A presentation on fibrinolytic system.pptx

fibronylytic system

1. FIBRINOLYTIC SYSTEM Department of omfs

2. CONTENTS INTRODUCTION HISTORY CLOTTING SYSTEM COMPONENTS OF FIBRINOLYTIC SYSTEM PATHWAY ROLE IN DISEASE LAB INVESTIGATIONS PHARMACOLOGY

3. INTRODUCTION fibrinolytic system, also termed the plasminogen–plasmin system, is an important physiological system and a key player in the haemostatic balance Fibrinolysis is the process of fibrin degradation by plasmin and is activated when fibrin is formed as the end product of blood coagulation Thus, the fibrinolytic system is crucial in regulating intravascular fibrin deposition and clearance, maintaining haemostasis and facilitating wound healing while avoiding thrombosis

4. HISTORY It was discovered by the Italian anatomist and physician Giovanni Battista Morgagni in the 18th century that in some cases, blood does not coagulate after sudden death In the late 19th century, it was observed that dissolved fibrin could not be brought to clot again despite the addition of thrombin. This indicated that fibrin clot breakdown was the result of enzymatic digestion In 1889, Denys and De Marbaix postulated the existence of a dormant enzyme that could dissolve blood clots, and the term “fibrinolysis” appears to have been used for the first time by Dastre in 1893 Dastre , 1893

5. CLOTTING SYSTEM Blood is a necessary component of the human body, and the loss of this fluid may be life-threatening. Blood is generated via hematopoiesis and ultimately becomes the delivery method for oxygen to the tissues and cells. The human body protects against loss of blood through the clotting mechanism.

6. The clotting mechanism is broken into 2 stages: Primary hemostasis: Formation of a weak platelet plug Secondary hemostasis: Stabilizing the weak platelet plug into a clot by the fibrin network

7. FACTORS AFFECTING CLOT STABILITY Many factors, including local calcium concentration, pH, and platelet numbers, affect clot stability • Stability is also based partly on fibrin fiber diameter , and the geometry of the fibrin network. • Local thrombin concentration also impacts clot structure, as higher thrombin concentrations generate more stable clots • Fragile clots are more susceptible to fibrinolysis and bleeding, whereas firm clots are more resistant, but may promote thrombosis • The variables that affect fiber architecture are ultimately important for fibrinolysis, since both fiber size and arrangement impact tissue plasminogen activator (tPA) binding and rates of fibrinolysis

8. COMPONENTS OF FIBRINOLYTIC SYSTEM Profibrinolysin (or plasminogen) Fibrinolysin(or Plasmin) Activators - Endogenous & Exogenous Inhibitors - For plasmin & For PLG activators.

9. PLASMINOGEN A plasma glycoprotein Produced by the liver activated by the action of specific enzymes: plasminogen activators. Degradation of fibrin Fibrin degradation products (FDP)s Effect of plasmin Lyses factor V and VIII Proteolysis of fibrinogen Removes small peptides

10. Plasminogen activators Intrinsic activators a. Agents endogenous to blood and may convert plasminogen to plasmin when blood comes in contact with a foreign surface. b. Includes: Factor XIIa , XIa , Kallikrein Extrinsic activators: a. Agents extrinsic to the blood and are widely distributed in almost all body tissues including vascular endothelium. b. Include Tissue-type plasminogen activator ( t-PA ), Urokinase plasminogen activator ( u-PA )

11. Hvas , C.L.; Larsen, J.B. The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment. Int. J. Mol. Sci. 

12. REGULATION OF FIBRINOLYSIS The plasmin-generating potential of plasma is sufficient to degrade completely all of the fibrinogen in the body in a very short period of time. It is prevented from doing so by: ▪ PLG activator inhibitors (PAIs) ▪ Inhibitors of plasmin itself (the antiplasmins)

13. Inhibitors of plasminogen activation 1. Plasminogen activator inhibitor-1(PAI-1) • Produced and secreted into the blood by endothelial cells. • present in the platelets • Rapidly inactivates t-PA and u-PA

14. 2. Plasminogen activator inhibitor- 2(PAI-2) • Inhibitor of tPA → Mainly produced by the placenta • Inhibition of fibrinolysis which occurs during pregnancy 3. Protein C pathway→Stimulates fibrinolysis by decreasing tPAI-1 activity

15. Inhibitors of plasmin a2-Antiplasmin Alpha 2 Macroglobulin Alpha 1 Antitrypsin Alpha 1 Antitrypsin Thrombin-activated fibrinolytic inhibitors

16. FIBRIN DEGRADATION PRODUCTS (FDPS) Begin to form as plasminogen is activated and plasmin begins to degrade the thrombus. Multiple FDPs, including fibrinopeptide B and other fibrin degradation monomers and dimers are released. Normally the FDPs are cleared from the circulation by macrophages.

