Chapter 87: Fibrinolysis and Thrombolysis

HYPERFIBRINOLYSIS

Pathophysiology

• Local activation of the fibrinolytic system accompanies the formation of the hemostatic plug and is important in repair of injury and reestablishment of blood flow.

• Excessive local or systemic fibrinolysis can prematurely degrade fibrin clots and lead to significant bleeding.

Systemic Hyperfibrin(ogen)olysis

• Endothelial cell plasminogen activator may be released in pathologic states in sufficient amounts to convert plasma plasminogen to plasmin.

• A hemorrhagic state may ensue with the following laboratory features:

  — Shortened euglobulin lysis time

  — Decreased levels of fibrinogen, plasminogen, and α₂-antiplasmin

  — Elevated levels of fibrin(ogen) degradation products

  — Normal platelet count

  — Low levels of factor V and VIII (due to proteolytic degradation by plasmin)

• Localized fibrinolysis may also cause abnormal bleeding in patients with either normal or defective hemostasis.

THROMBOLYTIC TREATMENT

Principles

• All fibrinolytic drugs are enzymes that accelerate the conversion of plasminogen to plasmin, a serine protease that degrades the insoluble fibrin clot matrix into soluble derivatives.

• The basic principle of all fibrinolytic therapy is administration of pharmacologic amounts of plasminogen activator to achieve a high local concentration at the site of the thrombus and thereby accelerate conversion of plasminogen to plasmin and increase the rate of fibrin dissolution.

• If large amounts of plasminogen activator overwhelm the natural regulatory systems, plasmin may be formed in the blood, resulting in degradation of susceptible proteins, the “lytic state.” Additionally, because high concentrations of activator are not limited to the site of thrombosis, fibrin deposits at other sites, including physiologic hemostatic plugs needed at sites of injury, may also dissolve, causing local bleeding that is often exacerbated by the hypocoagulable state caused by proteolysis of other coagulation factors by plasmin.

• Several therapeutic agents are available and approved for thrombolytic use (Table 87–1).

Streptokinase

• This single-chain polypeptide derives from β-hemolytic streptococci.

• It lacks intrinsic enzymatic activity but combines stoichiometrically with plasminogen to form a complex that possesses plasmin-like proteolytic activity.

• The streptokinase–plasminogen complex converts free plasminogen to plasmin.

• The activity of streptokinase is enhanced by fibrinogen, fibrin, and fibrin degradation products.

• The streptokinase–plasmin(ogen) complex is itself proteolytically degraded by plasmin.

• Allergic reactions to streptokinase, including fever, hypotension, urticaria, and bronchospasm, may occur, necessitating the use of ...