Heparin-induced thrombocytopenia (HIT)

Two forms of HIT are recognised

Type I HIT (Heparin-associated thrombocytopenia)

• A benign, non-immune form characterised by a mild, transient reduction in platelet count due to the direct effect of heparin on platelet activation. 
• It typically develops within the first 48 hours of therapy, is not associated with thrombosis, and resolves with continued heparin administration.

Type II HIT

• The clinically significant, immune-mediated variant. It is characterised by antibodies to PF4-heparin complexes, leading to platelet activation and extensive thrombin generation. 
• This form is associated with arterial and venous thrombosis, making it a life- and limb-threatening disorder. 
• When thrombosis occurs alongside thrombocytopenia, the condition is termed heparin-induced thrombocytopenia with thrombosis (HITT).

Agents associated with HIT

• Unfractionated heparin (UFH): carries the highest risk.
• Low molecular weight heparin (LMWH): lower risk but still causative.
• Fondaparinux: a synthetic pentasaccharide that binds antithrombin to inhibit factor Xa. It rarely induces HIT due to minimal cross-reactivity with PF4. While isolated cases of fondaparinux-associated HIT have been reported, observational studies support its safe use as a non-heparin anticoagulant.
• HIT occurs in up to 5% of patients exposed to heparin, independent of route, dose, or indication. Mortality has been historically high (around 20%), but with earlier recognition and intervention, rates below 2–10% are now achievable.

Types of thrombocytopenia associated with heparin use

Type I HIT (Heparin-associated thrombocytopenia)

• Non-immune mediated reaction.
• Appears within the first 1–2 days of heparin therapy.
• Results from a direct effect of heparin on platelet activation.
• Platelet count decline is mild, rarely below 100 × 10⁹/L.
• Not associated with thrombosis.
• Platelet counts normalise spontaneously, even if heparin is continued.

Type II HIT

• Immune-mediated, clinically significant variant.
• Caused by IgG antibodies binding to PF4–heparin complexes.
• Antibody–complex interaction cross-links Fc receptors → platelet activation, thrombin generation, and hypercoagulability.
• Typical onset is 5–14 days after heparin exposure.
• Rapid-onset possible within 24 hours if prior exposure occurred within 100 days.
• Delayed-onset may develop days after discontinuation of heparin.
• Associated with both venous and arterial thrombosis (HITT).
• Life- and limb-threatening if untreated.

Mechanistic considerations

• IgG antibodies appear rapidly (median 4 days), without an IgM phase, supporting a secondary immune response.
• Suggested sensitisation from prior environmental exposures, such as bacterial antigens similar to PF4–heparin complexes.
• HIT antibodies typically disappear within ~100 days but can cause recurrent HIT if re-exposure occurs during this period.

Risk factors and exposure settings

Type of heparin

• UFH: highest risk.
• LMWH: lower risk but still significant.

Clinical context

• Prolonged postoperative thromboprophylaxis carries greatest risk.
• Surgical patients (cardiac/orthopaedic) at higher risk than medical patients.

Minimal exposure

• HIT may develop even with heparin flushes or catheter locks.

Dose dependency

• Risk higher with therapeutic heparin compared with prophylactic dosing.

Fondaparinux and HIT

• Synthetic pentasaccharide that inhibits factor Xa via antithrombin.
• Can promote antibody formation but rarely activates platelets.
• Very low risk of inducing HIT.
• Widely used as a safe non-heparin anticoagulant in HIT management.

Platelet factor 4 (PF4) release and binding

• PF4 is stored in platelet alpha granules and released upon activation.
• It binds strongly to heparin, forming PF4–heparin complexes that act as immunogenic neoantigens.

Antibody formation

• Antibodies are typically IgG, though IgA and IgM may occur.
• HIT develops when IgG bound to PF4–heparin complexes cross-links FcγIIA receptors on platelets.
• This induces platelet activation, thrombin release, and additional PF4 secretion, creating a positive feedback loop.

Amplification and persistence

• Activated platelets shed procoagulant microparticles, fuelling thrombin generation.
• Monocytes and endothelial cells are activated, contributing to vascular injury and inflammation.
• Antibodies are generally transient, becoming undetectable within 100 days, but persistence occurs in some patients.

Formation of ultralarge complexes

• Unfractionated heparin and PF4 form ultralarge complexes (>670 kDa) that are highly immunogenic.
• These complexes are less common with LMWH and absent with fondaparinux, explaining the lower associated risk.

