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In recent years, an understanding of the molecular mechanisms of fibrinolysis has led to major advances in fibrinolytic and antifibrinolytic therapy. Characterization of the genes for all the major fibrinolytic proteins has revealed the structure and function of the relevant serine proteases, their inhibitors, and their receptors. The development of genetically engineered animals deficient in one or more fibrinolytic protein(s) has revealed both expected and unexpected roles for these proteins in both intravascular and extravascular settings. In addition, genetic analysis of human deficiency syndromes has defined specific mutations that result in human disorders reflective of either fibrinolytic deficiency with thrombosis or fibrinolytic excess with hemorrhage. All of these advances have led to development of more effective and safer protocols for fibrinolytic therapy, and for the rational use of antifibrinolytic agents under certain specific circumstances.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: A2, annexin A2; ASK, Australian Streptokinase; ATLANTIS, Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke; cAMP, cyclic adenosine monophosphate; CT, computed tomography; DIC, disseminated intravascular coagulation; EACA, ε-aminocaproic acid; ECASS, European Cooperative Acute Stroke Study; FDA, Food and Drug Administration; HC, homocysteine; IL, interleukin; ISTR, International Stroke Thrombolysis Registry; MAST-E, Multicenter Acute Stroke Trial–Europe; MAST-I, Multicenter Acute Stroke Trial–Italy; MELT, Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Study; MMP, matrix metalloproteinase; Mr, molecular mass; mRNA, messenger ribonucleic acid; NINDS, National Institute of Neurologic Disorders and Stroke; p11, protein p11; PAI, plasminogen-activator inhibitor; PLG, plasminogen; PROACT, Prolyse in Acute Cerebral Thromboembolism; SITS, Safe Implementation of Treatments in Stroke; STILE, Surgery versus Thrombolysis for Ischemia of the Lower Extremity; TAFI, thrombin-activatable fibrinolysis inhibitor; TGF-β, transforming growth factor-β; TOPAS, Thrombolysis or Peripheral Arterial Surgery; t-PA, tissue-type plasminogen activator; u-PA, urokinase plasminogen activator; uPAR, urokinase plasminogen activator receptor.

Fibrin, the insoluble end product of the action of thrombin on fibrinogen, is found in both intravascular and extravascular settings. In response to vascular injury, crosslinked fibrin is deposited in tissues and blood vessels, thus compromising the flow of blood. Once the vessel has healed, the fibrinolytic system is activated, converting fibrin to its soluble degradation products through the action of the serine protease, plasmin (Fig. 136–1A).

Figure 136–1.

Overview of the fibrinolytic system. A. Fibrin based plasminogen activation. The zymogen plasminogen (PLG) is converted to the active serine protease, plasmin (PN), through the action of tissue plasminogen activator (t-PA) or urokinase (u-PA). The activity of t-PA is greatly enhanced by its assembly with PLG through lysine residues (K) on a fibrin containing thrombus. u-PA acts independently of fibrin. Both t-PA and u-PA can be inhibited by plasminogen activator inhibitor 1 (PAI 1), their main physiologic regulator. By binding to fibrin, plasmin is protected from its major inhibitor, α2 plasmin inhibitor (α...

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