Coagulation 1
What are the 2 cofactors? What factors are they paired with?
-Cofactors = V and VIII - V and X together - VIII and IX together
What is the Normal INR? Why is INR used?
0.8-1.2 -to normalize results across all labs
T or F: tPA activation of Plasmin leads to fibrinolysis systemically, regardless of the site of injury.
False. This only occurs at the site of injury, d/t tPA only being active on Plasminogen bound to fibrin.
T or F: If a Pt has an serum CA of 6, they will likely exhibit increased bleeding, because they won't have enough Ca++ available for the coagulation cascade.
False. Very little calcium is needed for coagulation, and serum Ca++ levels won't effect coagulation
What is released in fibrinolysis?
Fibrin Degradation/Split Products (FDP or FSP)
Fibrin monomers polymerize with other Fibrin monomers to form long fibrin fibers, but they have weak, non-covalent bonds. What substance can strengthen the fibrin crosslinks and convert them to strong, covalent bonds?
Fibrin Stabilizing Factor (Factor XIII) [13]
Where is Factor VIII produced?
PLT, Vascular endothelium, megakaryocytes
What is required to start a cascade reaction?
Phospholipid surface
Protein C needs ___________ in order to function.
Protein S
What happens if FSP are produced at a greater rate than the body can clear them?
They accumulate and inhibit PLT, Thrombin, prevent fibrin cross-linking. *Inhibit primary hemostasis and the coagulation cascade*
What is the difference btw aPTT and PTT?
aPTT has a surface activator; more reproducible
Is TFPI a coagulant or an anticoagulant?
anticoagulant
Protein C also causes the release of ____, promoting fibrinolysis.
tPA
What is the other name for Factor VI?
there is no factor VI
What are the functions of Prostacyclin?
*-Potent Vasodilator* -Inhibit PLT activation, secretion, and aggregation
What is thrombomodulin?
-A protein present on INTACT vascular endothelium that binds/inactivates/removes Thrombin *If the endothelium is disrupted, no thrombomodulin is present.
What are the 4 processes involved with PLT activation?
-Adhesion -Shape change/mediator release -Aggregation -Phospholipid surface presentation
What happens after a portion of a factor is cleaved off?
-Becomes an activated cleavage enzyme (Serine Protease) -Goes on to cleave the next procoagulant -Process continues as chain reaction until Fibrinogen is cleaved to Fibrin (LOTS of cleavage)
vWF, part of factor VIII has 2 purposes, what are they?
-Bind PLT to vascular endothelium in primary hemostasis -Carry small VIIIc (the actual factor VIII coagulant)
In the single tissue factor pathway, what 2 effects can be caused by TF (Factor III)?
-Can trigger start of Extrinsic pathway (activate Factor VII) -Can combine with Factor VIIa to activate Factor IX and activate part of the Intrinsic pathway.
_______ and ________ granules release their contents after PLT activation.
-Dense -Alpha
The _______ pathway is faster (13-15 seconds) but produces less thrombin (small clot), while the ______ pathway is slower (5-10min) but produces more thrombin (larger clot)
-Extrinsic = faster, less thrombin -Intrinsic = slower, more thrombin
The PT tests the ______ and _______ pathways by adding ______ and ______ to the patient's blood?
-Extrinsic and Common pathways -Ca++ -Tissue Factor (III)
What are the other names for Factors I, II, III, and IV?
-Factor I = Fibrinogen -Factor II = Prothrombin -Factor III = Tissue Factor -Factor IV = Calcium Lemme know if you can think of a mnemonic... all i can come up with are X rated ones
What happens after factor XIII strengthens the fibrin crosslinks?
-Fibrin traps PLT, Plasma, and Cells -Within minutes, the clot retracts d/t strong bonds btw PLTs; pulling the edges of the damaged vessel closer together. -PLT continue to release procoagulants, including more Factor XIII
What is required for Factor XII to activate Factor XI? What can speed up this process?
-High molecular weight Kininogen REQUIRED -Prekallikrein accelerates the reaction
What are the 2 parts that compose factor VIII?
-High molecular weight VIII antigen -vWF
Factors circulate in the (active/inactive form) and are also called ________.
-Inactive -Procoagulant/Proenzyme
The PTT tests the _______ and ________ pathways by adding ______ and _____ to the pt's blood.
-Intrinsic and common -Ca++ -PF3
What is the significance of the GP IIa/IIIb receptor and what attaches to it?
-It allows PLT to adhere to each other -Fibrinogen binds to this receptor on 2 PLT, acting as a bridge attaching the 2 PLTs
What is the significance of the PLT phospholipid surface (Platelet Factor 3/PF3)?
-It initiates the coagulation cascade (usually intrinsic) leading to a strong clot
What is the significance of Tissue Factor Pathway Inhibitor (TFPI)?