Breakdown of immune tolerance

• Healthy individuals have tolerant PF4/heparin-specific B cells.
• Loss of tolerance allows pathogenic antibody production, explaining why not all heparin-exposed patients develop HIT despite common antibody detection.

Alternative mechanisms

• Some antibodies recognise PF4 bound to platelet chondroitin sulfate, activating platelets without heparin.
• This accounts for:
  • Delayed-onset HIT: appearing after heparin discontinuation.
  • Persistent HIT: platelet recovery delayed for weeks.
  • Spontaneous HIT syndrome: mimics HIT but occurs without prior heparin exposure, often post-infection or surgery.
  • Fondaparinux-associated HIT: very rare due to minimal cross-reactivity.

Clinical consequences

• Thrombocytopenia results from macrophage clearance of IgG-coated platelets and platelet aggregation.
• The overriding feature is hypercoagulability, leading to:
  • Venous thromboses such as DVT and pulmonary embolism.
  • Arterial events including myocardial infarction or stroke.
  • Skin necrosis, especially if warfarin is given in the acute phase.
• Thrombotic risk peaks within the first 10 days of heparin therapy but can persist up to 30 days after discontinuation.

Overall prevalence

• Reported prevalence of HIT ranges from 0.1% to 5% among patients exposed to heparin.
• Risk varies according to both patient-related and drug-related factors.
• Highest rates occur in postoperative and trauma patients (1–5%).
• Risk is much lower in medical patients receiving prophylactic heparin (<1%).
• Obstetric patients are rarely affected (<0.1%).

Type of heparin

• Unfractionated heparin (UFH): carries the highest risk.
• Low molecular weight heparin (LMWH): significantly lower risk but not negligible.
• Fondaparinux: synthetic pentasaccharide with negligible risk; does not cross-react with HIT antibodies and is considered safe in patients with a history of HIT.

Exposure and dosing factors

• Risk increases with therapeutic dosing compared with prophylactic dosing.
• Longer duration of therapy increases the likelihood of developing HIT.
• Even minimal exposures (e.g., heparin flushes for line patency) have been reported to trigger HIT in susceptible individuals.

Surgical versus medical patients

• Surgical patients have higher incidence, especially after cardiac and orthopaedic surgery, likely due to increased platelet activation and PF4 release during mechanical trauma.
• Medical patients have comparatively low incidence.

Population data

• In the United States, approximately 12 million patients (about one third of hospitalised individuals) are exposed to heparin annually.
• Risk estimates include:
  • ~0.76% in patients receiving therapeutic intravenous UFH.
  • <0.1% in patients receiving subcutaneous UFH prophylaxis.
  • Overall risk across all heparin-exposed patients: ~0.2%.
• Other studies report frequencies up to 5%, particularly in surgical patients receiving extended thromboprophylaxis (10–14 days).

Morbidity and mortality

• HIT is a severe prothrombotic disorder, with >50% of patients developing new thromboembolic events if untreated.
• Mortality rates historically approached 20–30%, but have declined with earlier recognition and treatment.
• Major morbidity occurs in ~10%, including limb amputation and disabling complications.
• Thrombotic complications may involve venous (DVT, PE) or arterial systems (stroke, MI, limb ischaemia).
• Early severe platelet count falls, particularly in elderly patients, are linked with higher risk of thrombosis.
• Although primarily prothrombotic, patients may still suffer major bleeding when treated with alternative anticoagulants; risk is higher in ICU patients, those with severe thrombocytopenia (<25 × 10⁹/L), or renal dysfunction.

Demographic risk factors

Sex

• Women have a 1.5–2-fold higher risk of HIT compared with men. Among those diagnosed, women are also more likely to progress to thrombotic complications.

Age

• Mean age at diagnosis is ~62 years. Incidence is significantly higher in older adults; two-thirds of cases occur in patients >60 years. HIT is much less common in children and young adults.

Race

• Studies suggest non-white patients have a 2–3 times higher risk of HIT-associated thrombosis compared with white patients.

Heparin exposure (type, dose, route, duration)

• Unfractionated heparin (UFH) has the highest risk; low molecular weight heparin (LMWH) lower; fondaparinux minimal.
• Therapeutic dosing carries greater risk than prophylactic dosing.
• Intravenous administration confers higher risk than subcutaneous.
• Longer exposure increases risk; very small exposures (e.g., line flushes/catheter locks) can still precipitate HIT in susceptible patients.

