Hirudin is a polypeptide, present in leeches (Hirudo medici-nalis) (Fig 24.3), and is a highly selective thrombin inhibitor.It is a naturally occurring 65 -amino acid polypeptide that is produced from the saliva of the medicinal leech. It is now being produced in other forms as a recombinant molecule.
Recombinant derivatives of hirudin include argatroban, biva-lirudin, desirudin, efegatran, inogatran, lepirudin, napsagatran, and ximelagatran.
Direct thrombin inhibitors target sites on the thrombin molecule responsible for substrate recognition and/or cleavage. The substrate recognition site (exosite 1) binds thrombin to fibrinogen prior to its enzymatic actions. The catalytic (active) site is responsible for activating platelets and the cleavage of fibrinogen to fibrin for thrombus formation. Direct thrombin inhibitors can block both the active site and exosite 1 or the active site alone, specifically inhibiting thrombin activity. Heparin is unable to inactivate thrombin because the heparin-activated antithrombin binds to the active site and blocks the fibrin-binding site. Because direct thrombin inhibitors do not bind to the fibrin-binding site, they can bind both unbound and fibrin-bound thrombin. They are also not inhibited by platelet factor 4.
The most common complication observed with selec-tive thrombin inhibitor therapy is haemorrhage, although the incidence of major bleeding is less when compared with other anticoagulants. Bleeding from puncture wound sites, anaemia, haematomas, haematuria, gastrointestinal and rectal bleeding, epistaxis, intracranial bleeding and haemothorax have been reported. Concurrent treatment with thrombolytics (e.g. rt-PA, streptokinase), coumarin derivatives (e.g. Vitamin K antago-nists), and drugs that affect platelet function may increase the risk of bleeding complications. Thrombolytics may enhance the effect on aPTT prolongation. Other non-haemorrhagic effects seen in clinical trials include hypotension, cardiac arrest, dyspnoea, fever, nausea, vomiting, diarrhoea, cardiac arrhythmias, and abnormal hepatic and renal function. Some of these complications are likely related to underlying disease processes. Acute allergic reactions and formation of antihirudin antibodies have also been reported.
Overdose results in significant haemorrhage which responds well to prothrombin complex concentrate.
Treatment involves symptomatic and supportive measures. If bleeding is suspected, monitor patient’s haematocrit, haemo-globin, activated partial thromboplastin time, INR, platelet count and fibrinogen. Monitor vital signs, ECG, renal and hepatic function in symptomatic patients. No specific antidotes are available for the direct thrombin inhibitors. If excessive anticoagulation occurs, discontinue the drug or decrease the infusion dosage. If necessary, blood loss and reversal of bleeding tendency can be managed with packed red blood cells and cryoprecipitate or fresh frozen plasma.