Therapeutic anticoagulation to prevent thrombosis → initial regimen by non-heparin/warfarin anticoagulants including parenteral direct thrombin inhibitors (e.g., argatroban, bivalirudin), heparinoid anticoagulants (e.g., danaparoid, fondaparinux — no interaction with PF4), NOACs (e.g., dabigatran, apixaban, edoxaban, rivaroxaban)

Critical point: This is therapeutic-dose anticoagulation, not prophylactic dose. Even patients with isolated HIT (no confirmed thrombosis yet) receive therapeutic anticoagulation because of the very high risk of subsequent thrombosis.

Cross-reactivity concern: Fondaparinux does NOT cross-react with HIT antibodies in vitro (it cannot form complexes with PF4). However, rare case reports of HIT associated with fondaparinux exist — these are exceedingly uncommon and may represent autoimmune HIT rather than true fondaparinux-induced HIT.

In practice: Fondaparinux is widely used as a first-line alternative in stable HIT patients in many centres, including in Hong Kong. Its ease of use (SC once daily, no monitoring) makes it attractive compared to IV DTI infusions.

From senior notes ^[2]: NOACs, e.g., dabigatran, apixaban, edoxaban, rivaroxaban

DOACs are increasingly used in HIT management, with growing evidence supporting their safety and efficacy. ASH 2018 guidelines now recommend DOACs as an acceptable alternative for HIT patients who are haemodynamically stable and do not have a specific contraindication.

Advantages of DOACs in HIT:

• Oral administration → no IV infusion required
• Predictable pharmacokinetics → no routine monitoring needed
• Do not interact with PF4 (completely different target)
• Do not affect INR (unlike argatroban → easier management)
• Some (rivaroxaban, apixaban) can be started without parenteral bridging

Limitations:

• Not suitable for haemodynamically unstable patients (absorption may be unreliable)
• Not suitable for patients who may need urgent surgery (reversal less established for Xa inhibitors; idarucizumab available for dabigatran)
• Renal dose adjustments needed (especially dabigatran — predominantly renally cleared)
• Limited trial-level evidence specific to HIT (mostly observational data and consensus guidelines)

From senior notes ^[5]: TTP: classically described as harmful (precipitate thrombosis) — the same principle applies to HIT

• Why: Platelet transfusion provides more substrate for the HIT antibodies to activate. Fresh donor platelets have PF4 in their α-granules → when circulating HIT antibodies encounter these new platelets, they form more immune complexes → more platelet activation → more thrombin → more thrombosis
• Exception: Platelet transfusion may be considered only if there is life-threatening bleeding (e.g., intracranial haemorrhage) AND the patient is simultaneously receiving therapeutic alternative anticoagulation. This is a rare scenario.

(Already discussed in Step 2 — Protein C depletion → venous limb gangrene / skin necrosis)

• LMWH (enoxaparin, tinzaparin, dalteparin) cross-reacts with HIT antibodies in > 90% of cases (the anti-PF4/heparin IgG recognises PF4 bound to LMWH just as it recognises PF4 bound to UFH)
• LMWH is therefore absolutely contraindicated in HIT
• From senior notes ^[15]: LMWH: lower risk of HIT — but this refers to causing HIT, not treating it. Once HIT has developed, LMWH must be avoided.

• Stopping heparin alone (without alternative anticoagulation) results in thrombosis in up to 50% of patients within 30 days
• The prothrombotic state persists for days to weeks after heparin cessation

• Problem: Cardiopulmonary bypass traditionally requires UFH for circuit anticoagulation. If the patient has active HIT or a recent history of HIT, UFH cannot be used.
• Solution:
  • Active HIT with positive antibodies: Use bivalirudin for intraoperative anticoagulation (short half-life → can be reversed quickly by simply stopping the infusion; no protamine needed)
  • Remote HIT (antibodies now negative, > 100 days since last episode): May cautiously use brief intraoperative UFH for the bypass circuit only, with no pre- or post-operative heparin exposure. This is because HIT antibodies are transient — once they have cleared, short re-exposure is unlikely to trigger recurrence (the ~5-day seroconversion window would need to pass before new antibodies appear)
  • Argatroban: Can also be used for bypass anticoagulation but is less well-studied than bivalirudin in this setting

