Clotting mechanism and anticoagulant.pptx

The clotting mechanism, also known as coagulation, is a vital physiological process that prevents excessive bleeding when blood vessels are injured. It involves a series of complex interactions between platelets, clotting factors, and the vascular system. The coagulation cascade consists of intrinsic and extrinsic pathways that ultimately lead to the conversion of fibrinogen into fibrin, forming a stable clot. This process ensures hemostasis while maintaining a balance to prevent unnecessary clot formation, which could lead to conditions such as thrombosis.

1. CLOTTING MECHANISM AND ANTICOAGULANTS GUIDED BY: DR. NEEMA SHETTY DR. ADITI MATHUR DR. ASHISH BALI DR. TRISHI PRESENTED BY: DR. BHAVIKA CHHAJED 1 ST YR. PG

2. CONTENTS INTRODUCTION PHYSIOLOGY OF HEMOSTASIS CLOTTING FACTORS MECHANISM OF BLOOD COAGULATION ANTI-COAGULANTS PRO-COAGULANTS/HEMOSTATICS MANGEMENT OF BLOOD LOSS APPLIED ASPECTS CONCLUSION REFERENCES

3. INTRODUCTION COAGULATION/BLOOD CLOTTING : Coagulation or clotting is defined as the process in which blood loses its fluidity and becomes a jelly-like mass few minutes after it is shed out or collected in a container. HEMOSTASIS : Set of process that regulate 2 important functions 1. They maintain blood in a fluid, clot - free state in normal vessel. 2. They are poised to induce a rapid and localised hemostatic plug at a site of vascular injury.

4. PHYSIOLOGY OF HEMOSTASIS : Hemostasis means prevention of blood loss It may be thought of as a tightly regulated sysment of interdepent factors Hemostasis consists of 3 phases : 1.Vascular constriction 2. Formation of platelet plug 3. Formation of a Blood clot as a result of Blood coagulation The first two phases constitute primary hemostasis and the remaining coagulation phase constitutes of the secondary hemostasis.

5. Thromboxane A2 from platelet membrane. Serotonin from dense granules of platelets. Endothelin from injured endothelium. Neurogenic reflex by pain receptors. VASCULAR CONSTRICTION

6. PRIMARY HEMOSTASIS PLATELET PLUG FORMATION:

7. SECONDARY HEMOSTASIS Coagulation or clotting is defined as the process in which blood loses its fluidity and becomes a jelly-like mass few minutes after it is shed out or collected in a container. COAGULATION OF BLOOD

8. FACTORS INVOLVED IN BLOOD CLOTTING Factor I - Fibrinogen Factor II - Prothrombin Factor III - Tissue Thromboplastin Factor IV - Calcium Ions Factor V - Labile Factor Factor VII - Stable Factor Factor VIII - Antihemophilic Factor Factor IX - Christmas Factor Factor X - Stuart- Prower Factor Factor XI - Plasma Thromboplastin Antecedent Factor XII - Hageman Factor Factor XIII - Fibrin Stabilizing Factor

9. MECHANISM OF BLOOD CLOTTING 1.Formation of Prothrombin Activation 2. Conversion of Prothrombin into thrombin 3. Conversion of fibrinogen into fibrin THREE STAGES

10. STAGE 1: FORMATION OF PROTHROMBIN ACTIVATOR Blood clotting commences with the formation of a complex of activated substance called prothrombin activator, which converts prothrombin into thrombin. It occurs through two pathways :

11. STAGE 2: CONVERSION OF PROTHROMBIN TO THROMBIN

12. STAGE 3: CONVESRSION OF FIBRINOGEN TO FIBRIN

13. D efined as the mass of coagulated blood which contains RBCs, WBCs and platelets entrapped in fibrin meshwork. The trapped RBCs are responsible for the red color of the clot. The external blood clot is also called scab. It adheres to the opening of damaged blood vessel and prevents blood loss. BLOOD CLOT Fibrin meshwork RBC’s Platele t

14. After its formation, the blood clot starts contracting. Straw-colored serum oozes out of the clot a fter about 30 to 45 minutes . CLOT RETRACTION : The process involving the contraction of blood clot and oozing of serum is called clot retraction . Contractile proteins, namely actin, myosin & thrombosthenin in the cytoplasm of platelets are responsible for clot retraction.

