Harpers

606 / CHAPTER 51Table 51–3. Comparison of some properties ofstreptokinase (SK) and tissue plasminogenactivator (t-PA) with regard to their use asthrombolytic agents. 1 SK t-PASelective for fibrin clot − +Produces plasminemia + −Reduces mortality + +Causes allergic reaction + −Causes hypotension + −Cost per treatment Relatively low Relatively high(approximate)1 Data from Webb J, Thompson C: Thrombolysis for acute myocardialinfarction. Can Fam Physician 1992;38:1415.Thrombin, formed from the coagulation cascade, isthe most potent activator of platelets and initiatesplatelet activation by interacting with its receptor onthe plasma membrane (Figure 51–8). The furtherevents leading to platelet activation are examples oftransmembrane signaling, in which a chemical messengeroutside the cell generates effector molecules insidethe cell. In this instance, thrombin acts as the externalchemical messenger (stimulus or agonist). Theinteraction of thrombin with its receptor stimulates theactivity of an intracellular phospholipase C. This enzymehydrolyzes the membrane phospholipid phosphatidylinositol4,5-bisphosphate (PIP 2 , a polyphosphoinositide)to form the two internal effector molecules,1,2-diacylglycerol and 1,4,5-inositol trisphosphate.Hydrolysis of PIP 2 is also involved in the action ofmany hormones and drugs. Diacylglycerol stimulatesCollagenProstacyclin TxA 2 Thrombin ADPAggregationFibrinogenR 1 R 2 R 3 R 4 R 5+++ ++PLCβ PIP 2AC PLA 2 PLGPllb-lllaPlasmamembranecAMPArachidonic acid+PKCSignalingeventsTxA 2–IP 3DAGActinCa 2+ Phosphorylationof light chain ofmyosinPhosphorylationof pleckstrinRelease of contentsof platelet granules(dense and alpha),including ADP;signaling eventsActomyosinChange of shapeFigure 51–8. Diagrammatic representation of platelet activation. The external environment,the plasma membrane, and the inside of a platelet are depicted from top to bottom.Thrombin and collagen are the two most important platelet activators. ADP is considereda weak agonist; it causes aggregation but not granule release. (GP, glycoprotein; R 1 –R 5 ,various receptors; AC, adenylyl cyclase; PLA 2 , phospholipase A 2 ; PL, phospholipids; PLCβ,phospholipase Cβ; PIP 2 , phosphatidylinositol 4,5-bisphosphate; cAMP, cyclic AMP; PKC,protein kinase C; TxA 2 , thromboxane A 2 ; IP 3 , inositol 1,4,5-trisphosphate; DAG, 1,2-diacylglycerol.The G proteins that are involved are not shown.)