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Learn about primary hemostasis, vessels' role in coagulation, platelets, and more for maintaining blood vessel health. Explore the mechanisms of clotting and preventing excessive blood loss. Discover the functions of the vascular system components in achieving hemostasis.
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Hemostasis & CoagulationAhmad Sh. Silmi Msc Hematology,FIBMS Unit 1: Primary Hemostasis
Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors Homeostasis State of fluid equilibrium within the blood vessels
Hemostasis • Arrest of bleeding • Events preventing excessive blood loss • Vascular spasm: Vasoconstriction of damaged blood vessels • Platelet plug formation • Coagulation or blood clotting
Haemostasis: • Vasoconstriction • Platelet activation • Haemostatic plug • Coagulation • Stable clot formation • Clot dissolution
Primary hemostasis • Involves: • Vasoconstriction • Platelet adhesion • Platelet secretion • Platelet aggregation
Vascular System • Blood Vessels • Arteries • Carry blood from the heart to capillaries • Thickest walls of the vasculature • Veins • Return blood from capillaries to the heart • Thinnest walls of vasculature • Capillaries • No vessel wall • Do not contribute to hemostasis
Vascular System: Blood Vessels • Construction • Endothelium • Single layer of endothelial cells, lining vessels • Coated by glycocalyx • Protects basement membrane • Produces Von Willebrand's factor (vWF), a part of Factor VIII • Secretes prostaglandins, plasminogen activators • Negatively charged, repels circulating proteins and platelets • Subendothelium • Smooth muscle and connective tissue with collagen fibers
Vascular System: Blood Vessels • Basement membrane • Collagen material – stimulates platelets • Connective tissue • Elastic fibers- provide support around vessels
Vascular System: Blood Vessels • Function • Endothelium • Controls vessel permeability • Controls blood flow rate • Produces and releases substances that inhibit OR stimulate platelets, coagulation and fibrinolysis • Subendothelium • Collagen within is whats exposed upon injury
Vascular Endothelium Products:Stimulators • Produces vonWillebrand factor (vWF) • Helps in platelet adhesion to collagen • Carries factor VIII • Tissue factor (TF) activates secondary hemostasis via extrinsic pathway • Tissue plasminogen activator (tPA) is released activating fibrinolysis
Vascular Endothelium Products:Inhibitors • Release of tPA activates release of plasminogen activator inhibitor (PAI-1) to inhibit fibrinolysis • Thromomodulin forms a complex with thrombin • Platelet aggregation via prostacyclin production
Vascular System: Function Following Injury • Initiate hemostasis • Vasoconstriction of the arterioles • Minimizes blood flow to injured area • Prevents blood loss • Immediate • Short-lived
Vasoconstriction • Mechanism • Neurogenic factors • Regulatory substances • Prolong vasoconstriction • Serotonin ( made by platelet activation & endothelium) • Thromboxane A2 ( made by platelet activation & endothelium) • Endothelin-1 (made by damaged endothelial cells)
Vasoconstriction • Vasodilation Counteracts Vasoconstriction • Endothelial cells • Prostaglandin (PGI2)/ Prostacyclin • Vasodilates to increase blood flow to bring fresh supplies of clotting substances • Inhibits platelet aggregation • Contraction of venules • Causes gaps between them which pushes fluids causing edema or swelling
Thought question… • Think about the last time you cut your finger with a piece of paper. Did your finger bleed immediately? • If not, what might have prevented the bleeding?
Answer.. • No, the finger probably did not bleed immediately, due to vasoconstriction of the blood vessels
Discussion • What actions of the endothelial cells prevent clotting from occurring within the blood vessels?
Answers.. • Since the endothelial lining has a negative charge, it normally repels coagulation proteins and platelets in the circulation. It synthesizes products that help to inhibit fibrin formation.
