Hemostasis and Platelet Plug Formation

• Platelet plug formation, or primary hemostasis, is the initial step in hemostasis.

Hemostasis

• The body uses hemostasis to prevent blood loss from injured blood vessels.
• Without hemostasis, even minor injuries could be life-threatening.
• Primary hemostasis involves platelets clumping to form a plug at the injury site.
• Secondary hemostasis reinforces the platelet plug with a fibrin protein mesh.
• The platelets are like bricks, and fibrin is the mortar in a wall.
• Primary hemostasis is further divided into endothelial injury, exposure, adhesion, activation, and aggregation.

Endothelial Injury

• Cutting an artery damages its layers, including the innermost endothelium, smooth muscle, elastic fibers, and collagen-containing connective tissue.
• A vascular spasm occurs when the smooth muscles near the injury reflexively contract, narrowing the vessel to reduce blood flow.
• Endothelial cells normally secrete nitric oxide and prostaglandins to relax smooth muscles.
• Endothelial injury decreases nitric oxide and prostaglandins and increases endothelin secretion, causing smooth muscle contraction.

Exposure

• The damage to endothelial cells exposes the collagen underneath.
• Damaged endothelial cells release Von Willebrand's factor, which binds to the exposed collagen.

Adhesion

• Platelets continuously circulate in the blood as fragments of megakaryocytes.
• Platelets contact Von Willebrand factor bound to collagen at the injury site.
• Platelets have a surface protein called GP1B that allows them to bind to Von Willebrand factor.

Activation

• Binding to Von Willebrand factor activates platelets.
• Activated platelets change shape, forming tentacle-like arms to grab other platelets.
• Platelets release more Von Willebrand factor, serotonin, and calcium.
• Platelets release adenosine diphosphate (ADP) and thromboxane A2, activating other platelets.
• The binding of more platelets causes a positive feedback loop.
• Undamaged endothelial cells secrete prostaglandin and nitric oxide, preventing platelet activation beyond the injury site.
• ADP and thromboxane A2 cause platelets to express GPIIB/IIIA on their surface.

Aggregation

• ADP and thromboxane cause platelets to stick to collagen and express GPIIB/IIIA.
• GPIIB/IIIA binds to fibrinogen, linking platelets together like handcuffs.
• Platelets attach to fibrinogen via GPIIB/IIIA, allowing rapid aggregation and platelet plug formation.
• During secondary hemostasis, fibrinogen is cleaved into fibrin, forming a protein mesh to stabilize the platelet plug.

Summary of Primary Hemostasis

• Primary hemostasis is the first step of hemostasis, forming a platelet plug to prevent blood loss.
• The five stages of primary hemostasis: endothelial injury, exposure, adhesion, activation, and aggregation.
• Hemostasis is the process of stopping blood flow after blood vessel damage.
• Secondary hemostasis involves the coagulation cascade, where a fibrin mesh reinforces the platelet plug, forming a blood clot.
• Anticoagulation occurs during primary and secondary hemostasis to regulate clot formation.
• Clot retraction and fibrinolysis occur after hemostasis to contract and degrade the clot.

Anticoagulation

• It prevents clots from enlarging and disrupting blood flow.
• Thrombin (factor II) is a crucial clotting factor with multiple pro-coagulative functions.
• Thrombin binds to platelet receptors, activates cofactors V and VIII, cleaves fibrinogen into fibrin, and cleaves stabilizing factor XIII into XIIIa.
• Protein C and antithrombin III are two proteins that help with anticoagulation.
• Protein C interacts with thrombomodulin on intact endothelial cells.
• The thrombin-thrombomodulin complex activates protein C and S.
• This protein complex then inactivates factors V and VIII, slowing down coagulation.
• Antithrombin III binds to thrombin and factor X, making them unavailable.
• Heparin binds to antithrombin, increasing its affinity for target proteins and enhancing anticoagulation.

