VISITH DANTANARAYANA

GROUP 201

ALSO KNOWN AS PLATELETS.

FRAGMENTS OF CYTOPLASM DERIVED FROM MEGAKARYOCYTES.

NO NUCLEUS

2 – 3 µm IN MAXIMUM DIAMETER

BICONVEX DISCOID SHAPED OR LENS SHAPED.

150,000 TO 400,000 PER CUBIC

MILLIMETER.

LOW PLATELET CONCENTRATION: THROMBOCYTOPAENIA

ABNORMALLY HIGH PLATELET CONCENTRATION: THROMBOCYTOSIS

Men as a group have slightly higher mean values than women.

FORMATION OF PLATELET PLUGS IN HEMOSTASIS.◦ ACTIVATION

◦ ADHESION

◦ AGGREGATION

◦ COHESION OR PLUG FORMATION

SUPPORTING COAGULATORY MECHANISMS

PHAGOCYTOSIS

STORAGE AND TRANSPORT OF SUBSTANCES

THE PROCESS WHICH CAUSES BLEEDING TO STOP, MEANING TO KEEP BLOOD WITHIN A DAMAGED BLOOD VESSEL.

HEMOSTASIS AS A WHOLE HAS THREE MAJOR STEPS:

VASOCONSTRICTION

VASCULAR-THROMBOCYTIC HEMOSTASIS

COAGULATORY HEMOSTASIS

SEEN AS A VASCULAR SPASM.

THE PAIN RECEPTORS OF THE SMOOTH MUSCLES OF THE DAMAGED VESSEL WALL INITIATES THE SPASM.

SEROTONIN AND THROMBOXANE RELEASED BY THE ENDOTHELIUM OF DAMAGED VESSEL WALL ALSO ASSIST IN THE PROCESS.

WHEN AN ANEURYSM RUPTURE OCCURS IT COULD RELEASE TOXINS THAT COULD INITIATE VASCULAR SPASMS IN NEARBY ARTERIES OR VEINS.

WHEN UNDAMAGED, ENDOTHELIAL CELLS ARE ATTACHED TO THE SUBENDOTHELIAL COLLAGEN BY VON WILLEBRAND FACTOR (VWF) WHICH THESE CELLS PRODUCE. VWF IS ALSO STORED IN ENDOTHELIAL CELLS AND SECRETED CONSTITUTIVELY INTO THE BLOOD. PLATELETS STORE VWF IN THEIR GRANULES.

VON WILLEBRAND FACTOR IS A TERTIARY GLYCOPROTEIN.

WHEN THE ENDOTHELIAL LAYER IS DISRUPTED, COLLAGEN AND VWF ANCHOR PLATELETS TO THE SUBENDOTHELIUM. PLATELET GP1B-IX-V RECEPTOR BINDS WITH VWF; AND GPVI RECEPTOR BINDS WITH COLLAGEN.

PAF is produced by a variety of cells, but especially those involved in host defense, such as PLATELETS, ENDOTHELIAL CELLS, NEUTROPHILS, MONOCYTES, AND MACROPHAGES.

Platelet activation begins seconds after adhesion occurs. It is triggered when collagen from the subendothelium, and/or tissue factor from the media and adventitia

Tissue factor also binds to factor VII in the blood, which initiates the extrinsic coagulation cascade to increase thrombin production. Thrombin is a potent platelet activator, which also promotes secondary fibrin-reinforcement of the platelet plug. Platelet activation in turn degranulates and releases factor V and fibrinogen, potentiating the coagulation cascade. So in reality the process of platelet plugging and coagulation are occurring simultaneously rather than sequentially, with each inducing the other to form the final clot.

GP IIB/IIIA ACTIVATION

GRANULE SECRETION

MORPHOLOGY CHANGE

COAGULATION FACILITATION

Platelets secrete thromboxane A2, which acts on the platelet's own thromboxane receptors on the platelet surface (hence the so-called "out-in" mechanism), and those of other platelets. These receptors trigger intraplatelet signaling, which converts GPIIb/IIIa receptors to their active form to initiate aggregation.

Platelets contain dense granules, lambda granules and alpha granules.

GRANULE CHARACTERISTICS: α granules (alpha granules) – containing P-

selectin, platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, B-thromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII).

δ granules (delta or dense granules) –containing ADP or ATP, calcium, and serotonin).

γ granules (gamma granules) – similar to lysosomes and contain several hydrolytic enzymes.

λ granules (lambda granules) – contents involved in clot resorption during later stages of vessel repair.

Aggregation begins minutes after activation, and occurs as a result of turning on the GPIIb/IIIa receptor, which allows these receptors to bind with vWF or fibrinogen.

THE CLOTTING FACTORS ARE THE GROUP OF CHEMICALS THAT ARE CONSTANT CIRCULATION IN THE BLOOD OR PRESENT IN TISSUES OF THE BLOOD VESSELS.

THESE COMPOUNDS ARE RESPONSIBLE FOR THE FORMATION OF A BLOOD CLOT.

