what is hemostasis?
the balance between procoagulants and anticoagulants.
what happens when there is injury to a blood vessel?
vessel contraction, platelet aggregation and fibrin formation
what does von willebrand factor do?
vWF binds to the edges of the perforation and to platelets, which stick together forming the primary hemostatic plug
what is the difference between the primary and secondary hemostatic plugs?
the platelets in the the secondary plug are more crammed together and the blood clot forms more tightly
what happens when platelets are activated?
quiescent platelets are nondescript, but when activated they they throw out pseudopods and give off inflammation activators
where do platelets come from?
megakaryocytes, have A LOT of DNA, found in the center of long bones
do platlets have nuclei?
what do platelets have inside them?
granules holding many of the molecules needed for blood clotting, ADP, PDGF, (platelet derived growth factor), mitochondria, glycogen for energy which they burn in glycolysis, and many surface receptors
what are some things that will cause a signal to happen in a platelet? can these signals be amplified?
ADP, serotonin, shear forces, thrombin, epinephrine, plasmin, PAF, Tx A2. these signals can be amplified.
what are two receptors on platelets that allow them to adhere to the subendothelium and aggregate together, and how do they work?
GpIIb-IIIa binds to fibrinogen which forms a bridge between platelets expressing GpIIb-IIIa, this creates aggregation. GpIb/IX/V binds to von Willebrand factors which bind to collagen on the subendothelium, allowing adhesion of the platelets expressing GpIb to the subendothelium. GpIIb-IIIa can also bind to von Willebrand factors.
how do GpIIb-IIIa and GpIb/IX/V bind to fibrinogen and vWF, (von willebrand factor)?
GpIIb-IIIa and GpIb/IX/V bind to RGD, (arginine, glycine, aspartate), that is found on both fibrinogen and vWF
what is another function of vWF in coagulation?
vWF also carries factor VIII in circulation, (one of the co-factors in the blood clotting cascade)
why would a deficiency in vWF cause more problems than a deficiency in GpIb/IX/V?
with a deficiency in GpIb/IX/V, adhesion wouldn’t work but clotting could still work, but with a deficiency in vWF, Factor VIII would not be present since vFW carries it, and therefore blood clotting could not occur
where do vWFs come from?
weibel-palade bodies in platelet cells and endothelial cells or synthesized by the liver
can vWF bind 2 platelets together?
how is arachidonic acid released inside platelet or endothelial cells?
on the cell membrane, phospholipids w/arachidonic acid in position 2 are cleaved by PLA2, (phospholipase A2),
what do leukotrienes do?
vasoconstrition, dialtion, vascular permeability
what enzymes synthesize arachidonic acid into prostaglandins or leukotrienes inside platelet or endothelial cells?
arachidonic acid is made into prostaglandins via cyclooxygenase or into leukotrienes via lipoxygenases
what happens to arachidonic acid once cleaved in the prostaglandin pathway of both platelet and endothelial cells?
phospholipase A2 cuts arachidonic acid from the #2 postion, (of 3 on the FA), which then folds up and PGH synthase,(includes cyclooxygenase as the 1st component), carries out the next rxn, creating PGH2 – common intermediate in both platelet or endothelial cells
where does arachidonic acid come from?
linoleic acid, omega 6 FA, (essential b/c human body can’t make double bonds that far out). aside: if people ate more omega 3, there might be another molecule in the #2 position, which may help people with RA or other inflammatory diseases
what happens to PGH2 in platelet cells?
an enzyme makes PGH2 into thromboxine A2, a prostaglandin that is a very powerful vasoconstrictor
what happens to PGH2 in endothelial cells?
PGH2 is made by another enzyme which makes prostacyclin, (PGI2), a prostaglandin which is a very good vasodialator
what is the general hemostatic pattern with platelets and endothelial cells?
platelets do something first and endothelial cells come back and do something later
what does aspirin, (salicylic acid), do in terms of the prostaglandin pathway? what do ibuprofen and other NSAIDs do?
ASA blocks cyclooxygenase permanently via methylation, ibuprofen and other NSAIDs only do this reversibly.
what is COX-1 and where is it found? COX-2? are they produced constitutively? what do drugs intended to cause less stomach irritation target?