-It is activated after the 1st Thrombin generation by the extrinsic pathway -Inhibits further extrinsic pathway coagulation and forces coagulation via the intrinsic pathway via TF+VIIa activation of factor IX
Abnormal PT can be caused by what conditions?
-Liver Dz -Vitamin K Deficiency (vit k dep factors = II, VII, IX, X) -Coumadin -Mass Transfusion -Consumptive coagulopathy
______ triggers the start of the Intrinsic pathway, while ______ triggers the start of the extrinsic pathway.
-PF3 = intrinsic (PLT are found inside vessels) -TF (III) = extrinsic (Tissue is found outside vessels)
Fibrin and Antiplasmin have the same binding site on Plasmin, why is this significant?
-Plasmin bound to fibrin cannot be deactivated by Antiplasmin. -As soon as Plasmin is released by fibrin, it is bound/deactivated by Antiplasmin
What are the 3 processes involved in hemostasis?
-Primary Hemostasis (PLT) -Coagulation Cascade (clot formation) -Fibrinolysis (lysis of clot and restoration of flow)
Beyond the site of vascular injury, the intact epithelium releases ________, which opposes the action of _______, preventing clotting in normal vasculature.
-Prostacyclin -TXA2
What is TFPI?
-Protein bound to endothelium that blocks the extrinsic pathway; forces intrinsic pathway -Released during PLT activation
Cofactors are also called Labile factors, because they have a _______ HL, which explains why ______ is stored frozen.
-Short -FFP (if not stored frozen, V and VIII degrade and the cascade won't work)
What is the first thing that happens after vascular injury? What causes this?
-Spasm -d/t locally released substances (mostly Thromboxane A2)
Is Spasm more intense in a crushed vessel or in a transected vessel? What implication does this have with regard to anesthesia?
-Spasm more intense in a crushed vessel (= more TXA2 released) -Surgical wounds tend to bleed more because less TXA2 is released at the site of injury.
Where is vWF synthesized? Where is it stored?
-Synth by vasc endothelial cells and megakaryocytes -Stored in PLT and vascular endothelial cells
Why would inhibiting TFPI treat hemophilia?
-TFPI blocks the extrinsic pathway, forcing the bulk of coagulation to occur via the intrinsic pathway; and Hemophilia involves abnormalities in the intrinsic pathway. -If you inhibit TFPI, a hemophiliac could continue to clot via the extrinsic pathway
ATIII has 2 binding sites, what does it bind to?
-Thrombin -Heparin
What are the binding sites for vWF (2)?
-exposed collagen of vascular endothelium -PLT Glycoprotein 1b receptor (GP1b)
What is the normal PT?
10-13 seconds
What is the normal PLT count?
150,000 - 400,000/mm3
What is the normal Bleeding time?
2-9 minutes -questionable significance -not uniform nor reproducible
What is the normal aPTT?
25-35 sec
What is the minimum PLT count required for surgery?
50,000/mm3
What is the normal PLT function test result?
>65% aggregation in response to a stimulus (stimuli = ADP, Epi, Collagen)
If a patient is lacking Factor XII, Prekallikrein, HMW Kininogen, or Factor XI, they don't exhibit the common symptoms of markedly abnormal bleeding, why?
Because the Single Tissue Factor Pathway activates the Intrinsic cascade distal to Factor XI (activates Factor IX)
What causes increased activation of Protein C?
Binding of Thrombin and Thrombomodulin and high levels of thrombin
The common pathway includes a positive feedback loop, which is that Thrombin activates Factor ___, which then goes on to pair with Factor X to activate Thrombin.
Factor V
T or F: Plasmin circulates freely and binds to fibrin.
False, Plasmin can't circulate freely b/c Antiplasmin will destroy it.
_________ is the dissolution of a fibrin clot, restoring normal blood flow.
Fibrinolysis
After PLT release their contents, what becomes exposed?
Glycoprotein IIb/IIIa receptor (GP IIa/IIIb)
An elevated PTT indicates deficiency/abn/inhibition of which factors?
HMW kininogen, prekallikrein, XII, XI, IX, VIII, X, V, II, I
What conditions can cause an abnormal PTT?
Hemophilia Mass transfusion Heparin
The presence of _______ increases ATIII's affinity for Thrombin by 100-1000 times.
Heparin ATIII has a low affinity for thrombin in the absence of heparin
All but 3 factors are produced in the liver, which 3 aren't produced in the liver?
IV (Ca++) III (TF) VIII
What triggers the start of the extrinsic pathway?
Injured tissue releases the phospholipid Tissue Factor (TF/Factor III)
Antithrombin III can also inactive all factors of the _______ pathway.
Intrinsic
How are FSP eliminated?
Kidneys, Liver, Reticuloendothelial system
What role does von Willebrand Factor (vWF) play in PLT adhesion?