15. FIBRINOLYSIS Lysis of blood clot inside the blood vessel is called fibrinolysis. It helps to remove the clot from lumen of the blood vessel. Requires a substance called plasmin or fibrinolysin. SIGNIFICANCE: allows reopening of affected blood vessel & prevents the development of infarction .

16. BLEEDING TIME Time interval from oozing of blood after a cut or injury till arrest of bleeding. Normal time – 3-6 mins. CLOTTING TIME Time interval from oozing of blood after a cut or injury till the formation of clot. Normal duration – 3-8mins. THROMBIN TIME (TT) Time taken for the blood to clot after adding thrombin to it. Use: to investigate the presence of heparin in plasma or to detect fibrinogen abnormalities. Involves observation of clotting time after adding thrombin to patient’s plasma. Normal duration - 12 to 20 seconds. It is prolonged in heparin therapy . LAB INVESTIGATIONS

17. PROTHROMBIN TIME (PT) Time taken by blood to clot after adding tissue thromboplastin to it. Indicates: total quantity of prothrombin in blood. Normal duration- 10 to 12 seconds. PARTIAL PROTHROMBIN TIME (PPT) Time taken for blood to clot after adding an activator such as phospholipid, along with calcium to it. Activated partial prothrombin time (aPPT). Useful in monitoring the patients taking anticoagulant drugs. Carried out by observing clotting time after adding phospholipid, a surface activator and calcium to a patient’s plasma. Phospholipid serves as platelet substitute. Commonly used surface activator is kaolin. Normal duration- 30 to 45 seconds.

18. INTERNATIONAL NORMALIZED RATIO (INR) Rating of a patient’s prothrombin time when compared to an average. It measures extrinsic clotting pathway system. Useful in monitoring impact of anticoagulant drugs such as warfarin and to adjust the dosage of anticoagulants. Patients should have regular blood tests to know their INR in order to adjust warfarin dosage. Blood takes longer time to clot if INR is higher . Normal INR is about 1. In patients taking anticoagulant therapy for atrial fibrillation, INR should be between 2 and 3. For patients with heart valve disorders, INR should be between 3 and 4. INR greater than 4 indicates that blood is clotting too slowly and there is a risk of uncontrolled bleeding.

19. ANTI-CLOTTING MECHANISM IN THE BODY Under physiological conditions, intravascular clotting does not occur. It is because of some physicochemical factors in the body. PHYSICAL Continous circulation of blood Smooth endothelial lining of blood vessels CHEMICAL Natural anti-coagulants by liver: HEPARIN Thrombomodulin + Thrombin Complex inactivates Protein-C+ S inactivates Factor V, VIII Prevents blood clot Inactive state of clotting factors

20. I. Used in vivo A. Parenteral anticoagulants Heparin, Low molecular weight heparin. ii. Heparinoids—Heparan sulfate, iii Danaparoid, Lepirudin, Ancrod. ANTICOAGULANTS B. Oral anticoagulants i) Coumarin derivatives ii) Indandione derivative iii) O ral direct thrombin inhibitor II. Used in vitro Heparin EDTA Oxalate Citrate

21. PARENTERAL ANTICOAGULANTS : It is a naturally produced anticoagulant. Found in the mast cells of the liver, lungs and intestinal mucosa abundantly because they receive embolic clots formed in slowly flowing venous blood. Basophils also secrete heparin. COMMERCIALLY, prepared from liver & other organs of animals. Available in liquid form or dry form as sodium, calcium, ammonium or lithium salts. Most expensive. Can be used in pregnancy(does not cross placental barrier). HEPARIN :

22. MECHANISM OF ACTION OF HEPARIN USES OF HEPARIN i. To prevent intravascular blood clotting during surgery. ii. While passing the blood through artificial kidney for dialysis. iii. During cardiac surgery, which involves heart lung machine. iv. To preserve the blood before transfusion. v.Used as anticoagulant in vitro while collecting blood for various investigations.

