10 Questions
What is the primary purpose of the fibrinolytic/thrombolytic cascade?
To limit clot formation to the immediate site of injury and remove components after tissue repair
Which of the following is a thrombolytic agent used to dissolve existing blood clots?
Streptokinase
What is the primary function of plasminogen activator inhibitor (PAI-1)?
To inactivate any inappropriate tissue plasminogen activator (tPA) in the plasma
Which of the following statements is true regarding the action of $\alpha_2$-antiplasmin (AP)?
It inactivates only free plasmin in the plasma, but not clot-bound plasmin
Which of the following is a common clinical application of thrombolytic therapy?
Treatment of acute myocardial infarction (heart attack)
Which of the following statements is true regarding the administration of thrombolytic therapy?
It is often given in combination with intravenous heparin or LMWH and aspirin
What is the primary function of intact endothelial cells in the regulation of coagulation?
To inhibit coagulation and promote fibrinolysis
Which of the following statements is true regarding heparin-induced thrombocytopenia (HIT syndrome)?
It is a serious adverse effect more apparent after treatment with unfractionated heparin (UFH)
What is the primary function of thrombomodulin expressed on the surface of intact endothelial cells?
To coordinate the protein C anticoagulant pathway
Which of the following is a synthetic heparin-like molecule?
Fondaparinux
Study Notes
Heparin and Fibrinolysis
Overview of Heparin
- Heparin is a linear polysaccharide found naturally in all animal tissues
- Stored in granules of mast cells and basophils
- Highest negative charge density of any known biological molecule
- Used to treat or prevent thrombotic disorders
Heparin Formulations
- Unfractionated heparin (UFH): mixture of different length polysaccharides, mean length 45 saccharide units (15,000 Da), short half-life (1-2 hours)
- Low-molecular-weight heparin (LMWH): fractionated to sequester molecules with low molecular weight but high density of critical pentasaccharide, 15 saccharide units (5000 Da), longer half-life (5-4 hours)
- Synthetic products (e.g., fondaparinux): minimal heparan sulfate pentasaccharide
Mechanism of Action
- Heparin regulates coagulation via antithrombin III (AT III)
- AT III is a plasma protein, weak inhibitor of thrombin (Factor IIa) and Factor Xa
- Heparin binds to AT III, inducing a conformational change that makes AT III a more efficient inactivator of coagulation factors
Indications for Heparin Therapy
- Venous thromboembolism (VTE) prophylaxis following orthopaedic surgery or general surgery in patients at high risk of VTE
- Deep vein thrombosis (DVT)
- Pulmonary embolism (PE)
- Myocardial infarction (MI)
- Urgent Acute coronary syndrome (ACS)
- Stroke or transient ischemic attack (TIA)
- Transitioning patients from other anticoagulant therapy in preparation for surgery
Adverse Effects of Heparin
- Bleeding risk increased with all anticoagulant drugs
- Heparin-induced platelet aggregation and depletion
- Heparin-induced thrombocytopenia (HIT syndrome)
- Osteoporosis
- Hypersensitivity
Heparin-Induced Thrombocytopenia (HIT)
- Immunological response that involves the generation of antibodies against a heparin-platelet factor 4 (PF4) complex
- More prevalent with UFH
- HIT syndrome: an immunological reaction that causes platelet activation, leading to thrombosis and bleeding
Fibrinolytic Cascade
- Purpose: to limit clot formation to immediate site of injury and to remove components of clot after tissue repair
- 4th step in haemostasis
- Thrombolytic agents: decrease the incidence of death following MI by approximately 25%
Fibrinolytic Cascade Mechanism
- Thrombin (generated in response to FXIIIa damage of endothelial cells) activates fibrinogen to form fibrin monomer
- Fibrin polymer is formed, and fibrin degradation products are produced
- Plasminogen is an inactive plasma protein that binds to both fibrinogen and fibrin
- Tissue plasminogen activator (tPA) is synthesized by intact endothelial cells and promotes plasmin formation from plasminogen
Control of the Fibrinolytic Cascade
- Plasminogen activator inhibitor (PAI-1) inactivates tPA
- α2antiplasmin (AP) only inactivates free plasmin in plasma, not clot-bound plasmin
Thrombolytic/Fibrinolytic Drugs
- Pharmaceutic tPA: used to lyse an existing fibrin-containing clot
- Genetically modified variants of tPA: longer half-life or higher affinity for clot-bound plasmin
- Streptokinase: purified from streptococcal bacteria
- Used for acute treatment of:
- Myocardial infarction (heart attack)
- Ischaemic stroke
- Deep vein thrombosis (DVT)
- Massive pulmonary embolism
- Acute limb ischaemia
Test your understanding of the pharmacology of therapeutic heparin formulations like UFH, LMWH, and fondaparinux. Identify drugs impacting the fibrinolytic pathway and endogenous antifibrinolytic proteins. Get ready for your THEPII CV course exam!
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