RPB

Hirudin

hirudin (native leech peptide); recombinant analogues lepirudin (Refludan) and desirudin (Iprivask, Revasc). The related synthetic analogue bivalirudin (Angiomax) has its own profile (#131)

Cardiovascular & circulation
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Note on this profile. Lepirudin and desirudin were approved prescription medicines. Both have been discontinued by their manufacturers and lepirudin's European marketing authorisation has been withdrawn, so this page describes medicines that are largely historical. Bivalirudin (#131) remains available and has taken over most of the clinical territory. Nothing here is a guide to anticoagulant use: these are hospital drugs given with laboratory monitoring and no reversal agent.

1What it is

Hirudin is the reason leeches work. Medicinal leeches have been used in bloodletting for at least two thousand years, and the practical observation that a leech bite bleeds for hours after the animal detaches was explained in 1884 when John Haycraft found an anticoagulant in leech secretions. Fritz Markwardt isolated and characterised hirudin in the 1950s and determined its structure, establishing it as the most potent natural inhibitor of thrombin known — binding with a dissociation constant in the femtomolar range, which is about as tight as protein–protein interactions get.

Thrombin is the enzyme at the centre of coagulation. Heparin, the workhorse anticoagulant, does not act on thrombin directly; it works by accelerating antithrombin, and it has two important weaknesses as a result. It cannot inactivate thrombin already bound within a clot, and in some patients it triggers an immune reaction against heparin–platelet factor 4 complexes that paradoxically causes thrombosis — heparin-induced thrombocytopenia, or HIT. A direct thrombin inhibitor solves both problems, and that is the clinical niche hirudin analogues were developed for.

Recombinant technology gave two products. Lepirudin was approved in the late 1990s specifically for HIT with thrombosis — a situation in which patients need anticoagulation urgently and cannot have heparin. Desirudin was approved for venous thromboembolism prophylaxis after hip replacement. Neither survived commercially. Lepirudin's manufacturer discontinued it in 2012 and the European authorisation was withdrawn; desirudin was never meaningfully marketed. Argatroban and bivalirudin (#131) — a 20-amino-acid synthetic peptide designed from the hirudin binding motifs, with reversible binding and a shorter — occupied the space instead.

Note that native hirudin is sulfated at tyrosine 63; the recombinant versions are not, which reduces affinity somewhat. "Hirudin" in the research literature may refer to either.

2How it's thought to work

Bivalent thrombin binding. The C-terminal tail of hirudin binds thrombin's exosite 1, the site thrombin normally uses to grip fibrinogen; the N-terminal domain occupies the catalytic site. Engaging both simultaneously produces the extraordinary affinity and makes inhibition effectively irreversible over clinical timescales.
Independence from cofactors. Unlike heparin, hirudin needs no antithrombin. It inhibits free thrombin and clot-bound thrombin equally, and is not neutralised by platelet factor 4 released from activated platelets — which is precisely why it works in HIT.
Downstream consequences. Blocking thrombin prevents fibrinogen cleavage, factor V, VIII and XIII activation, and thrombin-mediated platelet activation. The effect is broad and there is no antidote: no protamine equivalent exists.
Renal clearance. Both analogues are eliminated by the kidney essentially unchanged. In renal impairment they accumulate, which was the mechanism behind a substantial share of lepirudin bleeding events and the reason dosing recommendations were revised downward after approval.
The leech anticoagulant, and the molecule bivalirudin was derived from. It binds thrombin almost irreversibly, which is effective but leaves no easy way back if bleeding starts.Schematic — not to scale

3What the research shows

Graded A (historical standard of care)

Heparin-induced thrombocytopenia

The HAT-1, HAT-2 and HAT-3 prospective studies evaluated lepirudin in patients with confirmed HIT, using historical controls, and reported reduced rates of the composite of death, amputation and new thromboembolic complications compared with control cohorts (Greinacher 1999, Circulation; Greinacher 1999, Blood; Lubenow 2005, Blood). These were not randomised against an active comparator — randomising HIT patients to continued heparin would not have been acceptable — so the evidence is prospective cohort with historical comparison, which is the practical ceiling for this indication. [2][3][4]
Graded A (modest benefit, more bleeding)