Necessary for adhesion; forms a bridge btw the vascular endothelium and the PLT
What happens after PF3 is exposed?
PF3 activates XII, which then activates factor XI, which activates factor IX, combines with factor VIII to activate X. Xa combines with Va to form Prothrombin activator -> common pathway If the Intrinsic pathway can't be bought for $12, it can be bought for $11.98.
What triggers the start of the Intrinsic Pathway?
PLT exposes phospholipid surface (PLT phospholipid/PF3)
_______ is the proteolytic enzyme that breaks down fibrin.
Plasmin
Tissue Plasminogen Activator (tPA) initiates the conversion of ______ to ______.
Plasminogen to Plasmin
Fibrinolysis involves the conversion of ________ to _______.
Plasminogen to plasmin
The ________ __________ ______ tests the PLTs ability to aggregate.
Platelet Function Test
How does the smooth INTACT surface of vascular endothelium act as an anticoagulant?
Prevents PLT adhesion and activation (The phospholipid surface of disrupted endothelium is needed to start the cascade)
What substances do the alpha and dense granules release after PLT activation? What is the function of these substances?
Procoagulants -ADP, Serotonin, Factor V, Factor VIII, Factor XI, Fibrinogen, vWF, Ca++ -Increase PLT adhesion => increased release of Procoags (+ feedback loop)
______ and _____ are vitamin K dependent anticoagulants.
Protein C and Protein S
_______ is a cofactor that has no independent function.
Protein S (it's Stupid) Needed for Protein C to bind to endothelium
Both the intrinsic and extrinsic pathways end with the production of Prothrombin Activator, which initiates the Final Common Pathway. What makes up Prothrombin Activator?
Prothrombin Activator = Xa, Va, Ca++, and phospholipid surface
What are the steps of the Final common pathway?
Prothrombin activator (X, V, Ca++, PLT) convert Prothrombin (II) to Thrombin, which then acts with Ca++ to convert Fibrinogen to Fibrin, and Fibrin stabilizing factor is then released (XIII), which stregthens Fibrin crosslinks. The final common pathway can be purchased at the Five and Dime for 1 or 2 dollars on the 13th of the month.
ADP is a powerful PLT activator released by granules after activation, what does it lead to?
Synthesis and release of TXA2 leading to further constriction and PLT aggregation, and subsequently more ADP release (+ feedback loop)
In the Extrinsic pathway, what happens after TF is released?
TF activates Factor VII -> VIIa, which then activates Factor X -> Xa, which binds to factor Va (Prothrombin activator) -> common pathway The extrinsic pathway can be purchased for 37 cents
Antithrombin III binds and inactivates _________.
Thrombin
Protein C circulates in the inactive form and is activated by _________.
Thrombin
After release from PLT, ________ causes further PLT activation and aggregation.
Thrombin (IIa)
_______ is the cornerstone of coagulation and once formed by ANY pathway, it amplifies and propagates further cascade.
Thrombin (IIa)
T or F: After vessel injury, PLT form a temporary plug and release pro-coagulants.
True
T or F: If vWF is absent, the patient will exhibit signs of vW disease and hemophilia A.
True
T or F: PLT count is a static test, that only provides the number of PLTs and gives no indication of PLT function.
True
T or F: Plasminogen circulates freely and binds to fibrin.
True
T or F: Thrombin activates factor V, causes the release of factor VIII from vWF, and activates factor XI, which then activates factor IX.
True
An elevated PT indicates deficiency/abn/inhibition of which factors?
VII, X, V, II, I
Protein C cleaves _____ and _______, acting as a negative feedback loop to prevent overproduction of thrombin.
Va and VIIIa (the 2 cofactors needed for X and IX)
How does vWF circulate?
attached to Factor VIII (8)
Why should the Factors really be represented by arabic numerals?
because you young kids are too stupid to understand roman numerals
If circulating (inactivated) clotting factors become activated while circulating, why doesn't this cause coagulation of circulating blood?
blood dilutes and washes them away (b/c they can't adhere to intact endothelium)
tPA can only bind to/activate plasminogen if it is _____ __ ______; this prevents widespread fibrinolysis.
bound to fibrin
Which of the following is false regarding PLT? a. produced in marrow b. sequestered in the spleen c. nucleated cells d. HL of 10-14 days e. fragments of megakaryocytes
c is false. Platelets are anucleated and can't reproduce -The other choices are all true of PLT
What shape change do PLT undergo?
from disc shaped to spherical shape to cover vascular defect
Do PLT circulate in the active or inactive form?
inactive
How long does the Spasm phase last?
minutes to hours; until cascade occurs
What role does Ca++ (IV) play in coagulation?
provides a positive charge to anchor factors to PLT phospholipid surface/damaged tissue
Where is tPA produced?
vascular endothelial cells