Coagulation profile and its uses

pathology

1. Coagulation Studies Dr. Akshay Agarwal Moderator: Dr. Sangeeta Sharma

2. Important question how many for Coffee? Tea??

3. Index Physiological Clotting Mechanism Coagulation tests Inherited coagulation disorders Acquired coagulation disorders

4. Mechanism of Blood Coagulation 3 essential steps: Clotting cascade to form prothrombin activator Formation of thrombin Formation of fibrin

5. Clotting Cascade

6. Intrinsic Pathway Begins on exposure of the blood to vascular wall collagen which alters Factor XII and gets activated Platelets causing release of phospholipids

7. Intrinsic pathway Prothrombin activator Ca 2+ Ca 2+ Ca 2+

8. Extrinsic Pathway Begins on exposure to traumatized extravascular tissues that come in contact with blood Release of tissue thromboplastin

9. Extrinsic Pathway Prothrombin activator

10. Common Pathway 2 steps Conversion of Prothrombin to Thrombin Conversion of fibrinogen to fibrin

11. prothrombin thrombin fibrinogen Fibrinogen monomer Fibrin fibers Cross linked fibrin fibers Fibrin stabilizing factor C a 2+ C a 2+ Prothrombin activator Common Pathway

12. Some Facts about Clotting Factors All coagulation factors are made by hepatocytes in the liver except Factor VIII which is made by endothelial cells in the liver. Half life from 6 hours to 5 days The synthesis depends of availability of Vitamin K

13. Vitamin K dependent coagulation factors Prothrombin Factor VII Factor IX Factor X Protein C Protein S

14. Coagulation tests Prothrombin time (PT) Activated Partial thromboplastin time( aPTT ) Bleeding time Clotting time Mixing study

15. Prothrombin Time Screens for abnormalities in both extrinsic pathway and common pathway Normal range is 12-14 seconds Prolonged in: Vitamin K def. , warfarin therapy, DIC, liver failure Congenital afribrinogenemia Factor V & X def.

16. aPTT Screens for abnormalities in intrinsic and common pathway Normal range is 25-40 seconds. Causes of prolonged aPTT DIC Hemophilia Liver disease Afribrigonemia Factor V, X

17. Bleeding time Finger prick method (Duke) Time taken from the commencement of bleeding to when it ceases. Normally 1-3 mins Prolonged in Platelet defects - Thrombocytopenic purpura . Primary (Idiopathic) - Thrombocytopenic purpura Secondary - Thrombocytopenic purpura Vascular defects - Senile purpura Henoch Schonlein purpura Platelets are important in preventing small vessel bleeding by causing vasoconstriction and platelet plug formation.

18. Clotting time Clotting time is the interval between the moment when bleeding starts and the moment when the fibrin thread is first seen Normal range is from 2-7 mins prolonged in Hemophilia A & B vitamin K deficiency, liver diseases disseminated intravascular coagulation, overdosage of anticoagulants etc.

19. Mixing study Detects the presence of serum antibodies that are neutralizing the coagulation factors Mix patient’s plasma and normal plasma sp. Perform aPTT assay at following intervals Prolonged aPTT at Time 0 Time 1-2 hours at 37°C Interpretation corrected corrected Factor deficiency Not corrected Not corrected LA or Heparin corrected Not corrected Antibody inhibitor

20. Natural Inhibitors of Coagulation Antithrombin Major inhibitor of thrombin and factor Xa (CP) and factor Ixa , Xia, XIIa (IP) Inherited deficiency leads to life long venous thromboembolism It is a primary target for heparin based anticoagulant therapy

21. Protein C Acts by inactivating factor Va & VIIIa Protein S Cofactor for activated protein S Both C & S deficiencies lead to hypercoagulable state.

22. Inherited Coagulation Disorder All factor deficiencies are autosomal recessive except hemophilia A(factor VIII) & B (factor IX) which are X-linked recessive. All will present with elevated aPTT except Factor VII def– elevated PT Factor XIII def – will not be detected by routine tests. All will present with bleeding tendencies

23. Hemophilia A & B Signs and symptoms Unexplained and excessive bleeding from cuts or injuries, or after surgery or dental work Many large or deep bruises Unusual bleeding after vaccinations Pain, swelling or tightness in your joints Blood in your urine or stool Nosebleeds without a known cause In infants, unexplained irritability PTT will be prolonged and PT will be normal

24. Acquired coagulation disorders Due to decreased production Liver disease Vitamin K deficiency Due to increased consumption DIC Immune mediated Autoantibody against a specific clotting factor

25. Liver disease and Vitamin K def Liver disease evaluation is mandatory before evaluating clotting factor deficiencies. Impaired function due to hepatitis and cirrhosis will lead to decreased production Of note, factor VIII levels may be elevated in hepatitis because it is an acute-phase reactant Vitamin K participates in post-translational gamma- carboxylation of factors required for their activity.

26. DIC Results from uncontrolled local or systemic activation of coagulation leading to activation and consumption of platelets, factors and fibrinogen.

27. Diseases commonly associated with DIC Metastatic carcinoma ( Adenocarcinoma ) Tissue injury Acute promyelocytic leukemia Sepsis Obstetric disorders Amniotic fluid embolism Retained fetus Placental abruption

28. Antibodies to coagulation Factors May develop after factor replacement therapy or spontaneously. Lupus anticoagulant antibody is the most common antibody against factor VIII and V Associated with both venous and arterial thrombotic disease Can be detected by mixing studies

29. Other acquired conditions Systemic Amyloidosis Nephrotic Syndrome Hodgkin’s Lymphoma

30. Approach

31. Thank You