• Problem: Haemodialysis circuits require anticoagulation to prevent clotting
• Solution:
  • Argatroban is preferred (hepatically cleared → not removed by dialysis; short half-life for periprocedural control)
  • Regional citrate anticoagulation can also be used for the dialysis circuit
  • LMWH is absolutely contraindicated

• Problem: Warfarin is teratogenic; DOACs lack safety data in pregnancy
• Solution:
  • Fondaparinux is the preferred agent (some safety data in pregnancy; does not cross the placenta significantly)
  • Argatroban can be used if parenteral anticoagulation is needed
  • Danaparoid was historically used in pregnancy (category B) but has limited availability

• Rule: Once HIT is confirmed, document it clearly in the medical records as a drug allergy/adverse reaction
• All future heparin exposure is contraindicated unless:
  • HIT antibodies have cleared (confirmed negative SRA or ELISA, typically > 100 days after the episode)
  • Brief intraoperative heparin use for cardiac surgery may be considered by specialists under strict protocol (as described above)
• Patient should carry an alert card documenting HIT history

From senior notes ^[1][2]: Skin necrosis esp at site of heparin injection (classical)

• Pathophysiology: Subcutaneous heparin injection creates a local high concentration of heparin-PF4 complexes at the injection site → local immune activation → microvascular thrombosis in dermal and subcutaneous venules → tissue necrosis
• Presentation: Painful, erythematous, indurated plaque at SC injection site → progresses to central darkening → black eschar → full-thickness necrosis
• Significance: Highly specific for HIT — if you see necrotic skin lesions at heparin injection sites, the diagnosis is virtually certain
• Differential: Must be distinguished from warfarin-induced skin necrosis (see below) — the location at heparin injection sites is the key differentiator

From senior notes ^[2]: Hold and reverse warfarin: initial phase of warfarin administration can result in depletion of functional protein C ± S → transient hypercoagulable state

From Maksim's notes ^[15]: Warfarin side effects: Skin necrosis (0.02%): local thrombosis (∵ protein C/S deficiency)

• Pathophysiology: Warfarin inhibits all vitamin K-dependent factors, but Protein C has the shortest half-life (~6 hours) while procoagulant factors (especially Factor II, half-life ~60 hours) persist much longer. In the first 2–3 days of warfarin therapy, Protein C drops precipitously while procoagulant factors remain → transient hypercoagulable state → microvascular thrombosis in subcutaneous venules of fatty areas (breast, buttocks, thighs, abdomen)
• Why worse in HIT: The baseline prothrombotic state of HIT amplifies this transient hypercoagulable window → catastrophic skin necrosis and venous limb gangrene
• Presentation: Painful erythema → purpura → frank necrosis with black eschar in areas with abundant subcutaneous fat (breast, buttocks, thighs); typically develops 3–6 days after starting warfarin
• Prevention: Do NOT start warfarin during active HIT; only introduce warfarin when platelets ≥ 150 × 10⁹/L and patient is stably anticoagulated on an alternative agent ^[2]

• Pathophysiology: The most extreme form of warfarin-induced skin necrosis in HIT. The combination of (a) HIT-mediated thrombin generation, (b) warfarin-induced Protein C depletion, and (c) supratherapeutic INR → extensive microvascular and macrovascular venous thrombosis of an entire extremity → ischaemic necrosis
• Presentation: Painful, swollen, cyanotic limb (often bilateral lower limbs) → progresses to gangrene → amputation often unavoidable
• Risk factors: Starting warfarin without adequate alternative anticoagulation during active HIT; no overlap with DTI/fondaparinux; high-dose warfarin loading
• Key teaching point: Venous limb gangrene is almost entirely preventable — it occurs when warfarin is inappropriately given during active HIT. This is why understanding the management algorithm is crucial.