Acute coronary syndromes

Large randomised trials compared hirudin with heparin in unstable angina and myocardial infarction. GUSTO-IIb (n≈12,000) found a small early advantage that was not sustained at 30 days (GUSTO IIb Investigators 1996, NEJM). OASIS-2 (n≈10,000) reported a reduction in cardiovascular death or myocardial infarction with hirudin versus heparin, at the cost of more major bleeding requiring transfusion (OASIS-2 Investigators 1999, Lancet). The TIMI-9 and GUSTO-IIa trials were stopped early for excess intracranial haemorrhage at the doses initially chosen, which reset the field's dosing. The overall picture — marginal efficacy gain, clear bleeding penalty, no antidote — is why hirudins never displaced heparin in coronary care.

DVT prophylaxis after hip replacement

Randomised trials of desirudin versus unfractionated heparin and versus enoxaparin in elective hip replacement reported lower rates of venographically detected deep vein thrombosis with desirudin (Eriksson 1997, NEJM; Eriksson 1997, Lancet). Good-quality evidence for a product that was then not commercialised. [7]

Medicinal leech therapy

Live medicinal leeches are cleared in the United States as a medical device and are used in reconstructive and replantation surgery to relieve venous congestion in flaps and reattached digits, where the combination of blood removal and sustained bleeding from the bite is the therapeutic effect. Case series and small studies support this specific surgical use. Leech therapy for osteoarthritis has been studied in small randomised trials with reported symptom benefit, of generally low methodological quality; this is not evidence for hirudin as a pharmacological agent.
Graded D/—

Topical and oral "hirudin" products

Creams and supplements marketed with reference to hirudin or leech extract have no credible evidence of systemic anticoagulant effect; a 65-amino-acid peptide is not orally bioavailable.

4Reported side effects and interactions

Literature-reported

Common (literature). bleeding is the dominant and expected adverse effect — injection and puncture site bleeding, haematoma, haematuria, gastrointestinal haemorrhage, anaemia requiring transfusion. Major bleeding rates in the coronary trials were consistently higher than with heparin.

Serious / warnings. intracranial haemorrhage, which stopped two early trials at the initially selected doses; fatal haemorrhage; accumulation and overdose in renal impairment, the single most important dosing hazard, with lepirudin requiring substantial dose reduction or avoidance in significant renal dysfunction. There is no reversal agent — management of bleeding is supportive, with haemofiltration of limited value.

Community-reported

Community use: essentially none documented for the pharmaceutical analogues — these are intravenous or hospital-administered anticoagulants requiring laboratory monitoring, and both are off the market. Leech therapy and topical leech-extract products do have consumer use; the former should be distinguished from pharmacological anticoagulation, and the latter has no evidence behind it.

Immunogenicity. anti-hirudin antibodies developed in a large proportion of lepirudin-treated patients — reported in roughly 40–70% with prolonged treatment. Most were not neutralising and some paradoxically enhanced and prolonged the anticoagulant effect by delaying renal clearance, requiring closer aPTT monitoring the longer treatment continued. Serious anaphylactic reactions, including fatal cases, were reported on re-exposure in previously treated patients, leading to a specific warning against re-exposure.

Theoretical. cross-reactivity between hirudin analogues on re-exposure; interaction between antibody status and effective .

Interactions. additive bleeding risk with thrombolytics, antiplatelet agents, other anticoagulants and NSAIDs — the coronary trials combining hirudin with streptokinase or alteplase were where the intracranial bleeding appeared. Hirudins prolong aPTT, INR and thrombin time, which confounds monitoring of other anticoagulants and complicates transition to warfarin.

