Lecture 5 Flashcards
Coagulation
Antiplatelets
Drugs that inhibit platelet activation, adhesion, & aggregation
Anticoagulants
Drugs that inhibit clotting factors
Types of Thrombus (2)
- Thrombus - adheres to vessel wall
2. Embolus - intravascular clot that floats in blood. Can lead to things like pulmonary embolism
Antifibrinolytic
Drugs that inhibit the chemical transition of plasminogen to plasmin
Thrombosis Types (2)
- Arterial thrombosis - medium sized, due to artherosclerosis, platelet rich. Treated with platelet aggregation factors like aspirin
- Venous thrombosis - triggered by blood statis or disruption of hemostatic defense mechanisms. Fibrin rich clots with fewer platelets, treated with anticoagulants like warfarin
Platelets
- function in hemostasis
- cell fragments that shed from their parent cell that is confined in the bone marrow
- parent cell = megakaryocyte
- contain cytoplasm of parent
- live ~10 days
- 1/3 stored in spleen
- sympathetic stimulation releases platelets
Megakaryocyte
- Massive cell (~60 um)
- produce ~1000 platelets
- thrombopoietin stimulates megakaryocyte differentiation & platelet products
Platelet Anatomy
- Have glycogen granules for energy
- Mitochondria
- Granules that contain activation factors
- Open canalicular sytems (inverted socks) that, when activated, become pseudopodia
Step in Platelet Plug Formation (3)
- Vascular spasm
- Formation of platelet plug
- Blood coagulation (clotting)
Vascular Spasm
- vasoconstriction
- endothelial surface adhesion
Platelet Plug Formation
- exposed collagen activate platelets
- platelets release ADP which activate adjacent platelets
- reaction is contained in this area of damage via prostacyclin and NO
- actin-myosin complex contracts and pulls the endothelial layers together
- Vasoconstrictors released (serotonin, epi., TXA)
Blood Coagulation
Changes blood from liquid state to a solid clot
Heparin Mechanism of Action
Directly inhibits thrombin & platelet aggregation
Plavix Mechanism of Action
Inhibitor of platelet activation and aggregation by blocking the binding of P2Y metabolite to ADP which activates the surrounding platelets.
Tirofiban
Blocks the binding of fibrinogen to glycoprotein IIb/IIIa which inhibits platelet aggregation.
Clotting Process
- Adhesion (to collagen)
- Activation
- Aggregation
- Clot
- Fibrinolysis
Integrin Pathway (Activation)
After the platelet adheres to collagen, the [alpha]2[beta]3 receptor causes a cascade of actions that causes fibrinogen to unfold. This allows for platelet interactions
Platelet Aggregation
Once fibrinogen is unfolded, there is cross linking of other activated platelets that create a net
Agonists of Platelets (6)
- Adhesion
- Thrombin
- Thomboxane A2
- ADP
- Epinephrine
- Serotonin
Increased levels of these components lead to aggregation
Factors Stopping Coagulation (4)
- Prostacyclin (PGI2) - antiaggregatory
- NO - vasodilatory
- tPA - Fibrinolytic
- Thrombomodulin - antithrombotic
Prostacyclin (PGI2)
Released by normal endothelial cells which activate cAMP in platelets and inhibits Ca+2. This inhibits platelet aggregation. Less PGI2 is released by damaged endothelial cells which decreases cAMP release and leads to platelet aggregation
Thromboxane A2
Platelets react to this and it causes them to release granules containing ADP, platelet-activation factor, and thrombin. The release of these promote the conformational change in GP IIb/IIIa that allows for fibrinogen bonding and, by extension, platelet aggregation
Platelet Aggregation Pathway
- Initial stimulation by collagen releases platelet activation factors
- Activates platelet membrane phospholipases
- Increases arachidonic acid in platelet
- Increases the synthesis of PGH2 by COX I
- Increases thromboxane A2 formation
- Increases platelet aggregation
Aspirin Mechanism of Action
Blocks COX I inhibitors and the synthesis of PGH2. Lasts the lifetime of the platelet (~3-7 days) since it is unable to replace the COXI receptors.
Salicylic Acid
Another COXI receptor blocker like aspirin but it is a reversible reaction. Only lasts a few hours
Clot Formation Steps (3)
- Conversion of fibrinogen into fibrin which is catalyzed by thrombin.
- Fibrin forms a mesh/net at the injury site which traps platelets & RBCs
- Initial fibrin mesh is weak. Cross links rapidly form and strengthen the clot. This also enhances factor XIII which stabilizes fibrin.
Thrombin’s Actions (5)
- Converts inactive fibrinogen into active fibrin
- Activates factor XIII
- Positive feedback conversion of prothrombin into thrombin
- Increases platelet aggregation
- Indirect: aggregated platelets secrete P3 which stimulates prothrombin to thrombin conversion
2 Clotting Pathways
- Intrinsic - clotting within damaged vessel. All components in blood & blood is retained in vessels
- Extrinsic - tissue trama, tissue thromboplastin is released and takes a shortcut to retain blood in the tissue
Where Clotting Pathways Merge
The extrinsic pathway releases tissue thromboplastin and the intrinsic pathway releases factor IX which both active factor X that goes on to catalyze the conversion of prothrombin to thrombin.