CLOTTING FACTORS ARE USUALLY INACTIVE BUT ONCE THERE IS TISSUE INJURY TO THE WALL OF THE BLOOD VESSEL, THE FIRST FACTOR IS ACTIVATED.

THIS HAS A CYCLICAL EFFECT WITH EACH FACTOR ACTIVATING THE NEXT.

FACTOR I

Name : FIBRINOGENSource : LiverPathway : Both extrinsic and intrinsicActivator : THROMBINActions : When fibrinogen is converted into fibrin by thrombin, it forms long strands that compose the mesh network for clot formation.

FACTOR II

Name : PROTHROMBINSource : LiverPathway : Both extrinsic and intrinsicActivator : PROTHROMBIN ACTIVATORActions : Prothrombin is converted into thrombin which then activated fibrinogen into fibrin.

FACTOR III

Name : THROMBOPLASTIN / TISSUE FACTORSource : Platelets (intrinsic) and damaged endothelium (cells) lining the blood vessel (extrinsic).Pathway : Both extrinsic and intrinsicActivator : INJURY TO BLOOD VESSELAction : Activates factor VII (VIIa).

FACTOR IV

Name : CALCIUMSource : Bone and absorption from food in gastrointestinal tractPathway : Both extrinsic and intrinsicAction : Works with many clotting factors for activation of the other clotting factors. These are called calcium-dependent steps.

FACTOR V

Name : PROACCERIN / LABILE FACTOR / AC-GLOBULIN (AC-G)Source : Liver and plateletsPathway : Both extrinsic and intrinsicActivator : THROMBINAction : Works with Factor X to activate prothrombin (prothrombin activator).

FACTOR VII

Name : PROCONVERTIN / SERUM PROTHROMBIN CONVERSION ACCELERATOR (SPCA) / STABLE FACTORSource : LiverPathway : ExtrinsicActivator : FACTOR III (TISSUE FACTOR)Actions : Activates Factor X which works with other factors to convert prothrombin into thrombin.

FACTOR VIIIName : ANTI-HEMOPLYTIC FACTOR / ANTIHEMOPHILIC FACTOR (AHF) OR GLOBULIN (AHG) / ANTIHEMOPHILIC FACTOR ASource : Endothelium lining blood vessel and platelets (plug)Pathway : IntrinsicActivator : THROMBINActions : Works with Factor IX and calcium to activate Factor X.

DEFICIENCY : HEMOPHILIA A

FACTOR IXName : CHRISTMAS FACTOR / PLASMA THROMBOPLASTIN COMPONENT (PTC) / ANTIHEMOPHILIC FACTOR BSource : LiverPathway : IntrinsicActivator : FACTOR XI AND CALCIUMActions : Works with Factor VIII and calcium to activate Factor X.

DEFICIENCY : HEMOPHILIA B

FACTOR X

Name : STUART PROWER FACTOR / STUART FACTORSource : LiverPathway : Extrinsic and intrinsicActivator : FACTOR VII (EXTRINSIC) / FACTOR IX + FACTOR VIII + CALCIUM (INTRINSIC)Actions : Works with platelet phospholipids to convert prothrombin into thrombin. This reaction is made faster by activated Factor V.

FACTOR XIName : PLASMA THROMBOPLASTIN ANTECEDENT (PTA) / ANTIHEMOPHILIC FACTOR CSource : LiverPathway : IntrinsicActivator : FACTOR XII + PREKALLIKREIN AND KININOGENActions : Works with calcium to activate Factor IX.Deficiency : Hemophilia C

FACTOR XII

Name : HAGEMAN FACTORSource : LiverPathway : IntrinsicActivator : CONTACT WITH COLLAGEN IN THE TORN WALL OF BLOOD VESSELSActions : Works with prekallikrein and kininogen to activate Factor XI. Also activates plasmin which degrades clots.

FACTOR XIII

Name : FIBRIN STABILIZING FACTORSource : LiverActivator : THROMBIN AND CALCIUMActions : Stabilizes the fibrin mesh network of a blood clot by helping fibrin strands to link to each other. Therefore it also helps to prevent fibrin breakdown (fibrinolysis).

PREKALLIKREIN

Source : LiverPathway : IntrinsicActions : Works with kininogen and Factor XII to activate Factor XI.

KININOGEN

Source : LiverPathway : IntrinsicActions : Works with prekallikrein and Factor XII to activate Factor XI.

COAGULATION CAN PHYSICALLY TRAP INVADING MICROBES IN BLOOD CLOTS.

Also, some products of the coagulation system can contribute to the INNATE IMMUNE SYSTEM by their ability to increase vascular permeability and act as CHEMOTACTIC AGENTS FOR PHAGOCYTIC CELLS.

In addition, some of the products of the coagulation system are directly antimicrobial. For example, beta-lysine, an amino acid produced by platelets during coagulation, can cause lysis of many Gram-positive bacteria by acting as a cationic detergent.

Five mechanisms keep platelet activation and the coagulation cascade in check. They prevent the UNNECESSARY THROMBOSIS.