23. ADVERSE REACTIONS: Bleeding Heparin-induced thrombocytopenia (HIT) Hypersensitivity reactions(RARELY) Reversible alopecia CONTRAINDICATIONS: h aemophiliacs , patients with heparin-induced thrombocytopenia ( H IT), severe h ypertension, intracranial h aemorrhage, bacterial endocarditis, active tuberculosis, peptic ulcer, threatened abortion, cirrhosis, renal failure, etc .

24. LOW-MOLECULAR-WEIGHT HEPARINS (LMWHS): Enoxaparin, dalteparin, tinzaparin, ardeparin, reviparin Obtained by chemical/ enzymatic treatment of standard heparin. Molecular wt.= 4000-7000 Selectively inhibit factor Xa Lesser anti-platelet action. No significant effect on clotting time. USES: Prevention and treatment of venous thrombosis and pulmonary embolism. Unstable angina maintain the patency of tubes in dialysis patients. ADVANTAGES: Better bioavailability following SC injection. Longer action Lower risk of bleeding (because of less interaction with platelets) Lower incidence of thrombocytopenia (because less antigenic) and thrombosis Routine lab monitoring not required.

25. HEPARINOIDS: Heparin analouges that inhibit factor Xa . Longer shelf-life than unfractionated heparin. Lesser bleeding complications. FONDAPARINUX: Synthetic parenteral anticoagulant. Indirect thrombin inhibitor by binding to factor Xa . Administered subcutaneously. Useful in pulmonary embolism and deep vein thrombosis ( dvt ). DIRECT THROMBIN INHIBITORS: Lepirudin and bivalirudin combine directly and inactivate thrombin without binding to antithrombin III. They are used in patients who are at risk of heparin induced thrombocytopaenia .

26. ORAL ANTICOAGULANTS: Act only in vivo . Vitamin k antagonists. COUMARIN DERIVATIVES: Warfarin, dicoumoral Inhibit synthesis of vitamin k-dependent biologically active clotting factors.

27. Almost completely absorbed after oral administration. Long half-life= 40hrs. Duration of action=2-5 days. Highly bound to plasma proteins, metabolized in liver. Freely crosses placental barrier -contraindicated in pregnancy.

28. ADVERSE EFFECTS: Bleeding: Bleeding is the most important and common side effect of warfarin. Bleeding can occur anywhere—skin, pulmonary, gastrointestinal and urinary tract, cerebral, hepatic, uterine, etc. Epistaxis & bleeding gums may also be seen. Bleeding can be controlled by oral or parenteral vitamin K1 (depending on severity). Fresh frozen plasma should be given in severe bleeding. Teratogenic effect: Warfarin is contraindicated during pregnancy as it may cause foetal CNS abnormalities, foetal haemorrhage , abortion or intrauterine death. Skin necrosis : It is a rare complication that occurs within the first week of therapy. Other rare side effects: These include diarrhoea, alopecia, urticaria, dermatitis, abdominal cramps and anorexia.

29. Hemostatic disorders

30. Hemophilia Types :

31. Known as – Royal Disease. Incidence - 1 or 2/10000 of the population Caused by deficiency of factor VIII - complete or partial. Inherited as a sex linked recessive character appearing only in males. Transmitted to them by clinically normal female carriers. Hemophilia A

32. Clinical Manifestations At level 25-50% of normal Minor injuries do not bleed. No trouble unless suffered from major trauma. At level of 10-25% of normal More serious bleeding occur after minor injuries. Below 10% Bleeding into muscles and joints occur .