Vessel Repair & Clot Dissolution Steps (3)
- Clots aren’t permanent. Platelets recruit fibroblasts which lay down connective tissue that later becomes a scar
- Plasmin is formed from plasminogen by the catalyzation of factor XII. Plasmin trapped in the fibrin mesh later dissolves it
- Leukocytes phagocytize the clot
Thrombolytic Drugs
Streptokinase, Alteplase (tPA)
Thrombolytic Drug Mechanism
Converts plasminogen to plasmin which cleaves fibrin and lyses the thrombi.
Thrombolytic Drug Uses
Deep-vein thrombosis, weak MI, pulmonary embolisms
Thrombolytic Drug Adverse Effects
Hemorrhaging, cardiovascular accidents, and complications with pregnancy and metastatic cancers.
Fibrinogen Structure & Binding
Each molecule of fibrinogen has an E portion and due D domains. First they arrange in a D-E-D-D-E-D pattern. The E domain, by the end, binds to 6 D domain which causes D-dimers to form in response to factor XIIIa.
APC
Activated Protein C. Anticoagulant that is upregulated by the activation of thrombin.
APC Action
Inactivates factors VII & X. Increases endothelial barrier integrity and decreases endothelial inflammation. The latter lowers the adhesion of molecules and cytokines to the endothelium.
Lab Tests for Coagulation Disorders (5)
- CBC - platelet count should be about 150,000-350,000/mm^3
- Bleeding time (not preferred)
- Prothrombin Time (preferred) - ~10-14 seconds and related to the extrinsic pathway function
- Activated Partial Thromboplastin Time - related to intrinsic pathway function
- Thrombin Time & D-Dimer - (<200 ng/mL) relates to the quality of fibrinogen & fibrinolysis
Vascular Purpura & Petechiae
- pinpoint to diffuse hemorrhages
- breakdown of capillary endothelium barrier integrity
- Autoimmune process but can also relate to Scurvy or drug-induced disorders
- Looks like little red dots all over the skin
- Occurs when platelet count is between 50,000-100,000/mm^3
Reasons for Inappropriate Clot Formation - Thromboembolism (4)
- Roughened vessel surfaces (artherosclerosis)
- Imbalances of clotting-anticoagulation factors
- slow or stagnant blood
- Widespread release of tissue thromboplastin (septicemic shock)
Prevention Against Thromboembolisms
Tissue Plasminogen activator - released by lungs and is circulated in low concentrations to prevent clotting
Hemophilia
Cascade factor deficiency that leads to ineffective clotting. Most commonly is a lack of factor VIII
Venous Thrombus
- 3rd most common cardiovascular event after ACS/AMI & strokes
- Can lead to immobility, obesity, inflammatory diseases, surgery, & trauma
- Treatments: anticoagulants, antiplatelets, & surgery
Hemostasis Dirorder Classifications (2)
- Inherited - hemophilias, platelet disorders, fibrinolytic dirorders, connective tissue disorders, vascular
- Acquired - liver diseases, renal failure, vitamin K deficiency, drug use, thrombocytopenia
All lead to increased bleeding
Thrombocytopenia
-Platelet disorder
Causes:
-Decreased platelet production (marrow problem)
-Decreased platelet survival (drugs, heart valves (turbulence), pathogens)
-Splenic sequestration
-Platelet dilution (transfusions)
No symptoms until platelet count is <100,000/mm^3. Risk intracranial bleeding when count drops to ~20,000
Hemophilia A
- Coagulation disorder
- accounts for ~85% of hemophilia patients
- Deficiency of factor VIII
- X-linked, recessive
Hemophilia B
- Coagulation disorder
- factor IX deficiency
- severe disorder that leaves the patient with only about 1% normal coagulation activity
- Prolonged bleeding is the main issue causes by it, especially when its internal and undetected
- Possible to give factor VIII prior to surgeries or dental procedures to minimize the prolonged bleeding
Von Willebrand Disease
- Coagulation disorder
- Decreased or absent vWF, a factor VIII carrier protein that aids in platelet adherence to damaged endothelioum
Vitamin K Deficiency + Clotting
Can lead to coagulation problems since vitamin K is needed to synthesize factors II, VII, IX, & X
Disseminated Intravascular Coagulation (DIC)
“Death is Coming”
- Multiorgan dysfunction caused by multithrombi
- bleeding caused by consumption of platelets, fibrinogen, & other coagulation factors
- secondary fibrinolysis
Algorithm for Diagnosing DIC
Series of yes/no questions where no gets zero points and yes usually gets 2 points. The higher the points by the end of the survey, the higher the mortality rate or percentage. Questions take into account the levels of blood components and prolonged prothrombin time.