PROTEIN C

ANTITHROMBIN

TISSUE FACTOR PATHWAY INHIBITOR

PLASMIN

PROSTACYCLIN

HEMOPHILIAS - The three main forms are hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild bleeding tendency).

VON WILLEBRAND DISEASE - Defect in VON WILLEBRAND FACTOR (VWF), which mediates the binding of GLYCOPROTEIN IB (GPIB) to collagen.

BERNARD-SOULIER SYNDROME is a defect or deficiency in GPIb. GPIb, the receptor for vWF, can be defective and lead to lack of primary clot formation (primary hemostasis) and increased bleeding tendency. This is an autosomal recessive inherited disorder.

THROMBASTHENIA OF GLANZMANN AND NAEGELI (GLANZMANN THROMBASTHENIA) is extremely rare. It is characterized by a defect in GPIIb/IIIa fibrinogen receptor complex. When GPIIb/IIIa receptor is dysfunctional, fibrinogen cannot cross-link platelets, which inhibits primary hemostasis. This is an autosomal recessive inherited disorder.

THROMBOSIS is the pathological development of blood clots. These clots may break free and become mobile, forming an EMBOLUS or grow to such a size that occludes the vessel in which it developed.

An EMBOLISM is said to occur when the thrombus (blood clot) becomes a mobile embolus and migrates to another part of the body, interfering with blood circulation and hence impairing organ function downstream of the occlusion.

THIS LEADS TO ISCHEMIA AND THEN NECROSIS OF THE TISSUE.

Mutations in FACTOR XII have been associated with an asymptomatic prolongation in the clotting time and possibly a tendency toward THROMBOPHLEBITIS. Other mutations have been linked with a rare form of HEREDITARY ANGIOEDEMA (TYPE III).

PROCOAGULANTSThe use of adsorbent chemicals, such as zeolites, and other hemostatic agents are also used for sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin glue are used surgically to treat bleeding and to THROMBOSE ANEURYSMS.DESMOPRESSIN IS USED TO IMPROVE PLATELET FUNCTION BY ACTIVATING ARGININE VASOPRESSIN RECEPTOR 1A.

COAGULATION FACTOR CONCENTRATES ARE USED TO TREAT HEMOPHILIA, TO REVERSE THE EFFECTS OF ANTICOAGULANTS, AND TO TREAT BLEEDING IN PATIENTS WITH IMPAIRED COAGULATION FACTOR SYNTHESIS OR INCREASED CONSUMPTION. PROTHROMBIN COMPLEX CONCENTRATE, CRYOPRECIPITATE AND FRESH FROZEN PLASMA ARE COMMONLY USED COAGULATION FACTOR PRODUCTS. RECOMBINANT ACTIVATED HUMAN FACTOR VII IS INCREASINGLY POPULAR IN THE TREATMENT OF MAJOR BLEEDING.

TRANEXAMIC ACID AND AMINOCAPROIC ACID INHIBIT FIBRINOLYSIS, AND LEAD TO A DE FACTO REDUCED BLEEDING RATE. BEFORE ITS WITHDRAWAL, APROTININ WAS USED IN SOME FORMS OF MAJOR SURGERY TO DECREASE BLEEDING RISK AND NEED FOR BLOOD PRODUCTS.

ANTICOAGULANTS (ANTITHROMBICS, FIBRINOLYTIC, AND THROMBOLYTICS) ARE A CLASS OF DRUGS THAT WORK TO PREVENT THE COAGULATION (CLOTTING) OF BLOOD.

These oral anticoagulants are derived from COUMARIN, which is found in many plants. A prominent member of this class is WARFARIN (COUMADIN). It takes at least 48 to 72 hours for the anticoagulant effect to develop.

These anticoagulants are used to treat patients with deep-vein thrombosis (DVT), pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves.

Heparin is a biological substance, usually made from pig intestines. It works by activating ANTITHROMBIN III, which blocks thrombin from clotting blood.

LOW MOLECULAR WEIGHT HEPARIN, a more highly processed product, is useful as it does not require monitoring of the APTT coagulation parameter (it has more predictable plasma levels) and has fewer side effects.

FONDAPARINUX is a synthetic sugar composed of the five sugars (pentasaccharide) in heparin that bind to ANTITHROMBIN. It is a smaller molecule than low molecular weight heparin.

Drugs such AS RIVAROXABAN, APIXABAN AND EDOXABANWORK BY INHIBITING FACTOR Xa DIRECTLY (UNLIKE THE HEPARINS AND FONDAPARINUX, WHICH WORK VIA ANTITHROMBIN ACTIVATION).

A class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting THE ENZYME THROMBIN (FACTOR II).

THERE ARE 3 TYPES:

UNIVALENT

BIVALENT

ALLOSTERIC INHIBITORS

BATROXOBIN - A TOXIN FROM SNAKE VENOM

HEMENTIN – ANTICOAGULANT PROTEASE FOUND IN THE SALIVA OF THE GIANT AMAZON LEECH.