Timing of platelet count fall

• Typical onset 5–10 days after starting heparin (range 4–15 days).
• Rapid-onset within 24 hours if there was heparin exposure within the previous ~100 days (pre-formed antibodies).
• Delayed-onset several days to weeks after stopping heparin; ask about thrombotic symptoms developing up to ~3 weeks post-discharge.

Thrombotic symptoms and red flags

• Venous: new unilateral leg pain, swelling, discolouration (DVT); pleuritic chest pain, dyspnoea, syncope (PE).
• Arterial: acute limb ischaemia, stroke symptoms, myocardial infarction features.
• Thrombosis can precede thrombocytopenia (~25%); ask about events before any known platelet fall.
• History suggestive of venous limb gangrene, particularly if warfarin was started early.

Bleeding history (to differentiate from other thrombocytopenias)

• HIT is typically not associated with bleeding despite low platelets; ask specifically about absence of petechiae/ecchymoses or mucosal bleeding.
• Document any bleeding since alternative anticoagulants used for suspected HIT can increase bleeding risk.

Recent surgery or trauma

• Cardiac and orthopaedic surgery carry higher risk than medical indications.
• Establish the surgical/trauma timeline relative to heparin use and platelet fall.

Prior history of HIT or heparin sensitisation

• Previous HIT (timing, management, complications).
• Any re-exposure to UFH/LMWH since prior HIT and for how long (≥4 days increases recurrence risk).
• Prior hospitalisations with heparin exposure in the last 100 days (risk of rapid-onset).

Alternative causes of thrombocytopenia

• Intercurrent sepsis or severe infection.
• Recent/current drugs associated with thrombocytopenia (e.g., vancomycin, carbamazepine, sulfonamides, antineoplastics, quinine/quinidine, GP IIb/IIIa inhibitors).
• Autoimmune disease, liver disease with hypersplenism, disseminated intravascular coagulation risk factors.

Patient-related risk modifiers

• Female sex (1.5–2× higher risk than males).
• Older age (mean diagnosis age ~60+ years).
• Race/ethnicity: non-white patients may have higher HIT-associated thrombosis risk.
• Renal dysfunction increases bleeding risk when alternative anticoagulation is started.

Special historical clues

• Acute systemic reaction within 30 minutes of heparin dose (fever, chills, tachycardia, hypertension, dyspnoea, collapse) with abrupt platelet fall.
• Painful skin lesions/necrosis at or beyond heparin injection sites.
• Abdominal pain, refractory hypotension, Addisonian features suggesting adrenal haemorrhagic necrosis.

Medication and product history beyond anticoagulants

• Warfarin/VKA use (limb gangrene risk if used before platelet recovery).
• Mechanical circulatory support, central venous catheter use (upper limb thrombosis risk).
• Prior fondaparinux exposure (rarely associated with HIT; clarify timing/reactions).

Venous limb gangrene

• Complication of deep venous thrombosis in HIT.
• Strongly linked with premature initiation of warfarin due to severe protein C depletion.
• Can progress rapidly to irreversible ischaemia and limb loss.

Bilateral adrenal haemorrhagic infarction

• Presents with abdominal pain, refractory hypotension, and acute adrenal crisis.
• Caused by adrenal vein thrombosis with haemorrhagic necrosis.

Skin lesions at heparin injection sites

• Painful erythematous plaques that progress to purpura and necrosis.
• May occur without overt thrombocytopenia.
• Can spread to distal extremities or other sites beyond injection areas.

Acute systemic reactions

• Appear within 30 minutes of an intravenous heparin bolus.
• Manifestations: fever, chills, dyspnoea, tachycardia, hypertension, chest pain, flushing, or cardiopulmonary collapse.
• Rarely, fulminant anaphylactoid or anaphylactic responses may occur.

Thrombotic events detectable on examination

Deep venous thrombosis (DVT)

• New unilateral leg swelling, oedema, tenderness, or discolouration.

Pulmonary embolism (PE)

• Tachypnoea, hypoxia, hypotension, tachycardia, pleuritic chest pain.

Arterial thrombosis

• Acute focal neurological deficits suggesting stroke.
• Features of myocardial infarction.
• Acute limb ischaemia with absent pulses or cold extremity.

Cerebral venous thrombosis

• Headache, nausea, vomiting, altered consciousness, focal neurological deficits.

Other uncommon findings

Absence of bleeding

• Despite profound thrombocytopenia, petechiae, ecchymoses, or mucosal bleeding are typically absent.

Progressive venous limb gangrene

• Severe ischaemia often associated with supratherapeutic INR when warfarin is initiated prematurely.