COX is cyclooxygenase. COX-1 is found often in the stomach and is constitutive. COX-2 is inflammation-induced. drugs intended to cause less stomach irritation target COX-2.
what is the danger in taking too much ASA?
COX permanently blocked in platelets cannot be replaced because platelets do not have nuclei, (however endothelial cells do have nuclei and are thus capable of creating more COX)
how do platelets control vascular diameter?
platlets can release serotonin and thromboxane A2 which vasoconstrict
how do endothelial cells control vascular diameter?
endothelial cells release endothelins which vasoconstricts, and nitric oxide and prostacyclin, (PGI2), which vasodialate
what happens to the phospholipids on the inside of the cell plasma membrane once arachidonic acid is cleaved from the #2 position? what charge do they now have?
flipases move the newly negatively charged phospholipids to the extracellular surface, creating a negative charge important for the blood clotting process
what are characteristics of the blood coagulation cascade?
an ordered series of rxns, specificity of enzymes, amplification of effects, 2 independent but converging pathways
how is thrombin, (IIa) formed?
prothrombin, (II), is held to the outer surface of the cell membrane by Ca++ and the enzyme Xa cuts it in 2 places, via cofactor V, releasing thrombin, (IIa)
what is factor V activated by? where does it bind? what inactivates it?
factor V is activated by thrombin, (so is factor XIII), to Va. it binds to the receptors on the platelet surface. activated protein C, (APC), inactivates factor V to Vi, (factor XIII is inactivated similarly).
how do Ca++ ions bind factors to the cell surface?
b/c flipase flipped the negatively charged phospholipids out onto the surface, Ca++ can bind to them. various factors have negative carboxyl groups that can then bind to Ca++, attaching them to the cell surface
how are factors II,VII,IX,X,C, and S prepared to attach to cell Ca++ ions on the cell surface? where does this happen?
factors II,VII,IX,X,C, and S have glutamate residues with one carboxyl group, and then vit K adds another, giving them the right amount of negativity to bind to Ca++. this happens in the liver.
how does coumarin or wafarin keep factors II,VII,IX,X,C, and S from binding to the cell surface?
vitamin K is oxidized during activation of factors, and must be reduced before the next rxn. coumarin derivatives, (warfarin/dicoumarol), block the reductases and thus inhibit the recycling of vit K.
what do the negatively charged phospholipids exposed to the external side of activated platelets help to do?
concentrate reactants, achieve 2 dimensional diffusion, and orient the reactants for enzymatic reaction
how does a soft fibrin clot form?
the center of fibrinogen has little little alpha and beta fibrinopeptides that are cut off by thrombin, leaving a very sticky middle portion that lines up with other fibrin molecules to create non-covalent bonds. the clot becomes hard when the bonds become covalent via factor XIII. side note: fibrinopeptides are important to inflammation.
how is the soft fibrin clot, (non-covalent), made into a hard fibrin clot, (covalent)?
a lysine from one fibrin is bound to the glutamine of another covalently via a peptide bond created by transglutaminase, (factor XIIIa, a ligase)
what activates factor XIIIa?
what is the relationship between factor XIIa and kallikrein? what is the cofactor for this rxn?
factor XII is highly sensitive to activation and it changes prekallikrein to kallikrein. kallikrein then changes more factor XII to factor XIIa. the cofactor for this rxn is high molecular weight kininogen, (HMWK), which kallikrein takes a little peptide from to form bradykinin, (another inflammatory molecule)
what cells are at the core of anti-coagulation?
endothelial cells
how is thrombin inactivated?
endothelial cells make thrombomodulin, which thrombin binds to, this leads to activation of protein C, (APC), and APC inactivates factor Va->Vi as well as factor VIIIa->VIIIi
what happens with factor V Leiden?
there is a mutation in factor V where protein C, (APC), cannot inactivate factor V, and there is more clotting
how is a clot proteolyzed?
plasminogen is activated by plasminogen activator, (PA), to plasmin. plasmin is a protease which cuts the clot into small pieces.
what is the regulation of plasmin enacted by?
PAI blocks plasminogen activator, (PA), and alpha2-AP blocks plasmin itself
what are plasmin activators? where are they made? are there plasmin activators that can be given to patients?
