Platelets inhibit the lysis of pulmonary microemboli

Abstract

Using tracings of 125 I-labeled fibrin(ogen) in rodents, we examined the hypothesis that platelets impede the lysis of pulmonary emboli.125 I-Microemboli (ME, 3-10 micron diameter) lodged homogeneously throughout the lungs after intravenous injection in both rats and mice (60% of injected dose), caused no lethality, and underwent spontaneous dissolution (50 and 100% within 1 and 5 h, respectively). Although lung homogenates displayed the most intense fibrinolytic activity of all the major organs, dissolution of ME was much slower in isolated perfused lungs (IPL) than was observed in vivo. Addition of rat plasma to the perfusate facilitated ME dissolution in IPL to a greater extent than did addition of tissue-type plasminogen activator alone, suggesting that permeation of the clot by plasminogen is the rate-limited step in lysis. Platelet-containing ME injected in rats lysed much more slowly than did ME formed from fibrin alone.125 I-Thrombi, formed in the pulmonary vasculature of mice in response to intravascular activation of platelets by injection of collagen and epinephrine, were essentially resistant to spontaneous dissolution. Moreover, injection of the antiplatelet glycoprotein IIb/IIIa antibody 7E3 F(abЈ) 2 facilitated spontaneous dissolution of pulmonary ME and augmented fibrinolysis by a marginally effective dose of Retavase (10 g/kg) in rats. These studies show that platelets suppress pulmonary fibrinolysis. The mechanism(s) by which platelets stabilize ME and utility of platelet inhibitors to facilitate their dissolution deserves further study. pulmonary embolism; plasminogen activators; platelets; fibrinolysis; animal model; glycoprotein IIb/IIIa THE LUNG SERVES as a natural filter for thromboemboli of diverse sizes (12). Thrombotic occlusion of the main or lobar pulmonary arteries by large clots (massive pulmonary embolism, PE) is a common cause of morbidity and mortality (15,20). In contrast, pulmonary deposition of microemboli (ME) often does not cause acute symptoms (silent ME). Nevertheless, pulmonary ME is a relatively common accompaniment to acute lung injury (adult respiratory distress syndrome), hyperoxia, bleomycin toxicity, sepsis, trauma, surgery on the lower extremities, and angioplasty (2,21,30,33,36,39,40,44,52,53). Microembolism may lead to inflammation and edema acutely and contribute to the development of pulmonary fibrosis and hypertension over time (4,9,22,27,31).The treatment of PE, as with other venous thromboembolic conditions, is typically restricted to agents such as heparin that retard fibrin clot formation, with a relatively limited use of agents that promote fibrinolysis. Despite the effectiveness of such therapy, PE remains a common cause of mortality and morbidity. Thus there is a continuing need for more effective means to prevent and treat both PE and ME, based on a more thorough understanding of the mechanisms that regulate clot dissolution in the lung.For example, the role of platelets in PE and ME has received relatively little study. Recently, it has been shown tha...

An MRI study of the differences in the rate of thrombolysis between red blood cell‐rich and platelet‐rich components of venous thrombi ex vivo

“…3b). The correlation coefficient (r ¼ 0.734) confirmed a sound concurrence with confocal microscopy studies of model clots in vitro, where platelets were shown to impede the transport of thrombolytics into the clot (24,27). The correlation could serve for estimation of thrombolysis outcome if the initial platelet proportion is known.…”

“…Aged thrombi may contain also collagen type III that increases their compactness and impairs the response to thrombolysis (26). Further discrepancies in dissolution properties can be attributed to inefficient perfusion into the thrombus due to platelet coalescence, that is, Zahn lines, which impede the transport of the thrombolytic agent (27). In our study, platelet laminations were often found near the surface of thrombi, thus preventing efficient permeation of plasma containing rt-PA into the deeper layers (Fig.…”

Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature

“…However, prophylactic fibrinolysis by PECAM-targeted PA may help to prevent extension/recurrence of pulmonary thromboembolism 32,46 and attenuate acute lung graft rejection because of thrombotic occlusion of the pulmonary vasculature. 47 Because of the pan-endothelial nature of PECAM expression and the opportunity to enrich local delivery using catheters, 17 a wider utility to protect other vascular beds against imminent thrombosis can be envisioned.…”

“…10,32 One hour later, mice were killed and residual isotope was measured in the lungs. As in previous studies, 10,32 spontaneous dissolution of emboli in control mice at this time was approximately 50%.…”

“…After tail vein injection, these emboli form larger aggregates by incorporating additional fibrin and lodge in the pulmonary precapillary bed. 32 To model prophylactic fibrinolysis, we injected various doses of scFv-uPA and the same amount of nontargeted lmw-scuPA prior to injecting 125 I-emboli and measured the residual isotope in the lungs 1 hour later. At all doses tested, the fusion protein produced significantly greater clot lysis than enzymatically identical doses of nontargeted lmw-scuPA (P Ͻ .025) ( Figure 6A).…”