Organ-specific infarction

• Splenic, renal, mesenteric, or myocardial infarction may be inferred from focal signs.

Approach considerations

• Three key features help distinguish HIT from other thrombocytopenic conditions:
  • Platelet count typically falls 5–14 days after starting heparin.
  • Thrombocytopenia is usually mild to moderate; nadir rarely <15 × 10⁹/L.
  • Thrombosis (venous or arterial) often accompanies thrombocytopenia; in up to 25% of cases, thrombosis precedes platelet fall.
• Baseline platelet count should be checked before starting heparin.
• Monitoring:
  • High-risk patients (e.g., UFH after cardiac/orthopaedic surgery): platelet counts every 2–3 days from days 4–14.
  • Low-risk patients (e.g., medical patients on LMWH): routine monitoring not required.
• A platelet fall >50% from baseline, even if nadir >150 × 10⁹/L, or new thrombosis should prompt diagnostic testing.

Clinical probability scoring

4Ts score

• Assesses: Thrombocytopenia, Timing, Thrombosis, oTher causes.
• Interpretation:
  • 0–3 points: low probability (<1%).
  • 4–5 points: intermediate probability (~10%).
  • 6–8 points: high probability (~50%).
• Low scores exclude HIT; testing not recommended.
• Intermediate/high scores → proceed to laboratory testing.

HIT Expert Probability (HEP) score

• Alternative scoring system.
• 6–8: high suspicion, 4–5: intermediate suspicion, 0–3: low suspicion.

Laboratory testing

Immunoassays

• Detect anti–PF4/heparin antibodies.
• Types: ELISA, particle gel immunoassay, latex immunoassay.
• Advantages: rapid, widely available, highly sensitive (>99%).
• Limitations: low specificity (30–70%), many false positives.
• Interpretation:
  • Optical density (OD) thresholds:
    • OD 0.4–<1.0 → ≤5% chance of strong functional assay positivity.
    • OD ≥2.0 → ~90% chance of strong SRA positivity.
  • Higher OD values correlate with greater risk of thrombosis.
• Specificity can be improved by:
  • Using IgG-only ELISAs.
  • Adding excess heparin: ≥50% OD reduction indicates heparin-dependent antibodies.
• Rapid assays: high sensitivity, variable specificity; useful for quick screening.

Functional assays

• Assess platelet-activating potential of antibodies.
• Serotonin Release Assay (SRA):
  • Considered the gold standard.
  • Uses radiolabelled platelets to detect serotonin release in presence of heparin.
  • Sensitivity 69–94%, specificity up to 100%.
• Heparin-Induced Platelet Aggregation (HIPA):
  • Detects platelet aggregation in presence of patient serum and heparin.
  • Sensitivity variable (39–81%), specificity 82–100%.
• Functional assays confirm or exclude HIT in context of clinical suspicion; limited availability restricts use.

Imaging studies

Compression ultrasonography

• Recommended for all patients with suspected HIT, as asymptomatic DVT is common.
• Identifies new or extending thrombi.

CT pulmonary angiogram (CTPA)

• Used for suspected pulmonary embolism.
• Intraluminal filling defect on at least two views is diagnostic.

Ventilation–perfusion (V/Q) scan

• Alternative to CTPA.
• Preferred in renal impairment, contrast allergy, pregnancy, or younger patients.
• High-probability findings: multiple segmental perfusion defects with normal ventilation.

Neuroimaging

• CT venogram or MR venography for suspected cerebral venous thrombosis.
• Demonstrates intraluminal filling defects or abnormal flow within venous sinuses.

Sepsis or severe infection

• Presents with fever, hypotension, and multi-organ dysfunction.
• Disseminated intravascular coagulation (DIC) may complicate the course, leading to diagnostic confusion with HIT.
• Investigations: positive blood cultures; HIT antibody assay negative.

Disseminated intravascular coagulation (DIC)

• Abnormal coagulation profile: prolonged clotting times, low fibrinogen, raised D-dimer.
• Peripheral smear may show schistocytes.
• Unlike HIT, bleeding is often prominent.

Thrombotic thrombocytopenic purpura (TTP)

• Distinguished by severe neurological changes, anaemia, and sometimes fever.
• Investigations:
  • Microangiopathic haemolytic anaemia with schistocytes.
  • Normal coagulation tests.
  • Negative HIT antibody assay.

Haemolytic–uraemic syndrome (HUS)

• Classic triad: haemolytic anaemia, thrombocytopenia, and acute renal failure.
• Commonly associated with schistocytes on smear.
• Kidney injury is a dominant feature, unlike HIT.