All About Platelets… • Second major component of the hemostatic system
Platelets • What is a platelet? • Small 2-3 µm • Anuclear • Reddish-purple granules • Fragments of megakaryocyte cytoplasm
Platelets • Life span • 9-10 days • Normal Range • 150-440 x 109 /L
Platelet: Side noteSeen in conditions with increased need and/or destruction Giant platelets Micromegakaryocytes= Dwarf Megs • May Hegglin anomaly, Bernard-Soulier syndrome, pregnancy, malignancy • Seen in malignant disorders such as CML and MDS
Anatomy of a Platelet • Peripheral zone: Responsible for platelet adhesion and aggregation • Glycocalyx: • Contains glycoprotein receptors: • GPIb binds von Willebrand’s factor needed for platelet adhesion to collagen • GPIIb/IIIa bind fibrinogen needed for aggregation • Bind ADP and thrombin, promoting aggregation • Factors I, V, VIII on surface, involved in 2o hemostasis • Plasma membrane: • Exposed on platelet activation • Layer called PF3 (platelet factor) surface for interaction of plasma coagulation factors • Initiation of formation of thromboxane A2. This stimulates aggregation and vasoconstriction
Anatomy of a Platelet • Structural or Sol-Gel zone: Responsible for platelet retraction/contraction functions and platelet shape • Microtubules • Cytoskeleton • Binding protein • Organelle zone: Responsible for storage and platelet release functions • Granules • Dense bodies, alpha granules, lysosomal granules and microperoxisomes • Mitochondria • Glycogen
Platelet Receptors • GPIb/IX – vWF • Required for PLT adhesion • GPIIb/IIIa – Fibrinogen • Required for PLT aggregation • Phospholipid (Pl) • Bind vitamin K dependent proteins , Ca++ dependent • Bind Va and VIIIa (called “PF3” in this context)
Platelet Granules DENSE • Plasma Derived Fibrinogen – PLT aggrgation Ig Albumin • Megakaryocyte Derived vWF – PLT adhesion, VIII carrier Coagulation Factor V • Plasminogen – source of plasmin • PAI-1 – inhibits activation of fibrinolysis • a2-antiplasmin – plasmin inhibitor • PF4 – inactivates heparin • PLT-derived Growth Factor (PDGF) – tissue repair • Thrombospondin – PLT aggregate stabilizer • Fibronectin – PLT binding • ALPHA • ATP • ADP • Serotonin • Calcium Ions
PLATELET STRUCTURE PF4, ß-TG, PDGF, TGF-ß, fibrinogen, VWF, etc. ADP, ATP, Ca2+, serotonin, etc.
Production of Platelets • Made in Bone marrow • Need dictates the amount of platelets produced. • Stimulus for production is the platelet mass in circulating blood ~ 80 % and megakaryocyte mass in bone marrow • Originate from CFU-GEMM to form CFU-Meg • Cytokines and growth factors such as IL-3 and GM-CSF influences progenitor stages
Platelet Development • Megakaryoblast • 10-15 µm • Increased nuclear: cytoplasmic ratio • Promegakaryocyte • 80 µm • Dense alpha and lysosomal granules • Basophilic megakaryocyte • Megakaryocyte
Production of Platelets • Precursor Cell= Megakaryocyte • Produces about 2000-4000 platelets • Platelets are released via sinuses of bone marrow
Production of Platelets • Thrombopoietin (TPO) • Regulates platelet development • Influences all stages of megakaryocyte production • Produced in the liver, kidney and spleen
Production of Platelets • How does TPO work? • Maintains a constant number of platelets in peripheral blood by binding Mp1 (platelet receptor). Bound TPO can not stimulate proliferation of bone marrow progenitor cells • The higher the platelet count, the more TPO is bound and stimulation of bone marrow is decreased.
Thought question… • If a patient had a low platelet count what will happen?
Answer… • TPO increases the number of megakaryocytes in the bone marrow, increases size and DNA count of megakaryocytes and increases maturation rate
Function of Platelets • Surveillance of blood vessel continuity • Checks endothelial lining for gaps and breaks • Fill-in small gaps caused by separation of endothelial cells • Formation of primary hemostatic plug • Surface for coagulation factors to make secondary hemostatic plug • Aid in healing injured tissue
Formation of Primary Hemostatic Plug • Once the platelets “normal” environment is changed, they become activated or adhesive • Three stages of plug formation: • Adhesion • Release reaction • Aggregation
Stage 1: Platelet Adhesion • It is the binding of platelet to non platelet surface: sub endothelial collagen • involves changes from a disc shape to a slightly broader, plate like form to increase surface area • a number of plasma proteins are required for normal platelet adhesion. • Thrombin • Fibronectin • vWF • vWF is the largest component of factor VIII and secreted by platelets and by vascular endothelial cells.
Adhesion cont’d Collagen – vWF –Platelet • vWF bridge physical distance between platelate and sub endothelial collagen • Increase bond that seal platelet to the vessel wall • reversible
Stage 1: Platelet Activation • Platelets undergo a shape change from disc to spiny sphere with projections • Activation required for 1O hemostatic plug formation • Activation continues until Ca ++ threshold met • Outcome • Activation of GPIIb/IIIa receptors for fibrinogen • Secretion of granules within platelets into tissues
Platelet Shape Change George Lancet 2000; 355:1531
Stage 2: Platelet Secretion & Release • Requires ATP • It is release of contents of the granules of platelet • Primarily ADP stimulates aggregation • Cathecolamine (especially epinephrine) and serotonin enhance vasoconstriction • Granules trigger a secondary aggregation which is irreversible
Platelets contain 3 types of secretary granules: • Lysosome containing acid hydrolyses • α-granules containing platelate specific proteins (Plt factor 4, β- thromboglobulin, as well as other proteins such as Platelet derived growth factor and coagulation proteins found in plasma (fibrinogen & von Willebrand’s factor) • -granules containing ATP, ADP, Calcium & serotonin