17. Pathologic Effect of FDPs 1. Anti-thrombin activity. 2. Interference with polymerization of fibrin monomer. 3. Interference with platelet activity. 4. Individual FDPs may have immunomodulatory effects. 5. Some FDPs appear to have thrombo-regulatory properties.

18. LAB INVESTIGATIONS DYNAMIC ASSEY a) Euglobulin Lysis Time and Plasma-Based Clot Formation and Lysis Assays i ) The ELT is sensitive to the fibrinolytic capacity of the patient’s plasminogen/plasmin-tPA system ii) it has the disadvantage of excluding the effect of antifibrinolytic proteins b) Plasmin Generation i ) The assays use a fluorogenic substrate with high specificity for plasmin and continuously measure fluorescence after sample activation with tissue factor and tPA ii) E xogenous tPA is added to enhance fibrinolysis and so the assay is less sensitive to the effect of the patient’s endogenous tPA.

19. Fibrin Clot Structure i ) F ibrin clot structure, i.e., fibre thickness , fibrin density and pore size , are the main determinants of lysis time . ii) can be assessed in the microscope or determined through measuring fibrin clot permeability Viscoelastic test Viscoelastic tests include: a) thromboelastography (TEG ® ), b) rotational thromboelastometry (ROTEM ® ), and c) Sonoclot ® *  viscoelastic tests are implemented worldwide to guide transfusion strategy in the bleeding patient 

20. Measurement of Circulating Factors Circulating Pro- and Antifibrinolytic Proteins i ) Specific assays are available either in-house or commercially for most of the pro- and antifibrinolytic proteins known today, including plasminogen, α2-antiplasmin, PAP complex, tPA, PAI-1 and -2, and TAFI.

21. Fibrin Degradation Products i ) Measurement of fibrin degradation products (FDPs) in plasma has been performed for decades, and FDPs in some form are among the most commonly investigated coagulation biomarkers worldwide ii) The first ELISAs were developed in the late 1980s, and fibrin D-dimer measurement was in clinical use in 1991. This marker has since been implemented in the diagnosis of various prothrombotic conditions, most notably venous thromboembolism and disseminated intravascular coagulation. However, as fibrin D-dimer and other FDPs reflect both fibrin formation and breakdown, they are not particularly specific for fibrinolysis speed, and plasma levels of FDPs have not been demonstrated unambiguously to be good markers for increased or decreased fibrinolytic capacity. Other routine coagulation assays, such the prothrombin time (PT/INR) and activated partial thromboplastin time ( aPTT ), reflect clotting times only and are not sensitive to fibrinolytic capacity at all. Thus, we still lack reliable markers for fibrinolysis in the routine coagulation laboratory.

22. Fibrinolysis in Specific Clinical Settings

23. Pharmacology Antifibrinolytics such as aminocaproic acid (e-aminocaproic acid) and tranexamic acid are used as inhibitors of fibrinolysis. Their application may be beneficial in patients with hyperfibrinolysis because they arrest bleeding rapidly if the other components of the hemostatic system are not severely affected. This may help to avoid the use of blood products such as fresh frozen plasma with its associated risks of infections or anaphylactic reactions. The antifibrinolytic drug aprotinin was abandoned after identification of maJor side effects, especially on kidney.

24. Future aspect In the last 75 years, the map of the fibrinolytic system has been established and is still expanding Studies applying viscoelastic assays, modified to identify changes in fibrinolysis related to clinical outcome are awaited, as this will identify patients who will benefit from antifibrinolytic or profibrinolytic treatment. Particularly in major trauma and brain trauma, fibrinolysis changes with time and may shift from hyper- to hypofibrinolysis , closing the window for antifibrinolytic treatment within a short time after trauma. (Ref: 2023, Hvas , C.L.; Larsen, J.B. The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment. Int. J. Mol. Sci.) 

25. In sepsis and VTE, hypofibrinolysis predominates, but treatment options are limited and awaited. Inhibitors of PAI-1, α2-antiplasmin, and TAFI may in time progress to clinical trials, as may low-dose thrombolysis. In pulmonary embolisms, the refinement of thrombolysis and mechanical removal of the clot are part of ongoing clinical trials In conclusion, investigations of fibrinolysis in the clinical setting, as well as the further development of laboratory assays, are needed, and hold potential for major improvements in patient care and outcome. (Ref: 2023, Hvas , C.L.; Larsen, J.B. The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment. Int. J. Mol. Sci.) 

26. references 1. Hvas , C.L.; Larsen, J.B. The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment.  Int. J. Mol. Sci.   2023 ,  24 , 14179 1. Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015; 29 (1): 17-24. doi:10.1016/j.blre.2014.09.003 2. Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost . 2009;7(1):4–13. 3. Cesarman -Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. Br J Haematol . 2005;129(3):307–21 4. Sembulingam K, Sembulingam P. Essentials of medical physiology. JP Medical Ltd; 2019. 5. Mehta PJ. Practical Medicine for Students and Practitioners, Thirteenth edition, 1998