Ch. 7 Hemostasis Flashcards
Describe the difference between primary and secondary hemostasis
Primary - interactions between platelets and endothelium which lead to a platelet plug
Secondary - a cascade of proteolytic reactions involving coag factors that lead to the generation of fibrin polymers to stabilize those platelet plugs
What is the lifespan of a platelet in a dog or cat?
6-8 days
Where does thromboxane A2 come from?
platelets synthesize thromboxane from arachidonic acid, which is mediated by COX 1
Where do platelets adhere?
either to endothelial collagen via the platelet glycoprotein VI receptor
OR
to collagen bound vWF via the glycoprotein Ib receptor
What do platelets release to recruit more platelets?
Thromboxane A2 and adenosine diphosphate (ADP)
What is platelet integrin αIIbβ3 receptor?
agonist binding to this receptor leads to a conformational change in the receptor which exposes more binding domains for fibrinogen
What is thrombopoeitin?
Made in the liver, stimulates platelet production
What aids in platelet adhesion to each other?
Collagen & vWF
Weak binding to subendothelium
Activation of integrin αIIbβ3
What aids in platelet activation?
Membrane flipping
Shape change
What is the common pathway of secondary hemostasis?
Activation of factor X to Xa
Xa with cofactor Va will activate prothrombin (II) to thrombin (IIa)
Thrombin will then cleave fibrinogen to fibrin
What pathway does PT coag test?
The extrinsic (so tissue factor when in presence of platelet phospholipid in calcium coverts VII to VIIa) and common
What pathway does aPTT coag test?
Intrinsic (so XII converting XI to XIa, then XIa plus VIIIa plus platelet phospholipid and calcium converting X to Xa) and common
What does the cell based model of coagulation reflect:
- tissue factor is the primary physiologic initiator of caogulation (contact activation playing no role in vivo)
- coagulation is localized and controlled by cellular surfaces
Coagulation occurs in three overlapping phases: initiation (on tissue factor bearing cells), amplification, and propagation (on platelets)
What is the initiation phase of the cell based model of coagulation
basically the tissue factor initiated (or considered extrinsic) pathway that will generate small amounts of thrombin
VII and tissue factor (aka factor III) will bind together and then activate X
Factor X will combine with Va to make small amounts of thrombin
What occurs in the propagation phase of the cell based model of coagulation
activated platelets express high affinity for binding sites for coag factors
XI binds and is activated by thrombin
XIa will then activate IX
IXa will complex with VIIIa to activate X (which is basically the intrinsic pathway)
Xa and Va will make complexes to activate prothrombin
What are three inhibitors of platelet reactivity within the normal endothelium?
Prostacyclin (PGI2)
Ectoadenosine diphosphatase (ecto-ADPase)
Nitric oxide
Which COX pathway is predominant in endothelial cells?
COX 2
*COX 1 predominant in platelets
How does prostacyclin inhibit platelet reactivity?
limits platelet response to thromboxane
how does ecto-ADPase inhibit platelet reactivity?
metabolizes ADP, which is an agonist of platelet activation
How does nitric oxide inhibit platelet reactivity?
NO is produced by endothelial cells
it diffuses into platelets and decreases the intracellular Ca2+ flux, which will suppress the conformational change in the integrin αIIbβ3 receptor (the receptor becomes a binding site of fibrinogen)
What are the three natural anticoagulant pathways
antithrombin
activated protein C
tissue factor pathway inhibitor
How does antithrombin act?
It is a circulating alpha 2 globulin made by the liver
Inactivates coag proteins, most notably by inactivating thrombin and Xa
Also will inactivate VII, IX, XII, XII and kallikrein
Its rate of inhibition is even greater when it is working with heparin
It also inhibits neutrophil adherence
How does activated protein C inhibit coagulation
It is activated by the thrombin-thrombomodulin complex
protein C along with its cofactor protein S will inactivate V and VIII –> slows rate of thrombin formation
Also enhances fibrinolysis via inactivation of plasminogen activator inhibitor 1 (PAI-1)
Also limits inflammatory responses and decreases endothelial cell apoptosis
How does Tissue factor pathway inhibitor regulate coagulation?
binds to and inactivates factor Xa
this complex will then bind to VIIa-TF complex and inactivate them all
How is plasminogen converted to plasmin (a degrader of fibrin)
either by tissue type plasminogen activator
or
urokinase type plasminogen activator
These activators are controlled by activator inhibitors. The most important is plasminogen activator inhibitor 1 which is stored in platelet alpha granules and released upon platelet activation
What are the major inhibitors of the fibrinolytic system?
Plasminogen activator inhibitor 1
thrombin activatable fibrolysis inhibitor
alpha 2 antiplasmin
What is the normal range of a BMBT in dog and cat
Dog - less than three minutes
cat - 34-105 seconds
What is a BMBT testing?
reflects in vivo primary hemostasis
prolonged with thrombocytopenia, thrombopathia, and vasculopathy
How much of a factor must be deficient for PT or APTT to be prolonged?
about 25-30%
PT is very sensitive to vitamin K deficiency/antagonism
What does activated clotting time measure? ACT test
evaluates intrinsic and common pathways
less sensitive than APTT
What do fibrin split product tests measure?
these measure fibrin degradation products - elevated concentrations indicate increased fibrinolysis and/or fibrinogenolysis
May be elevated with DIC or thromboembolism, neoplasia, IMHA, hepatic failure, sepsis, SIRS, heat stroke, trauma, GDV, warfarin tox, hemorrhage, PLN, cushings, heart failure - not very specific!