Drug-induced thrombocytopenia

• Triggered by a range of medications: vancomycin, quinine/quinidine, sulfonamides, chemotherapy, carbamazepine, glycoprotein IIb/IIIa inhibitors.
• Platelet nadir frequently <20 × 10⁹/L (rare in HIT).
• Petechiae and mucosal bleeding may be seen.
• Diagnosis relies on careful drug history; no confirmatory test.

Postoperative thrombocytopenia

• Platelet counts often fall transiently within 24–48 hours after surgery, then recover spontaneously.
• Rebound thrombocytosis is common; the postoperative peak should be considered the new baseline.
• More prolonged or delayed thrombocytopenia (>4 days) should prompt evaluation for HIT.
• Cardiovascular surgery patients often develop HIT antibodies but rarely progress to clinical disease.

Immune thrombocytopenia (ITP)

• Characterised by isolated thrombocytopenia without thrombosis.
• Platelet counts often very low (<20 × 10⁹/L).
• Diagnosis of exclusion once HIT and other causes are ruled out.

Splenomegaly with platelet sequestration

• Leads to moderate thrombocytopenia through pooling of platelets in the spleen.
• Associated with chronic liver disease and certain haematological disorders.
• Typically not linked to thrombosis.

Transfusion reactions

• Can cause acute, transient thrombocytopenia shortly after blood product administration.
• Timing of onset in relation to transfusion is critical for recognition.

Initial approach

Management is guided by 4Ts score

• ≥4 (intermediate/high probability): discontinue all heparin products immediately, including LMWH and line flushes; initiate non-heparin anticoagulation.
• ≤3 (low probability): laboratory testing not required; heparin may be continued if no uncertainty exists about the score.

Vitamin K antagonists (e.g., warfarin)

• Should not be started in acute HIT before platelet recovery.
• If already initiated, reverse with vitamin K due to risk of venous limb gangrene from protein C depletion.
• Start only once platelet counts have recovered (>150 × 10⁹/L or baseline) and overlap with a non-heparin anticoagulant for at least 5 days until INR is therapeutic.

Platelet transfusion

• Generally contraindicated as transfusions may worsen thrombosis.
• Consider only for life-threatening bleeding or high-risk procedures with severe thrombocytopenia.

Choice of non-heparin anticoagulant

Parenteral direct thrombin inhibitors

• Argatroban: preferred in renal impairment; safe in haemodialysis.
• Bivalirudin: useful for urgent cardiac surgery or PCI; requires dose adjustment in renal impairment.

Indirect factor Xa inhibitors

• Danaparoid: effective but availability varies by region.
• Fondaparinux: rarely associated with HIT; used off-label for treatment; contraindicated in severe renal impairment.

Direct oral anticoagulants (DOACs)

• Rivaroxaban, apixaban, dabigatran: supported by growing observational evidence; safe in stable patients.
• Edoxaban: limited evidence (single case report).

Special situations

Cardiac surgery and PCI

• Elective surgery: delay until HIT antibodies are negative (≈60–100 days).
• Urgent cardiac surgery: bivalirudin first-line, argatroban as alternative.
• PCI: bivalirudin preferred; argatroban second-line.

Renal impairment

• Argatroban: drug of choice (hepatic clearance).
• Bivalirudin/danaparoid: may be used with renal dose adjustment.
• Dialysis patients: regional citrate anticoagulation or saline flushes may substitute once platelets recover.

Pregnancy and breastfeeding

• None of the agents are licensed.
• Danaparoid and fondaparinux have been used; limited safety data available.
• Warfarin safe in breastfeeding but contraindicated in pregnancy.
• DOACs should be avoided in both pregnancy and lactation.

Platelet recovery and transition therapy

Platelet recovery

• Defined as platelet count >150 × 10⁹/L or back to baseline if chronically low.
• With thrombosis: treat for at least 3 months.
• Without thrombosis: treat until platelet recovery, usually ~4 weeks.

Transition to oral anticoagulants

• Warfarin: initiate only after platelet recovery, overlap with parenteral non-heparin anticoagulant ≥5 days.
• DOACs: rivaroxaban, apixaban, dabigatran may be started without overlap after platelet recovery.
• Fondaparinux: can be continued long-term; preferred in pregnancy where warfarin is contraindicated.

Adjunctive and rescue therapies

High-dose IVIG

• Blocks Fc receptor–mediated platelet activation in refractory HIT.
• Used as adjunct in difficult cases and when heparin re-exposure is unavoidable (e.g., surgery in antibody-positive patients).