Markers researchers commonly monitor

These follow the approved labels and the trial protocols, and this is a drug class where monitoring is not optional:

MarkerWhy it's watched
aPTT (activated partial thromboplastin time)the routine monitoring assay for both products, with a target ratio around 1.5–2.5 times baseline; checked 4 hours after initiation and after every rate change. Its relationship to hirudin concentration is non-linear at high levels, which is a known limitation.
Ecarin clotting timethe more accurate assay for direct thrombin inhibitor concentration, used in research and where available clinically.
Platelet countthe defining measurement in HIT; recovery of the platelet count is the signal that the diagnosis was right and treatment is working.
Haemoglobin and haematocritbleeding is the main adverse effect and may be occult.
Creatinine and eGFRboth drugs are renally cleared and accumulate; this is the most important safety parameter and the one most often missed.
INRprolonged by hirudins independently of warfarin effect, which makes the transition to oral anticoagulation genuinely tricky and is a documented source of error.
Anti-hirudin antibodiesnot routinely available, but the explanation for an unexpectedly prolonged effect during extended treatment.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Both products were hospital pharmacy items supplied as powder for with water for injection or saline, then further dilution for infusion, prepared immediately before use and discarded per label. Lepirudin dosing was weight-based and aPTT-adjusted with a target ratio of roughly 1.5–2.5 times control, checked four hours after any rate change; desirudin was a fixed 15 mg dose with aPTT monitoring and dose reduction in renal impairment. The practical hazards documented in the literature were weight-based arithmetic errors and failure to reduce the dose for renal function. Neither product is currently marketed, so this section is historical rather than operational.

6Commonly studied alongside

Bivalirudin (#131), the surviving synthetic hirudin-derived analogue and the direct successor; argatroban, the small-molecule direct thrombin inhibitor that took over the HIT indication and is hepatically cleared, making it preferable in renal impairment; dabigatran as the oral direct thrombin inhibitor descendant of the same pharmacological idea; fondaparinux, heparin and enoxaparin as the comparators throughout the trial programme.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

RegionStatus (checked —)
United StatesLepirudin (Refludan) was FDA-approved for HIT with thrombosis; discontinued by the manufacturer in 2012 and no longer marketed. Desirudin (Iprivask) was FDA-approved for post-hip-replacement DVT prophylaxis; discontinued. Live medicinal leeches are cleared as a class II medical device
European UnionRefludan was EMA-authorised; the marketing authorisation has been withdrawn. Revasc (desirudin) authorisation also withdrawn †
United KingdomPreviously licensed in line with the EU; no longer marketed †
AustraliaNot currently marketed †
South AfricaNot currently registered †
SportNot prohibited by WADA. Anticoagulants are not performance-enhancing and are not listed

8Open questions

  • Why did two well-evidenced products fail commercially — bleeding profile, lack of an antidote, the arrival of argatroban and bivalirudin, or the small size of the HIT market?
  • Does the enhanced anticoagulant effect from non-neutralising anti-hirudin antibodies have a useful analogue in antibody-based anticoagulant design?
  • Are there other pharmacologically useful components in leech saliva, which contains dozens of antihaemostatic and anti-inflammatory proteins beyond hirudin?
  • What is the actual mechanism of symptom benefit in leech therapy for osteoarthritis, if it is real?

9References

  1. 1Markwardt F (1991). Hirudin and derivatives as anticoagulant agents. Thromb Haemost. PubMed
  2. 2Greinacher A et al. (1999). Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation. PubMed · DOI
  3. 3Greinacher A et al. (1999). Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation. PubMed · DOI
  4. 4Lubenow N et al. (2005). Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of three prospective studies. Blood. PubMed · DOI
  5. 5The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators (1996). A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. NEJM. PubMed
  6. 6Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators (1999). Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation. Lancet. PubMed
  7. 7Eriksson BI et al. (1997). A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. NEJM. PubMed · DOI
  8. 8European Medicines Agency. Refludan EPAR — withdrawal of marketing authorisation. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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11Page history

31 Oct 2026Profile published — awaiting medical review

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