• Pathophysiology: As discussed in the management section — transfused platelets carry PF4 in their α-granules → circulating HIT antibodies activate the transfused platelets → more procoagulant microparticle release → more thrombin → worsening thrombosis
• Clinical scenario: A well-intentioned clinician sees low platelets and orders platelet transfusion → paradoxical worsening of the thrombotic state
• Prevention: Do NOT transfuse platelets in HIT except for life-threatening haemorrhage with concurrent therapeutic alternative anticoagulation

• If HIT goes unrecognised and heparin continues, the positive feedback loop (heparin → PF4-heparin complexes → antibody binding → platelet activation → PF4 release → more complexes) escalates
• Consequence: Rapidly worsening thrombocytopenia, progressive thrombosis, multi-organ ischaemia, death
• This is the most common reason for catastrophic outcomes in HIT — delayed diagnosis

• All alternative anticoagulants carry bleeding risk (argatroban, bivalirudin, fondaparinux, DOACs)
• Risk is amplified if:
  • The patient is still moderately thrombocytopenic (platelet ~50–60 × 10⁹/L — low enough to impair primary haemostasis)
  • Post-surgical patients with fresh surgical wounds
  • Over-anticoagulation (e.g., argatroban dose not adjusted for hepatic impairment)
• Monitoring: Regular APTT (for DTIs), clinical vigilance for bleeding signs, and awareness of reversal options (stop infusion for DTIs; idarucizumab for dabigatran; andexanet alfa for Xa inhibitors in some centres)

• Occurs only if platelets drop exceptionally low ( < 20 × 10⁹/L — rare in HIT)
• Occasionally seen in autoimmune HIT where antibodies activate platelets independent of heparin → can cause more profound thrombocytopenia
• Also possible if concurrent DIC develops from extensive thrombosis (consumption of coagulation factors superimposed on HIT)

• Pathophysiology: Extensive DVT damages venous valves → chronic venous insufficiency → venous hypertension in the affected limb
• Presentation: Chronic leg swelling, pain, skin changes (haemosiderin deposition → brown discolouration, lipodermatosclerosis), varicose veins, and in severe cases, venous ulceration
• Incidence: Up to 30–50% of patients with HIT-associated proximal DVT develop PTS
• Prevention: Adequate anticoagulation duration, early mobilisation, compression stockings (though evidence for stockings is debated)

• Pathophysiology: Unresolved organised thrombus in pulmonary arteries → chronic obstruction → increased pulmonary vascular resistance → pulmonary hypertension → right heart failure
• Incidence: ~2–4% of patients after acute PE (not specific to HIT but HIT-PE may be more extensive)
• Presentation: Progressive exertional dyspnoea, exercise intolerance, signs of right heart failure (raised JVP, peripheral oedema, hepatomegaly) months to years after PE
• Diagnosis: V/Q scan (mismatched perfusion defects), right heart catheterisation
• Treatment: Pulmonary endarterectomy (surgical) for operable disease; balloon pulmonary angioplasty or medical therapy (riociguat) for inoperable disease

• Cause: Acute limb ischaemia from arterial thrombosis or venous limb gangrene from warfarin-induced Protein C depletion
• Incidence: Historical data suggest 5–10% amputation rate in patients with unrecognised HIT; modern series with prompt recognition and treatment report lower rates (~2–3%)
• Impact: Major disability, rehabilitation needs, prosthetic fitting

• If bilateral adrenal haemorrhagic infarction occurs, the patient may develop permanent primary adrenal insufficiency (Addison's disease)
• Long-term management: Lifelong glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) replacement
• Stress dosing: Must increase steroid doses during illness, surgery, or physiological stress

• If ischaemic stroke occurs as a complication of HIT, long-term neurological deficits (hemiplegia, aphasia, cognitive impairment) may persist
• Rehabilitation needs are identical to stroke from any other cause

• Once HIT is documented, the patient carries a lifelong label of "heparin allergy"
• Practical consequences:
  • Cannot receive standard VTE prophylaxis with LMWH → must use fondaparinux or DOACs
  • Complicates future cardiac surgery (cardiopulmonary bypass traditionally requires UFH) — requires specialist planning with bivalirudin or delayed re-exposure protocol if antibodies have cleared
  • Complicates haemodialysis (must use citrate or argatroban for circuit anticoagulation)
  • Emergency situations (massive PE, acute coronary syndrome) require modified protocols
• Education: Patient must be counselled about their HIT history, given an alert card, and all future healthcare providers must be informed