coagulation Flashcards
extrinsic pathway
plasma-mediated, initiation of hemostasis
AKA primary hemostasis
key: tissue factor
intrinsic pathway
amplifies and propogates hemostasis
aka secondary hemostasis
key: thrombin
common pathway
results in an insoluble fibrin clot
hemostasis is regulated by interactions between what three factors
vessel walls, circulating platelets, and clotting proteins in the plasma (FFP)
fibrinolysis definition
the orderly breakdown of a stable clot
in normal hemostasis what predominates - anticoagulants or procoagulants?
anticoagulants
what elicits vasoconstriction, the first step of the clotting pathway
damage to the endothelium that exposes the underlying ECM will elicit a contraction
also can be triggered by thrmobin, hypoxia, and high fluid sheer stress
what are the three major biochemical and physical change stages when forming a platelet plug
adhesion
activation
aggregation
thrombocytes
thrombus/clot + cells
what is the normal concentration of platelets per microliter
150,000-400,000
at what concentration of platelet per microliter do you start spontaneously bleeding and when is it lethal
<50,000 = spontaneous bleeding <10,000 = lethal
what is the life of a platelet
8-12 days (so you need to stop your antiplatelets for 8-12 days - or give them platelets)
platelet inhibitors
adenosine, insulin, NO, PGE2 and PGI2
platelet activators
adrenalin, cholesterol, thrombopoeitin, vWF, PGE2(viaEP3)
platelet adhesion
exposure to the subendothelial matrix proteins allows platelets to undergo a conformational change to adhere to the vascular wall
aka - matrix activates it and makes it sticky
von Willebrand factor
produced in the endothelium and platelets, released by endothelial cells and activated by platelets and its primary function is to bind other proteins
it is a bridging molecule between the subendothelial matrix and platelets forming crosslinks
GPIb-V-IX complex
binds vWF allowing platelet adhesion and platelet plug formation at sites of vascular injury
bernard soulier syndrome
absence of GPIb-V-IV receptor
when is vWB factor mainly activated
in conditions of high blood flow and shear stress
vWB disease
1 in 100 individuals are deficient but it is only clinically significant in 1 in 10,000
deficiency of vWB factor shows primarily in organs with small vessels and is diagnoses by measuring the amount of vWB factor in a vWB factor antigen assay and the funtionality of vWB factor wiht binding assays
factor 8 is also measured
type 1 vWB disease
60-80%
failure to secrete vWB factor into circulation or cleared too quickly
this is mild and often undiagnosed until bleeding following surgery, easy bruising, or menorrhagia
type 2 vWB disease
15-30%
this is a qualitative defect of the vWB factor and so effects vary
could have a decreased ability to either bind GPIb or VIII
type 3 vWB disease
most severe, homozygous defective gene, complete absence of production of vWB factor - leads to extremely low levels of factor VIII since it does not exsist to protect it from proteolytic degradation
platelet type vWB disease
in this type the problem is actually a defect of the platelet’s GPIb receptor
what are GPIIb/IIIa inhibitors?
they are a class of antiplatelets that block the ability of fibrinogen to form around aggregated platelets so no fibrinogen bridging of platelets to other platelets can occur
examples - abciximab (reopro), etifibatide (integrilin), tirofiban (aggrastat)
what is different about abciximab than other antiplatelets?
it irreversibly binds to its receptor so it takes 24hours to restore platelet function and is eliminated by plasma proteases
the other two (eptifibatide and tirofiban) reversibly bind to their receptors and it only takes 4-6 hours to restore platelet function and they are eliminated renally
platelet activation
occurs after platelets adhere to endothelial wall, and intracellular signaling pathways are activated when ligands bind to platelet receptors to begin a serious of physical/biochem changes
platelets develop pseudopod-like membrane extensions to increase SA
platelet recruitment
mediated by other platelets releasing granular contents
this also activates them
thromboxane A2 inhibitors
aka cox inhibitors
aspirin inhibits the ability of cox enzyme to synthesize the precursors of thromboxane within platelets
naproxen is nonselective
P2Y12 receptor
amplify the response to ADP and draw forth the completion of aggregation
ADP receptor antagonist prodrugs
ticlopidine (ticlid)
clopidogrel (plavix)
prasurgrel (efient)
ADP receptor antagonists - direct acting
ticagrelor - brilinta
cangrelor - kengrexal
what is the last step of the formation of a platelet plug?