33. Spontaneous bleeding Hemorrhage in GIT Bleeding in Joints Blood in Urine Symptoms- Post-extraction Hemorrhage

34. Oral Ulcerations & Ecchymosis in toddlers Sharp teeth can be prone to oral bleeding Recession of the attached gingiva & bone loss Pseudohaemophilia Tumour

35. Diagnose the exact nature of the disorder. Replacing the missing factor VIII in the blood. Factor VIII concentrate commercially available as cryoprecipitated antihemophilic factor for intravenous infusion. Treatment

36. Also known as – Hemophilia B Caused by Factor IX deficiency. Pattern of inheritance and clinical manifestations are similar as in Hemophilia A. PT is normal and aPTT is prolonged Christmas disease

37. Also known as Pseudohemophilia . Most common congenital disorder of hemostasis, 1% prevalence. Due to deficiency of Von- Willebrand Factor. Binding with plasma proteins (especially factor VIII) is the main function of von Willebrand’s factor. Disease Causes deficiency of Factor VIII and it suppresses Platelet Adhesion. Von Willebrand’s disease

38. Treatment: Replacement therapy. Antifibrinolytics. Topical agents.

39. Occurs due to low number of platelets in circulating blood. Most common abnormality of hemostasis that result in bleeding in the surgical patient. May also occur acutely as a result of massive blood loss followed by replacement with stored blood. Thrombocytopenia

40. Spleen is palpable in some patients. Palatal Petechiae Bleeding Gums Petechial rash Purplish Blotches Ecchymosis

41. PRO-COAGULANTS/HEMOSTATICS Drugs that promote coagulation & control bleeding by vasoconstriction are called coagulants. LOCAL AGENTS ASTRINGENTS ADRENALINE THROMBIN GELATIN SPONGE FIBRIN GLUE COLLAGEN ALGINATE TRANEXAMIC ACID HEMOCOAGULASE BONE WAX OSTENE SYSTEMIC AGENTS VITAMIN K FIBRINOGEN ANTEHEMOPHILIC FACTOR ETHAMSYLATE DESMOPRESSIN TRANEXAMIC ACID HEMOCOAGULASE

42. LOCAL AGENTS Also called STYPTICS. commonly used to control bleeding from capillaries and minute vessels e.g. bleeding following tooth extraction, abrasions, epistaxis, etc. Astringents: Precipitate proteins locally in the bleeding site and control capillary oozing. E.G.- Tannic acid, ferric chloride, ferric sulfate , aluminum chloride, aluminum sulfate , Adrenaline: Topical application of adrenaline brings about vasoconstriction of bleeding capillaries. Cotton pad soaked in 0.1% adrenaline solution is applied on the bleeding site to control capillary oozing.

43. Fibrin glue: Consists of fibrinogen, factor XIII, thrombin, Ca 2+ and other clotting components. Used to control bleeding during surgical procedures or as a spray on the bleeding surface. Fibrin sponge: The fibrin sponge is non-antigenic and is obtained from bovine material. Chemically treated to avoid allergic reactions. Applied on the bleeding site. Fully absorbed by the tissues within 4–6 weeks. Natural collagen sponge: White sponge material, non-antigenic and fully absorbable. Stimulates the platelet aggregation & activates coagulation factors XI & XIII; thereby enhancing haemostasis .

44. Calcium alginate/Alginic acid: Obtained from sea weeds. Available in powder form in special 5-mg packages. Absorbable haemostatic placed over the bleeding sites, a protective film is formed which compresses the capillaries & stabilises the blood clot. Used to promote wound healing. Microfibrillar collagen: Collagen derived from bovine skin causes contact activation in addition to direct platelet aggregation. Ineffective in thrombocytopaenia. A bsorption time is 3 months.

