How platelets safeguard vascular integrity

Abstract

The haemostatic role of platelets was established in the 1880s by Bizzozero who observed their ability to adhere and aggregate at sites of vascular injury. It was only some 80 years later that the function of platelets in maintaining the structural integrity of intact blood vessels was reported by Danielli. Danielli noted that platelets help preserve the barrier function of endothelium during organ perfusion. Subsequent studies have demonstrated further that platelets are continuously needed to support intact mature blood vessels. More recently, platelets were shown to safeguard developing vessels, lymphatics, as well as the microvasculature at sites of leukocyte infiltration, including inflamed organs and tumours. Interestingly, from a mechanistic point of view, the supporting role of platelets in these various vessels does not necessarily involve the well-understood process of platelet plug formation but, rather, may rely on secretion of the various platelet granules and their many active components. The present review focuses on these nonconventional aspects of platelet biology and function by presenting situations in which platelets intervene to maintain vascular integrity and discusses possible mechanisms of their actions. We propose that modulating these newly described platelet functions may help treat haemorrhage as well as treat cancer by increasing the efficacy of drug delivery to tumours.

Figure 1. Platelets support the integrity and barrier function of resting and developing blood vessels

A. Ultrastructural changes of the resting endothelium associated with severe thrombocytopenia. Upper panels: the endothelium of a normal capillary (Control) is of a fairly uniform thickness but is attenuated by more than 50% in animals rendered thrombocytopenic by platelet antiserum (Thrombocytopenic), thereby nearly allowing a vesicle (arrow) to bridge its thickness. Arrow: Basement membrane. Lower panels: Localisation of the intravascular contrast agent Thorotrast (T), 5 minutes after intravenous injection in either control or thrombocytopenic rabbits. While Thorotrast was observed only in the vascular lumen of control animals, it was seen also in the extracellular space of thrombocytopenic animals, showing the reduced barrier function of the endothelium during thrombocytopenia. Arrow: Basement membrane. Adapted from Ref. [11], with permission of the American Society of Hematology; permission conveyed through Copyright Clearance Center, Inc. B. Effect of platelet depletion on angiogenesis. Photographs of eyes from control and thrombocytopenic mice, 72 and 96 h after intracorneal implantation of hydron pellets containing 80 ng of basic FGF. Note the undefined borders of the vessels due to haemorrhage in the eyes of platelet depleted mice. Reproduced from Ref. [41], with permission; copyright (2006) National Academy of Sciences, USA.

Figure 2. Platelets secure inflamed vessels

Photographs of progressing immune complex-induced skin inflammation in dorsal skinfold chambers of control and thrombocytopenic mice. In the absence of platelets, petechial bleeding (arrowheads) was detected as early as 20 minutes after the onset of inflammation while there were virtually no petechial spots in nondepleted control animals.

Figure 3. Schematic of the maintenance of tumour vascular integrity by platelets

Left: The tumour microenvironment provides proinflammatory and pro-coagulant signals that result in endothelial activation, in leukocyte infiltration and local degranulation of platelets. The factors released from activated platelets stabilise the tumour vasculature by inhibiting the activity and/or the release of injurious products from tumour infiltrating-leukocytes. Right: During thrombocytopenia, the absence of the leukocyte-countering activities of platelets leads to cytotoxic intratumour haemorrhage through leukocyte-induced vascular breaches. Induction of tumour haemorrhage by targeting platelets enables improvement of chemotherapy efficacy by increasing the accumulation of the circulating drugs in the tumour. Insets, representative photographs of subcutaneous Lewis lung carcinoma tumours from control (left) and thrombocytopenic (right) mice.