platelet aggregation
what does the glycoprotien IIb/IIIa do when activated
they are on platelet surface and they bind fibrinogen to provide for crosslinking with adjacent platelets
formation of blood clot after platelet adhesion, activation, and aggregation
soluble fibrinogen becomes insoluble fibrin via thrombin which is then crosslinked into a stable mesh
what is the key step in blood clotting
the conversion of fibrinogen (I) to fibrin (Ia) by thrombin (IIa)
when is the intrinsic pathway triggered
when blood contacts a negatively charged surface (like the exposed subendothelial collagen)
begins with damage to blood vessels themselves
primary complex forms on collagen and thrombin is generated by way of factor XII
ends when merged into common pathway to activate factor X
may be more involved with inflammation, amplification and propagation of the hemostatic response to maximize thrombin generation
when is the extrinsic pathway activated
when blood contacts cells outside the vascular endothelium
nonvascular cells express tissue factor which initiate this pathway
follows damage o blood vessel, factor VII comes into contact wiht tissue factor to form TF-VIIa complex that activates factor X to promote Xa which starts the common pathway
what designates the beginning of the common final pathway
the activation of factor X to promote prothrombin to form thrombin which turns fibrinogen into fibrin
most coagulation factors are enzymes with the exception of
vWB and tissue factor (III) which are glycoproteins
most coagulation factors are synthesized where with the exception of what
liver
calcium (IV) - comes from diet
vWB - synthesized from endothelial cells and platelets
which factors are vitamin k dependent for utilization
II, VII, IX, X
what is the activity of thrombin
converts fibrin to fibrinogen***
also:
activates platelets and factor XIII (fibrin stabilizing factor)
Converts factor V and VIII into active forms
activates factor XI
upregulates TF
stimulates vascular endothelium to down regulate fibrinolytic activity
what all do you need to promote prothrombin to thrombin
Xa
Va
Calcium (IV)
“prothrombin activator”
what is the role of fibrin in a blood clot
it creates covalent bonds and crosslinks all fibers to create meshwork in all directions of blood cells, platelets, and plasma which adhere to the surface of damaged blood vessel
why do cobwebs stop clotting
they are rich in vitamin K
when does clot lysis occur?
when plasminogen is activated to plasmin by t-PA which is released from teh tissue, vascular endothelium, plasma and urine
what is plasmin
an enzyme which digests fibrin, fibrinogen, factor V, factor VIII, prothrombin, and factor XII
what is an example of an exogenous plasminogen that can be used clinically to dissolve intravascular clots
streptokinase
thrombolytics
possess inherent fibrinolytic effects of enhances the body’s fibrinolytic system by converting endogenous pro-enzyme plasminogen to the fibrinolytic enzyme plasmin
more capable of dissolving newly form clots which are platelet rich and have weaker fibrinogen bonds
prothrombin time
evaluates the extrinsic pathway
a sample of blood plasma is incubated with tissue factor in the presence of calcium
it is particularly sensitive to 3 of the 4 vitk dependent factors (II, VII, and X)
what is the problem with prothrombin times
commercial PT reagents vary markedly in their responsiveness to warfarin-induced decreases in clotting factors and are not interchangeable between labs
use INR for standardization
partial thromboplastin time
indicates the performance of the intrinsic pathway
a sample of blood is triggered by adding an activator surface plus phospholipid and calcium
ACT
performed by mixing whole blood with an activated substance to initiate activation of the clotting cascade
reliable for high heparin concentrations
influenced by hypothermia, thrombocytopenia, coagulation deficiencies
viscoelastic testing - thromboelastometry (TEG) and rotational thromboelastometry (ROTEM)
a global assay for whole blood clotting including coagulation factors, inhibitors, anticoagulant drugs, platelets, and fibrinolysis
bleeding time
sensitive test of platelet function
a small standardized incision is made in the underside of the forearm and the amount of time it takes for bleeding to stop is recorded
heparin concentration measurements
increasing concentrations of protamine are added to samples of heparin-containing blood and time to clot is measured.
the sample in which heparin and protamine are most closely matched will clot first
1mg protamine will inhibit 1mg (100u) of heparin
platelet function test
centrifugation of patient blood to obtain platelet-rich plasma
it is then analyzed in a cuvette at 37C placed between a light source and a photocell
what is the normal bleeding time
3-10 min
what is the normal platelet count
150,000-350,000 mm3
what is the normal prothrombin time
12-14sec
what is the normal INR
0.9-1.2
what is the normal aPTT
25-35s
what is the normal thrombin time
<30sec
what is the normal active coagulation time
80-150s
what is the normal level of fibrinogen
> 150mg/dL