TPA, (tissue plasminogen activator), made in vascular endothelial cells. there is also SEU, (single chain eurokinase). streptokinase can be injected and works as a plasmin activator.
where do inhibitors of protease enzymes come from? what are the two basic kinds?
clotting enzymes and others are produced in the liver and circulate in the blood. the inhibitors usually either inactivate or trap blood clotting factors. inactivation is usually enacted in the “suicide substrate” method, where the complex of inhibitor+clotting factor is cleared from circulation
what does alpha2-macroglobulin do?
a large molecule acts as a trap for clotting factors. it is shaped like a mouth with residues that attract clotting factors, that alpha2-macroglobulin folds over, trapping them. the clotting factors are still active, just no longer free, and the complex is cleared from circulation.
what are serpines?
suicide inhibitors of serine proteases, that enzymes bind to, but the bond is irreversible and the complex is cleared from circulation
what are some examples of serpines?
alpha1-protease inhibitor, (alpha1P1), antithrombinIII, (ATIII), plasminogen activator inhibitor, (PAI-1, PAI-2), alpha1-antiplasmin, (alpha1AP), and C1-Inh
what is alpha1-protease inhibitor do, what is it related to?
alpha-1PI inhibits many clotting factors, it was formerly called alpha1-antitrypsin. it is a serpin.
what does antithrombin III do?
inhibits mostly factor X and thrombin. it is a serpin. it can also inhibit IX, XI, and XII
what does C1-Inhibitor do?
C1-Inh inhibits most everything along the intrinsic pathway
what do the protease inhibitors have in common?
they are all serine inhibitors, b/c protease has a serine in it
what is the tissue factor pathway inhibitor? what is it made by?
TF is the co-factor for the extrinsic pathway, (factor VII->VIIa and VIIa activates factor X). endothelial cells produce TF, thus inhibiting factors VIIa and Xa
what does heparin do, where does it come from? what are the different types?
heparin can be made in endothelial cells or it can be administered to pts. it binds to antithrombinIII, (ATIII), to enhance its inhibitory activity, (by conformational changes in ATIII and actually pulling in thrombin or factor Xa). there is high and low molecular weight, (HMW+LMW). HMW also activates PAI but LMW is used clinically
what are 2 tests for primary hemostasis?
platelet count, to determine # of thrombocytes, (looking for thrombocytopenia). bleeding time is tested blotting every 15 sec until bleeding stops, this can help assess clotting factors and platelet count.
what is the PTT?
partial thromboplastin, (phosphoplipid), time -> tests the intrinsic and common pathways. it is done by putting the pt’s plasma, a phospholipid, kaolin, and Ca++ into a test tube. 2 electrodes move towards each other until a bloot clot forms, and then the machine stops. this tests for heparin or severe deficiencies of the common or instrinsic pathway. it is relatively slow, as it goes from factor XII to XI, X, prothrombin, fibrin, (25-27 sec avg).
how does the PTT measure effects of heparin?
heparin enhances antithrombin III, which primarily inhibits factor Xa and thrombin, (factor IIa), in the common pathway. it also inhibits factors IXa, XIa, and XIIa of the intrinsic pathway. thus if heparin is present, it should take longer for the clot to form
what is the PT test? how is it done and what does it measure?
prothrombin time. in a test tube the pt’s plasma, phospholipid, tissue factor, (cofactor for extrinsic pathway), and Ca++ are mixed. this tests the pt’s common and extrinsic pathways and is used to test the effect of coumadin and the presence of deficiences. this test takes a shorter time, (VII->VIIa, X->Xa, II->IIa ~15 secs)
what is the INR?
international normalized ration, which is used to standardize PT from various labs. it is calculated by dividing the pts PT/PT notmal mean. a ratio of 1 = normal, around 10-12 sec, a ratio of 2 means the pt is 2x normal, (20-24 sec). 3x-4x is probably too much coumadin.
what does coumadin do?
blocks action of vitamin K in the liver, post-translational additon of a gamma carboxyl group on factors II, (thrombin), VII, IX, X, and proteins S and C, (S is C’s cofactor). this takes time as the liver is making new blood clotting factors
what test would you use for a pt with a factor VIII deficiency?
what test would you use for a pt with a PF4, (platelet factor 4), deficiency?
what test would you use for a pt with a factor VII deficiency?
what test would you use for a pt with a factor XII deficiency?
what test would you use for a pt on heparin?
what test would you use for a pt on coumadin?
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