Platelet Inhibition

• Healthy endothelial cells release nitric oxide and prostacyclin.
• These molecules reduce thromboxane A2 production, preventing platelets from expressing GPIIB/IIIA proteins and sticking together.

Clot Retraction

• It occurs about an hour after primary and secondary hemostasis.
• Activated platelets contain actin and myosin proteins.
• Lamellipodia increase the surface area of platelets.
• Integrin αIIbβ3 receptors bind to fibrin in the presence of thrombin, activating actin and myosin.
• Actin and myosin contraction tightens the fibrin mesh, making the clot rigid and contracted.
• Clot retraction pulls wound edges together, allowing endothelial cells to repair the tissue.

Fibrinolysis

• Approximately two days after injury, the body dissolves the blood clot through fibrinolysis.
• Plasminogen is converted into plasmin by tissue plasminogen activator (tPA).
• Endothelial cells release tPA in response to coagulation factors.
• Endothelial cells also release plasminogen activator inhibitor 1 and antiplasmin to regulate plasmin activity.
• Plasmin acts as a protease, cutting fibrin into smaller pieces and dissolving the clot.
• Coagulation factors IXa, XIIa, kallikrein, and protein C also activate plasmin.
• tPA can be used clinically to dissolve blood clots.

Quick Recap of Final Stages

• Anticoagulation, with protein C and S and antithrombin III, prevents excessive clot formation.
• Clot retraction stabilizes the clot and pulls wound edges together.
• Fibrinolysis, dependent on tPA converting plasminogen to plasmin, dissolves clots.

Vitamin K

• Vitamin K regulates blood coagulation by assisting in the conversion of certain coagulation factors into their mature forms.
• Without vitamin K, the body cannot effectively control clot formation.
• Hemostasis divided into primary and secondary phases.
• Secondary hemostasis reinforces the platelet plug with fibrin.
• Coagulation factors (I-XIII, but no VI) must be activated to form fibrin.
• Most coagulation factors produce Vitamin K in liver cells.

Vitamin K Sources and Forms

• Vitamin K is abundant in green leafy foods and synthesized by bacteria in the gastrointestinal tract.
• Vitamin K quinone is the dietary form mobilized from fat cells or the digestive tract to the liver.
• Quinone reductase converts vitamin K quinone into vitamin K hydroquinone.
• Vitamin K hydroquinone acts as a cofactor, donating electrons to gamma glutamyl carboxylase.
• Gamma glutamyl carboxylase converts coagulation factors II, VII, IX, and X into their functional forms by adding a carboxyl group.
• Vitamin K epoxide is the oxidized form after carboxylation.
• Epoxide reductase converts vitamin K epoxide back into vitamin K quinone, allowing vitamin K to be reused.
• Warfarin blocks epoxide reductase, preventing vitamin K recycling and the activation of factors II, VII, IX, and X.

Coagulation Cascade

• It begins with the extrinsic and intrinsic pathways.
• The intrinsic pathway starts when factor XII contacts activated platelets or collagen.
• Activated factor XII activates factor XI, which activates factor IX, which activates factor X.
• Factor X starts the common pathway, activating factor II, which activates factor I to build the fibrin mesh.
• Activated factor II activates factors V, VIII, XI, and XIII.
• Factor V is cofactor for X, factor VIII is a cofactor for factor IX, and factor XIII helps fibrin form crosslinks.
• In the extrinsic pathway, exposed tissue factor activates factor VII, activating factor X and starting the common pathway.
• Vitamin K is essential for all the clotting steps

Secondary Hemostasis

• Factors XII, XI, IX, VIII, VII, V, and IV are essential for the initiation of coagulation.
• Proteins C and S inhibit the coagulation cascade by inactivating factors Va and VIIIa.

Hemostasis prevents blood loss from injured vessels. Primary hemostasis is the first step, involving platelet clumping to form a plug. Secondary hemostasis reinforces this plug with fibrin. Primary hemostasis includes endothelial injury, exposure, adhesion, activation, and aggregation.