IV. On the action of a secretion obtained from the medi­cinal leech on the coagulation of the blood

Haycraft, John Berry

doi:10.1098/rspl.1883.0135

Cited by 60 publications

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“…Leech hirudin is the most potent natural inhibitor of coagulation known (1)(2)(3)(4). A very stable noncovalent 1:1 complex is rapidly and specifically formed with a-thrombin, thereby abolishing its ability to cleave fibrinogen (4).…”

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confidence: 99%

Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis.

Harvey¹,

Degryse²,

Stefani³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

191

102

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Cloned cDNAs have been isolated that encode a variant of hirudin, a potent thrombin inhibitor that is secreted by the salivary glands of the medicinal leech, Hirudo medicinals. This variant probably corresponds to a form that has been purified from leech heads but differs in amino acid sequence from the hirudin purified from whole leeches. There are at least three hirudin transcripts detectable in leech RNAs that are different in size, site of synthesis, inducibility by starvation, and relationship to hirudin activity. The new hirudin variant predicted by the cDNA and the heterodisperse transcription products suggest a hirudin protein family. The hirudin cDNA was expressed in Esckerichia coli under the control of the bacteriophage X PL promoter. The recombinant product is biologically active, inhibiting the cleavage by thrombin of fibrinogen and a synthetic tripeptide substrate.Leech hirudin is the most potent natural inhibitor of coagulation known (1-4). A very stable noncovalent 1:1 complex is rapidly and specifically formed with a-thrombin, thereby abolishing its ability to cleave fibrinogen (4). To date there is no evidence that it can interact with other components of the human coagulation cascade (5, 6).Hirudin is a polypeptide of 65 amino acids that is stable to extremes of pH and heat (4). It contains six cysteine residues grouped in the NH2-terminal half of the protein, an acidic COOH-terminal half, and one sulfated tyrosine (7). A hirudin form with isoleucine at the NH2 terminus was first purified from leech heads (H. medicinalis) (4, 8) in which activity was found to be concentrated in the salivary glands. Subsequently, Bagdy et al. (9) adopted new purification schemes using whole leeches instead of heads, yielding a form with Val-Val as the first two NH2-terminal amino acids. The amino acid sequence of the "whole body form" has been determined by independent groups (8, 10), and valine residues at positions 1 and 2 have been confirmed. Both forms had a specific activity of around 8000-10,000 antithrombin units/mg. However, more recently, Baskova et al. (11) Hirudin Activity. Antithrombin activity in leech or bacterial extracts was measured in a clotting assay (4) using citrated human platelet-poor plasma as a fibrinogen source or in a colorimetric assay using the thrombin chromogenic substrate Tos-Gly-Pro-Arg-p-nitroanilide (Chromozym TH, Boehringer Mannheim; Tos = tosyl) (7). Standard curves Abbreviation: kb, kilobases. tPresent address:

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mentioning

confidence: 99%

Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis.

Harvey¹,

Degryse²,

Stefani³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

191

102

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“…In 1884, Haycraft termed the anticoagulating substance contained in leech saliva hirudine. 7,8 In 1955, Markwardt was the first to isolate hirudine from the pharyngeal glands of leeches. 4 In 1983, Whitlock et al 9 reported A hydrophylia in the mucous secretions and gut of the medicinal leech.…”

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Aeromonas Septicemia After Medicinal Leech Use Following Replantation of Severed Digits

Levine

Frangos

Hanna

et al. 2009

American Journal of Critical Care

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Medicinal leeches are used to control venous congestion. Aeromonas in the leech gut are essential for digestion of blood. This case report describes a patient who had Aeromonas bacteremia develop after leeching. He had an injury to his hand that required replantation of his thumb. Following the surgery, leech therapy was started with ampicillin-sulbactam prophylaxis. Sepsis developed. Blood cultures were positive for Aeromonas that were resistant to ampicillinsulbactam. The antibiotic was changed to ciprofloxacin on the basis of the sensitivity profile of the organisms. Cultures from the leech bathwater confirmed it as the source of the Aeromonas. Clinicians who use leech therapy must be aware that leeches can harbor Aeromonas species resistant to accepted prophylactic antibiotics and that sepsis may occur.

