18.5 Platelets and Hemostasis

intrinsic mechanisms of clot formation

*initiated by clotting factors in the blood*

completion of coagulation

*once factor X is activated the steps are the same for E and I pathways* 1. factor X combines with Factor III & V with Ca and PF to produce prothrombin activator 2. acts on a globulin called prothrombin (factor II) and converts it to the enzyme thrombin 3. Thrombin then converts fibrinogen into shorter strands of fibrin monomer 4. These monomers bond to each other end to end and form longer fibers of fibrin polymer 5. Factor XIII cross-links these strands to create a dense aggregation that forms the structural framework of the blood clot

hemophilia

-deficiency of clotting factors -hereditary disease -sex linked recessive, occurs predominately in males, can inherit it only from Mom -results in impaired coagulation cascade (impaired clotting) *inhibits enzyme that mediates thromoxane A2 production*

hemophilia A

-deficiency of functional plasma clotting factor VIII- damages INTRINSIC mechanism -accounts for 80% of cases -sex linked, recessive, occurs mainly in males -may arise from defects in FVIII gene or von Willebrand factor (mutations impair the ability of the procoagulant to bing to protein factor VIII)

platelet structure

-no nucleus -contain mitochondria, microtubules and microfilaments, lysosomes, granules and canalicular systems -canalicular system: facilitate rapid deployment of particles to other cells- lead into the "big wide world" -pseudopods when activated for locomation

platelet plug formation

-positive feedback cycle that is activated quickly and can seal a small break in a blood vessel -when vessel is broken-> platelets contact the collagen and grow pseudopods that adhere to the vessels and other platelets-> pseudopods contract and connect the walls of the vessels together -loser than a clot, more delicate -platelets do not adhere to a healthy blood vessel -when platelets aggregate they degranulate

platelet function

-secrete vasoconstrictors -form platelet plugs -secrete procoagulants (blood clotting) -initiate formation of a clot dissolving enzyme (dissolve clots) -secrete chemical attractants for neutrophils and monocytes -internalize bacteria -secrete growth factors (increase cell productivity to build new cells/tissues)

stages of thromopoiesis

1. MK development in adult bone marrow 2. endomitosis to create polypoid nucleus 3. cytoplasmic maturation 4. proplatelet formation and release 5. preplatelet and proplatelet interconversion 6. platelet release

extrinsic pathway of initiation

1. damaged blood vessels release factor III 2. factor III combines with factor VII to form a complex that activates factor X when Ca is present

three mechanisms of hemostasis

1. vascular spasm 2. platelet plug formation 3. blood clotting- coagulation

intrinsic pathway of initiation

3. platelets degranulate and release factor XI 4. cascade reaction leads to activation of factor XI, IX, VIII (in this order) and finally to factor X

which pathway for initiation of coagulation is fastest?

EXTRINSIC (requires fewer steps)

coagulation

aka *clotting* -last and most effective defense against bleeding -mot important process is conversion of fibrinogen to fibrin

Why is it important for people with hemophilia that they not use aspirin?

aspirin is a blood thiner and people with hemophilia have a difficult time form clots- which means aspirin may cause them to bleed excessively

How then are plasma levels of TPO regulated?

carried out by the target of TPO-megakarocytes and platelets degrade the hormone following its binding to specific receptor membranes

hemostasis

clotting stopping the flow of blood

procoagulants

clotting factors -most are produced by the liver -always present in the plasma in an inactive form -once one is activated it activates the next and so on... *cascade reaction*

platelet production

division of hemopoiesis called *thrombopoiesis*

thrombopoiesis

driven by the secretion of *thrombopoeitin TPO* in the liver -hemopoietic stem cells produce receptors for TPO -stem cells give rise to megokaryoblast--> megakaryocytes--> platelets -majority of process probably happens in lung blood vessels, most platelets are stored in the spleen -megakaryoblast duplicates DNA repeatedly w/o undergoing division which results in in megokaryocyte and then platelets -megokaryocytes reside in *red bone marrow*

Does atherosclerosis drive clot formation by extrinsic means, or by intrinsic means

extrinsic mechanism of clot formation -this is caused by plague building up on the walls of arteries and causing further build up and eventually blockage of the artery

what is the functional significance of fibrin?

fibrin is important because this is what binds platelets and blood cells to help clog the cut and form clotting -blood cells and platelets stick to fibrin in order to seal the cut

extrinsic mechanisms of clot formation

initiated by clotting factors (procoagulants) released by the damaged blood vessels and perivascular tissues *factors involved come from external sources to the blood itself*

clot retraction

occurs after clot formation -platelets form pseudopods -pseudopods adhere to fibrin strands and contract, drawing the edges of the broken vessels together

initiation of coagulation

occurs by both extrinsic and intrinsic pathways -first half of this is completed by *extrinsic* and then the last half is completed by *intrinsic factors*

PDGF

platelet derived growth factor -stimulates fibroblast and smooth muscle cells to multiply and repair the damaged vessels -occurs after clot formation -clot is then disposed of-- this is called *fibrinolysis* = clot dissolution

platelet repulsion

platelets do not adhere to prostacyclin coated endothelium of healthy blood vessels --prevents coagulation when it is not needed

after completion of coagulation

positive feedback system takes over -seals the damage more quickly -thrombin works with factor V to accelerate process of prothrombin activator which produces more thrombin -During the pathway each enzyme activated later produces more molecules than the previous step

degranulation

process that occurs upon platelet formation -exocytosis of cytoplasmic granules -release factors that stimulate hemostasis such as --serotonin a vasoconstrictor --ADP which attracts platelets and stimulates process -thromboxane A2- promotes platelet aggregation, degranulation and vasoconstriction

thrombopoietin concentration

produced in liver -production is independent of the platelet levels already in the blood -feedback control where the end cells regulate the concentration of their growth promoter

anticoagulants

suppresses the function of thrombin *Antithrombin*- secreted by the liver, deactivates thrombin before it can act on fibrinogen *Heparin*- secreted by basophils and mast cells, interferes with the formation of prothrombin activator, blocks the action of thrombin on fibrinogen, and promotes the action of antithrombin

dilution of plasma thrombin

the normal flow of blood prevents thrombin from forming clots when healthy- if blood flow decreases than thrombin will begin clotting --> happens during circulatory shock when circulation slows

______________________ stimulates all of the stages of thrombopoeisis

thrombopoeitin -acts during proliferation and differentiation of MK progenitors AND maturation of MKs into platelets TPO action *increases* closer to platelet stage