Platelets and the Endothelium: Linking Three Important Syndromes

By Stephanie L. Perry, M.D. and
Thomas L. Ortel, M.D., Ph.D.

The underlying etiology and clinical presentation of sepsis, heparin-induced thrombocytopenia (HIT), and antiphospholipid antibody syndrome (APS) has been well characterized over the years. However, the platelet endothelial interactions common to all three syndromes are receiving greater attention to explain the similari- ties of venous and/or arterial thrombosis and thrombocytopenia. In yesterday's Education Session, Platelet- Endothelial Interactions: Sepsis, HIT, and Antiphospholipid Syndrome, experts on these syndromes gave an out- standing review on the clinically important issues of diagnosis and treatment of these often devastating disor- ders, as well as giving insight into their common pathogenic cause of a procoagulant state with associated thrombocytopenia.

Dr William Aird began the session with a discussion of the different functional activities of the endothe- lium and how these activities are regulated in space and time referred to as "endothelial cell heterogeneity" or "vascular diversity". He further explained how the platelets and endothelial cells communicate via dif- ferent mechanisms, and how this communication can become "excessive", resulting in increased interaction between the two types of cells and ultimately to a procoagulant state. In sepsis, the homeostasis is inter- rupted by monocyte/tissue macrophage binding to the lipopolysaccharide of the bacterial wall, activating clotting factors which interact with "protease-activated receptors" on moncytes, platelets, and endothelial cells to induce the inflammatory response. In addition to platelet entrapment in fibrin clots, the activated endothelium leads to platelet sequestration. Dr. Aird also discussed five proven therapies for improving the survival in patients with sepsis, including (1) low tidal volume ventilation, (2) low-dose glucocorticoids, (3) intensive insulin therapy, (4) rapid hemodynamic support, and (5) activated protein C therapy. These thera- pies may play a role by protecting the endothelium which in turn has led to the improvement in patient survival.

In discussing HIT, Dr. Theodore Warkentin pointed out that HIT antibodies can activate endothelial cells and monocytes. It is the development of pathogenic IgG antibodies to platelet factor 4 (PF4) and heparin which bind to the platelet surface and become cross-linked that cause platelets to be easily destroyed. The PF4 molecules form tetramers which then binds to heparan sulfate on endothelial cells. Thrombin generation results from the procoagulant activity of platelet microparticles, and possibly by endothelium and monocytes. Dr. Warkentin also reviewed the importance of treating patients with direct thrombin inhibitors (DTIs) and emphasized the need to overlap DTI therapy with oral antico- agulation to avoid warfarin-associated necrosis.

The last speaker, Dr. Jacob Rand, reviewed the current proposed mechanisms of thrombosis in patients with APS. In this autoimmune syndrome, patients develop antibodies to phospholipid-binding protein cofactors, usually ß2-glycoprotein I. In addition to causing platelet activation and aggregation, antiphospholipid anti- bodies have been noted to effect the endothelium in a similar fashion as lipopolysaccharide. A recent study also suggests the involvement of the toll-like receptor family in the interaction between antiphospholipid antibodies and an immortalized human microvascular endothelial cell line.

In a related topic to be presented in the Scientific Committee on the Thrombo-Inflammatory Role of Platelets, Dr. David Phillips will present work using a murine model to better elucidate the role of the transmembrane protein, CD40L, in regulating inflammation and thrombosis. He will also present new findings of how this relates to GP IIa-IIIb as both an "inflammatory mediator to platelet func- tion" and to "thrombosis". (Session today from 7:30 a.m. - 9:15 a.m.)