Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin
Basic science / preclinical published in Haemostasis (1991)
Abstract
Recombinant hirudin (r-hirudin) is currently under development as an anticoagulant for use in surgery, therapeutic anticoagulation, disseminated intravascular coagulation and other pathologic states involving the generation of thrombin. Circulating levels of r-hirudin as an antithrombotic agent range from 2 to 20 micrograms/ml (0.1-1.0 mg/kg) as determined in an animal model of stasis thrombosis. In order to establish a relationship between the r-hirudin circulating level and bleeding, we utilized a rabbit ear blood loss model. r-Hirudin did not produce any loss of blood at dosages up to 20 micrograms/ml i.v. (1.0 mg/kg). When the circulating levels were maintained at 20 micrograms/ml for periods of up to 3 h, no increase in blood loss was observed. At 50 and 100 micrograms/ml initial circulating levels (2.5 and 5.0 mg/kg) a dose-dependent increase in the blood loss was observed which was equivalent to that observed with 1.25 and 2.5 mg/kg i.v. heparin. Such levels of r-hirudin are not expected in clinical usage. In contrast to heparin, the anticoagulant actions of r-hirudin were not neutralized by protamine sulfate, platelet factor 4, other polycationic agents and heparinase. In our studies, the blood loss induced by greater than 2.0 mg/kg i.v. dosages of r-hirudin in an animal model was neutralized by the administration of an activated prothrombin complex concentrate at 25 U/kg. In a similar experimental setting, r-factor VIIa was also partially effective. These studies suggest that r-hirudin anticoagulation may not require neutralization, since bleeding effects are not observed at effective antithrombotic dosages in individuals with normal hemostatic status.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Resumen
Recombinant hirudin (r-hirudin) is currently under development as an anticoagulant for use in surgery, therapeutic anticoagulation, disseminated intravascular coagulation and other pathologic states involving the generation of thrombin.
Por qué esto importa para la hirudoterapia
Este estudio examinó la relación dosis-dependiente entre los niveles circulantes de hirudina recombinante (r-hirudin) y el sangrado utilizando un modelo de pérdida sanguínea en oreja de conejo, e investigó si diversos agentes podían neutralizar los efectos anticoagulantes de la r-hirudin. El resumen informa que a dosis antitrombóticas de hasta 20 microgramos/ml no se produjo sangrado, mientras que niveles circulantes más elevados produjeron pérdida sanguínea dosis-dependiente comparable a la de la heparina; el sulfato de protamina, el factor 4 plaquetario, los agentes policatiónicos y la heparinasa no lograron revertir la r-hirudin, mientras que el concentrado de complejo protrombínico activado a 25 U/kg neutralizó el sangrado y el r-factor VIIa mostró eficacia parcial. Dado que la hirudin es el conocido anticoagulante asociado con las sanguijuelas medicinales, estos datos de dosis-respuesta y reversibilidad son de relevancia conceptual para la farmacología subyacente a la hirudoterapia. Sin embargo, todos los hallazgos se derivan de un modelo animal de anticoagulación sistémica utilizando un compuesto recombinante y no de la terapia con sanguijuelas en sí, y se indica explícitamente que las dosis asociadas con sangrado superan los niveles clínicos esperados.
Citación
Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin.
Fareed J et al. · Haemostasis, 1991
Contexto clínico relacionado
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Añadido a la biblioteca ASH: March 18, 2026 · Última actualización del sitio: June 18, 2026