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“…Given its important role as the fi nal common mediator of the coagulation cascade and its potent activation of platelets, thrombin has been identifi ed as a target for new anticoagulant agents. The development of direct thrombin inhibitors (DTIs) has its origins in the discovery of the anticoagulant agent hirudin in the salivary glands of the medicinal leech Hirudo medicinalis in the 1880s [5] . The potential of hirudin as an antithrombotic agent was fi rst investigated in the 1920s [6] , but it was only in the 1990s that hirudin was introduced into clinical use.…”

Section: From Leeches To Ximelagatran: a Journey Of Discoverymentioning

confidence: 99%

Ximelagatran in Orthopaedic Surgery

Eriksson

2005

Pathophysiol Haemos Thromb

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Ximelagatran represents the first new oral anticoagulant since the introduction of warfarin almost 60 years ago, and has been evaluated for the treatment and prevention of a range of venous and arterial thromboembolic disorders. The MElagatran THRomboprophylaxis in Orthopaedic surgery (METHRO) and EXpanded PRophylaxis Evaluation Surgery Study (EXPRESS) studies have investigated the efficacy and safety of subcutaneous (s.c.) melagatran followed by oral ximelagatran in preventing venous thromboembolism (VTE) in patients undergoing total hip replacement or total knee replacement. In METHRO II, immediate pre-operative-initiated s.c. melagatran followed by post-operative ximelagatran dose-dependently reduced VTE, with the highest dose (melagatran 3 mg/ximelagatran 24 mg twice daily) associated with a significantly reduced incidence of VTE compared with the low-molecular-weight heparin (LMWH) dalteparin (15.1 vs. 28.2%; p < 0.0001). In METHRO III, the efficacy of s.c. melagatran 3 mg/ximelagatran 24 mg twice daily initiated post-operatively (4–12 h after surgery) was comparable to that of the LMWH enoxaparin initiated 12 h before surgery (total VTE incidence, 31.0 and 27.3%, respectively). Rates of severe bleeding were also comparable between treatments (melagatran/ximelaga tran = 1.4%; enoxaparin = 1.7%). Treatment with melagatran/ximelagatran was significantly more effective when initiated earlier (4–8 h) rather than later (8–12 h) after surgery (total VTE incidence, 27.5 vs. 35.4%; p = 0.0034). Based on the results of METHRO II and III, the EXPRESS study evaluated the efficacy and bleeding profile of s.c. melagatran 2 mg immediately before surgery, followed by s.c. melagatran 3 mg on the evening of the day of surgery and then ximelagatran 24 mg twice daily. This regimen was significantly more effective than enoxaparin (total VTE incidence, 20.3 vs. 26.6%; p < 0.0004). Excessive bleeding (as judged by the investigator) was more frequent with melagatran/ximelagatran, but rates of fatal bleeding, critical-site bleeding and bleeding requiring re-operation did not differ between the groups. Taken together, the METHRO and EXPRESS studies demonstrate that melagatran/ximelagatran has comparable or superior efficacy to LMWHs in the prevention of VTE in orthopaedic surgery patients, and that the timing and dose of melagatran is important in optimizing the balance of efficacy and bleeding risk.

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IV. On the action of a secretion obtained from the medicinal leech on the coagulation of the blood

Cited by 60 publications

References 0 publications

Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis.

Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis.

Aeromonas Septicemia After Medicinal Leech Use Following Replantation of Severed Digits

Ximelagatran in Orthopaedic Surgery

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IV. On the action of a secretion obtained from the medi­cinal leech on the coagulation of the blood

Cited by 60 publications

References 0 publications

Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis.

Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis.

Aeromonas Septicemia After Medicinal Leech Use Following Replantation of Severed Digits

Ximelagatran in Orthopaedic Surgery

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IV. On the action of a secretion obtained from the medicinal leech on the coagulation of the blood