45. Haemocoagulase : Haemocoagulase enzyme complex is isolated from the venom of Bothrops atrox (viper). Mechanism of action: It has a powerful haemostatic effect. It promotes coagulation by two enzymes: One has thrombin like action (converts fibrinogen to fibrin) Another has thromboplastin- like action. Also shortens the bleeding and clotting time; thereby it controls capillary bleeding.

46. Pharmacokinetics: available for topical, intravenous, intramuscular and subcutaneous administration. Rapid onset of action—within 5–10 min of i.v. ; 20–30 min after i.m. administration and within a minute of topical application (spray/soaked swab). Indications: To control bleeding following tooth extraction or any other dental procedure. For prevention and treatment of haemorrhagic conditions of different etiology. Adverse effects are rare.

47. Tranexamic acid: Bind to plasminogen and plasmin and prevent the binding of fibrin to these proteins ; and thus reduces bleeding. It is available for oral, i.v. & topical administration. In dentistry, tranexamic acid soaked gauze or mouthwash can be used to reduce b leeding postoperatively in haemophiliacs and in patients on anticoagulant therapy.

48. Bone wax: Sterilised , non-absorbable mix of waxes. Consists of seven parts by weight of wax (white bees wax, paraffin wax and an isopropyl ester of palmitic acid), two parts of olive oil and one part of phenol. It is white and available as a solid rectangular plate weighing 2.5 g. Indicated in cases of bleeding from the bone or from chipped edges of bone. Haemostatic mechanism is through mechanical obstruction of the osseous cavity containing the bleeding vessels. Softened with the fingers to desirable consistency and then applied over the bleeding site. Frequent use may lead to the formation of wax granuloma (foreign body).

49. MECHANICAL METHODS Pressure: Firm pressure should be applied over the bleeding site using either fingers or gauze for at least 5 min. controls most haemorrhages by counteracting the hydrostatic pressure of the bleeding vessel. Haemostat: Application of haemostat at the bleeding points helps in direct occlusion of the bleeding vessel. Su tures and ligation: Severed blood vessels may be tied with ligatures. A ligature replaces the haemostat as a permanent method of effective haemostasis .

50. THERMAL AGENTS Surgical cutting instruments have been modified using thermal agents in order to achieve haemostasis during surgery. These thermal agents coagulate and seal the blood vessels as they cut achieving haemostasis and a bloodless field during surgery. CRYOSURGERY LASER ELECTROCAUTERY

51. Heat achieves hemostasis by denaturation of protein, which results in coagulation of large areas of tissues. In cauterization heat is transmitted from the instrument by conduction directly to the tissues. Electro cautery has replaced direct heat application. Electro Cautery

52. Cooling is applied to control bleeding. Mostly involves use of liquid Nitrogen. Direct cooling is effective and acts by increasing the local intravascular hematocrit and decreasing blood flow by vasoconstriction. Temperature ranging between -20°C to -180°C are used and freezing occurs around the tip of the cannula within 5 seconds. Cryosurgery

53. Hemorrhage is the excessive loss of blood due to rupture of blood vessels. Haemostasis is the process of forming clots in the walls of damaged blood vessels and preventing blood loss. Balance of 5 factors- Vessel wall, platelets, platelets inhibitor, Coagulation factors, Fibrinolytic system is essential for hemostatic balance. Proper use of haemostatic agents at proper time helps in blood clotting. Conclusion

54. Gupta A, Epstein JB, Cabay RJ. Bleeding disorders of importance in dental care and related patient management. Journal of the Canadian Dental Association. 2007 Feb 1;73(1). Guidelines on oral anticoagulation: Third edition. Management of Life-threatening hemorrhage from facial fracture. Preeca Siritongtaworn . J. Med. Assoc. Thai. Vol. 88(3) 2005. Life-threatening hemorrhage after extraction of third molars: Case report and management protocol. Hassan G. Moghadam , Marco Journal of dental sciences vol 49 no.4 223-230 References