Fkpm, a Promising Solution for the Acute Pulmonary Thromboembolism

Background: With an extremely high morbidity and mortality, pulmonary thromboembolism (PTE) has greatly impacted the life quality of patients survived a thromboembolic event. PTE is mainly originated from blood clots from the venous system or the right heart, which clog the pulmonary artery or its side branches. Patients with deep venous thrombosis, heart diseases and certain malignancies have higher risk of PTE. Therefore, efficient and effective therapy against PTE is of great clinical significance. As commonly used thrombolytic drugs, tissue plasminogen activators (tPAs) convert plasminogen to plasmin, which primarily promotes dissolution of blood clots. FKPM is a genetically recombined human tPA, with a unique residue substitution, characterized by high biological activity, long half-time, and high stability. Here our studies have provided strong evidence for the advantaged thrombolytic potential of FKPM, in comparison to the well-acknowledged clinical thrombolytic drug against PTE, Alteplase.

Methods: Acute thromboembolism models were established by injection of autologous thrombus into the pulmonary artery. Pulmonary angiography, hemodynamics, blood gas, haematological, blood biochemical and coagulation indexes, anatomical observation and tissue pathological examination were applied for assessment of thrombolytic effects.

Results: We successfully established both dog and monkey acute pulmonary thromboembolism models, the specificity and replicability of which were verified by pulmonary angiography, the classic diagnostic method of PTE. Angiography studies also indicated that upon administration of FKPM, the pulmonary thrombus was largely dissolved and blood flow was recovered. Besides, a minimal effective concentration (4K unit) of FKPM was determined, since this or larger amount of FKPM was able to reduce the blood blocking area by 90%. Drug effect of FKPM was also reflected as rescue of the elevated blood pressure (systolic, diastolic and mean arterial blood pressure) by pulmonary thrombus. Administration of 4K or more FKPM resulted in a dramatic decrease of the pulmonary pressure to a level similar to that of the sham operation group. Prothrombin time, activated partial thromboplastin time and thrombin time were remarkably extended immediately upon drug administration, and were recovered to the level detected before thrombus injection at day 6 after drug administration. Hematological, blood biochemical and blood gas indexes, anatomical and tissue pathological examinations supported the thrombolytic potential of FPKM as well.

Conclusions: All these results suggested a promising thrombolytic potential of FKPM, which was further supported by the similar outcome in the rhesus monkey acute pulmonary thromboembolism model. Since rhesus monkey owns a blood coagulation and fibrinolysis system more similar to that of human, it is very promising that FKPM could dissolve partial or total thrombus, recover reperfusion of lung tissue, avoid permanent tissue damage, alleviate the symptoms of patients suffering PTE, and reduce the fatality and recurrence rate of PTE patients.