Avoidance of heparin

• All forms of heparin (including LMWH and flushes) should be avoided lifelong, except in rare situations such as antibody-negative remote HIT during cardiac surgery.
• Patients should be counselled and medical records updated to flag HIT diagnosis.

Long-term monitoring

• Risk of thrombosis remains high for 2–4 weeks after diagnosis; anticoagulation must be continued beyond platelet recovery.
• Minimum treatment duration:
  • With thrombosis: 3 months.
  • Without thrombosis: at least until platelet recovery.
• Platelet transfusions reserved for bleeding complications, not for isolated thrombocytopenia.

Overall outcomes

• Historically, mortality in HIT was reported at ~20%, with a similar proportion of survivors experiencing major complications such as limb loss or stroke.
• With earlier recognition and improved management, current mortality and major morbidity rates have decreased but remain significant at 6–10%.
• Prognosis is best when HIT is suspected promptly, heparin is discontinued immediately, and appropriate non-heparin anticoagulation is initiated.

Platelet recovery

• Platelet counts typically recover within 4–7 days (median 4 days) once heparin is discontinued and treatment is started.
• In more aggressive cases or with delayed diagnosis, recovery may take longer.
• Recovery indicates suppression of thrombin generation and stabilisation of the prothrombotic state.

Antibody persistence

• HIT antibodies are usually transient, resolving spontaneously within ~100 days.
• Long-term complications are uncommon in patients who survive the acute illness without major thrombotic sequelae.
• The major ongoing risk is recurrence if patients are re-exposed to heparin, particularly within 100 days of the initial episode when antibodies may persist.

Complications

Venous thromboses

• Deep venous thrombosis.
• Pulmonary embolism.

Arterial events

• Myocardial infarction.
• Transient ischaemic attack.
• Ischaemic stroke.
• Limb artery occlusion, which may necessitate amputation.

Cutaneous lesions

• Skin necrosis at or near heparin injection sites.

End-organ damage

• Adrenal haemorrhagic infarction.
• Bowel infarction.
• Splenic infarction.
• Gallbladder ischaemia.
• Hepatic infarction.
• Acute kidney injury.

Death

• Frequently the result of major thrombotic complications such as pulmonary embolism or stroke.

New venous or arterial thrombotic events

• Thrombosis is the hallmark complication of untreated HIT.
• Occurs in 30–50% of patients during the acute phase.
• Associated mortality from thrombotic events is 5–10%.
• Prompt use of non-heparin anticoagulants can reduce thrombotic risk by 50–70%.

Deep vein thrombosis (DVT)

• One of the most frequent manifestations.
• May present with unilateral swelling, pain, or discolouration of the limb.
• Often detected even in the absence of overt symptoms through screening imaging.

Pulmonary embolism (PE)

• A common extension of DVT in HIT.
• May cause acute dyspnoea, chest pain, tachypnoea, hypotension, or sudden collapse.

Arterial thrombosis

• Less common than venous events but often more catastrophic.
• Can manifest as acute limb ischaemia, myocardial infarction, or ischaemic stroke.
• May lead to long-term disability or death.

Limb amputation

• Reported in 6–10% of HIT patients with severe ischaemia.
• Risk remains despite anticoagulation once critical ischaemia develops.
• No specific non-heparin anticoagulant has been shown to reduce amputation rates once limb ischaemia is established.

Venous limb gangrene

• Historically linked to inappropriate initiation of warfarin without overlap therapy.
• Caused by early depletion of protein C, tipping the balance towards hypercoagulability.
• May present as distal limb necrosis in the presence of venous thrombosis but intact arterial flow.

Treatment-related bleeding

• Risk varies with the anticoagulant chosen and underlying comorbidities.
• Major bleeding occurs in 3–14% of treated patients.
• Balancing the risk of thrombosis against bleeding is critical in management.

Skin necrosis

• Can occur at sites of heparin injection or over areas with venous thrombosis.
• May progress to haemorrhagic necrosis requiring surgical intervention.

End-organ damage

• Arises from thrombotic occlusion of arterial or venous circulation.
• Organs reported to be affected include adrenals (haemorrhagic infarction), bowel, spleen, gallbladder, liver, and kidneys (acute kidney injury).

Death

• Mortality is largely due to major thrombotic complications such as pulmonary embolism, stroke, or widespread arterial occlusion.
• Despite improvements in recognition and therapy, mortality remains significant.

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