Causes of fluidity of blood inside the circulatory system (Factors against intravascular clotting) These factors prevent blood clotting - in normal state. - in injury, they limit the process of coagulation to the site of injury. - help recanalisation of thrombosed blood vessels.

1- Smoothness of endothelium prevents clotting: - Prevent contact activation of XII - Endothelium has –ve charges  repels –ve charged platelet & clotting factors Thrombomodulin (cover endothelium) binds with thrombin preventing its action. Also, it activates protein C (anticoagulant). - Release of prostacyclin (major inhibitor of platelets aggregation) from the healthy endothelium.

2- Anticoagulant in the blood A- Blood flow: The circulating blood Removes activated coagulation factors to be inactivated in liver, spleen and bone marrow B- Fibrin: adsorb 90% of thrombin formed during this process preventing more coagulation. C- Antithrombin III: Combine and inhibit the remaining thrombin and factor Xa

D- Protein C: E- Protein S: activated by thrombin and inhibits the clotting factors V and VIII, and Xa . E- Protein S: potentiate the effect of protein C

Proposed Mechanism of Thrombomodulin, Protein C and Protein S F-Va, VIIIa, Xa Prothrombin Thrombin x Ca++ PS Ca++ Protein C Activated Protein C Thrombin Thrombomodulin

F- Plasmin: G- Heparin: Causes breakdown of fibrin, fibrinogen, prothrombin, factor V ,VIII and XII G- Heparin: - The most powerful anticoagulant - –ve charged mucopolysaccharide - Secreted by mast cells and basophile cells in minute amounts

Mechanism of its action of heparin 1.It combines with antithrombin III  inhibition of thrombin 2. Also, it inhibits the activated factors IX,X ,XI and others.

Heparin mechanism of action Antithrombin III Thrombin

Heparin Thromboplastin

Prevention of blood clotting outside the body ( in vitro anticoagulants) - Removal of Ca++ ions: * by addition of Na oxalate (toxic) or by EDTA (Ethelyne diamine tetraacetic acid). * by Na citrate (not toxic). - Addition of heparin as in artificial kidney machine

Drugs preventing blood clotting inside the body (in vivo anticoagulant drugs)

There are two types of anticoagulants drugs Heparin Coumarin Origin: - Animal origin from - Plant origin as warfarin mast cells and basophils and Dicumarol Mechanism of action: - Anti-thrombin - Inhibits platelet aggregation - Prevent activation of IX, X, XI - Competitive inhibition with vit K in liver. So prevent formation of factors II, VII, IX & X and protein C & S. Site of action: -In vivo and in vitro -In vivo only Onset: -Rapid -Delayed onset (1-3 days) Duration: -Short duration (4-6 h.) then hydrolysed by heparinase enzyme. -Long duration (3 days) Mode of administration: -Intravenous or intra-muscular (as it is digested by the stomach) -Orally Antidote: -Protamine sulphate 1% (It has strong positive charges to neutralize the negative charges of heparin) -Vitamin K or blood transfusion

Coumarin

Fibrinolytic System Definition Fibrinolysis means lysis and removal of blood clot after stoppage of bleeding and healing of the vascular wall This is produced by enzyme called plasmin (fibrinolysin) which present in plasma as inactive plasminogen.

Mechanism After stoppage of bleeding, tissue plasminogen activator (t-PA) converts plasminogen into plasmin which lyses the blood clot into fibrin degradation products( FDP). After lyses of the blood clot, plasmin, t-PA and FDP are removed by the phagocytic cells. Then the inhibitor to t-PA limit its effect to site of blood clot only.

Fibrinolytic System inhibitors Activators Plasmin Factor XII & thrombin uPA, tPA tPA Inhibitor Plasmin Plasminogen Alpha-2 anti-plasmin Fibrin Clot Fibrin(ogen) Degradation Products

Activation of plasminogen & fibrinolysis 1- Tissue plasminogen C: (t-PA) Released from injured tissue & endothelium but the plasma contains a physiological inhibitor to the t-PA to balance its effect 2- Factor XII & thrombin.

3- Other physiological activators as: a- Urokinase enzyme in the urine to lyse blood clots in the urine. b- Enzymes in uterine cavities to prevent blood clot in these sites  passage of uterine blood to outside 4- Exogenous activators as : streptokinase enzyme (from bacteria). It is used as treatment to dissolve the clot.

Inhibition of fibrinolysis: 1- Inhibition of plasmin: by 2 antiplasmin. 2- By tissue plasminogen activator (t-PA) inhibitor.

Tests of hemostatic function 1) Platelets count: 150.000 to 350.000/mm3 2) Bleeding time: Prolonged in purpura and Von Willbrand’s disease. 3) Clotting time: Normally 4-10 minutes. - Measure the intrinsic pathway of clotting. - Prolonged in haemophilia ( factors VIII, IX, & XI) and Von Willbrand’s disease.

4) Prothrombin time: - It is a test of extrinsic pathway - Normally 10-15 seconds. Prolonged in: - vit. K deficiency (decrease fat absorption in cases of obstructive jaundice)  prothrombin, factors VII,XI,X. - liver diseases or - coumarin treatment

Bleeding tendencies : (1) Vitamin K deficiency: Effect:  synthesis of clotting factors II & VII & IX & X by the liver  bleeding tendency.

(2) Purpura Causes and types of purpura: Due to: is a haemorrhagic disease in the skin and the mucous membrane with small purplish spots. Causes and types of purpura: A- Thrombocytopenic purpura: Due to: decrease platelets count below 60.000/mm3

B- Non-Thrombocytopenic purpura: Due to: Abnormal vascular or platelets function even its count is normal. Clinical picture of purpura: subcutaneous small spots of blood (petechiae).

Laboratory findings: (in thrombocytopenic type) - Decrease Platelet count (in thrombocytopenic type) - Prolonged bleeding time - Poor clot retraction - Normal clotting time.

Petechiae

(3) Hemophilia There are 3 types of haemophilia: is a hereditary disease (sex-linked), recessive disease transmitted by females( X- chromosome) to males but females themselves rarely suffer. There are 3 types of haemophilia: Haemophilia (A) (85%) due to deficiency of factor VIII. Haemophilia (B) (10%) due to deficiency of factor IX which is called Christmas disease. Haemophilia (C) (5%) due to absence of factor XI. It affects both male and female and most common in Jews.

Haemophilia is characterized by: The intrinsic pathway is affected: Normal bleeding time Prolonged clotting time. Ecchymoses (large spots of blood)

Ecchymoses

Ecchymoses Petechiae

(4) Von Willebrand’s disease It is caused by the decrease of Willebrand factor with adhere platelets to site of injury. It is characterized by: Severe bleeding tendency Prolonged bleeding time. Prolonged clotting time (associated by decrease VIII).