What do D dimers indicate?
They indicate the activation of thrombin and plasmin and are specific for active cogulation and fibrinolysis
Very sensitive and more specific than fibrin split products but still not very specific
How decreased must fibrinogen be to prolong PT, APTT, or ACT?
severely as in less than 50-100mg/dL
fibrinogen concentrations are determined by the thrombin clot time
it is an acute phase protein so concentrations may be elevated with inflammation
What is R (reaction time) on a TEG
represents the time of latency from the test initiation until the beginning of fibrin formation (an increase in the amplitude of 2 mm)
What is the clotting time (K) on a TEG
This is the time to clot formation and measured from R to an amplitude of 20 mm
What is the angle (alpha) on a TEG?
it is the rapidity of fibrin accumulation and cross linking
Dependent largely on fibrinogen
The slope from R to K
What is MA on a TEG?
maximum amplitude - the strength of a clot
What are the four technical causes of surgical bleeding
- inadequate repair of vessels or vascular structures that have been opened
- occult or undiagnosed injury to the vascular system
- damage to organs or structures within the operative field
- damage during surgery or post op to organs or structures remote from the surgical site
What theories explain how acute traumatic coagulopathies are made?
DIC with a hyperfibrinolytic phenotype
enhanced thrombomodulin thrombin protein C
catecholamine induced endothelial damage
What six factors will influence the development of acute traumatic coagulopathy?
- tissue injury - initiates coagulation, elevated thrombin then activates protein C
- hypoperfusion
- inflammation - proinflammatory cytokines like TNF alpha, IL1, IL6 will enhance anticoagulation and hyperfibrinolysis
- acidemia - increases fibrinogen degradation and impairs coag factor activity
- hypothermia - platelets are very temp sensitive
- hemodilution - fibrinogen is the first factor that becomes critically reduced
the last three are more going to result in trauma induced coagulopathy
What components does fresh frozen plasma contain?
all the hemostatic factors including the coag factors, vWF, albumin, globulins, and natural anticoagulants too
contraindicated in heparin coagulopathy
What components are high in frozen (stored) plasma?
highest in factors II, VII, IX, and X
What components are high in cryoprecipitate?
factors VIII, vWF, fibrinogen, fibrinectin
This is made from FFP’s heavier proteins
What components are high in cryosupernatent
the plasma that remains after cryoprecipitate is removed so it is high in all but vWF, VIII, fibrinogen, and fibronectin
What plasma transfusion products would be appropriate for a dog with vWF deficiency?
fresh frozen plasma
cryoprecipitate
What plasma products would be good for a patient with low protein?
fresh frozen plasma
cryosupernatent
what are the best products for platelet increase?
platelet rich plasma or platelet concentrate
Properties of Desmopressin
desmopressin, or DDAVP, is a syntehtic vassopresin that works on V2 receptors to release vWF which increases platelet function as well as release VIII and plasminogen from the endothelium
Assists in vWF type 1 disease but not type 2 or 3
What are epsilon aminocaproic acid and tranexemic acid?
these are antifibrinolytics that are lysine analogues
they block the binding and activation of plasminogen
they also have some antiinflammatory effect by inhibiting interleukin
How long should you wait before taking a patient on aspirin to surgery?
discontinue and wait 7-10 days
verify you are in the clear with a BMBT
Use platelet transfusion or desmopressin if bleeding occurs
How long should you wait before taking a patient on NSAIDs to surgery
at least 24 hours
use platelet transfusion if bleeding occurs
How long should you wait before taking a patient on clopidogrel to surgery
discontinue and wait 7-10 days
verify you are in the clear with a BMBT
Use platelet transfusion or desmopressin if bleeding occurs
How long should you wait to take a patient on unfractionated heparin to surgery
at least 6 hours
check with APTT or TEG
use protamine with uncontrolled bleeding
How long should you wait to take a patient on low molecular weight heparin to surgery
at least 24 hours
check via anti factor Xa or a TEG
use protamine with uncontrolled bleeding
How long should you wait before taking a patient on warfarin to surgery?
3-7 days
verify via PT or TEG
give plasma or vitamin K for uncontrolled bleeding
What breeds are overrepresented in type II vWF deficiency
this is uncommon and reported in german shorthair and wirehaired pointers
usually results in severe bleeding
a disproportionate loss of high molecular weight multimers
type 1 by contrast is just low levels
What breeds have familial forms of type 3 vWF deficiency been reported in
it is almost a complete absence of vWF and has been reported in shelties, scotties, chesapeake bay retrievers, and dutch kooikers
Why are platelet transfusions more effective in thrombocytopathic than penic patients?
For thrombocytopenic patients, a large tranfusion must be performed to elevate the levels and then those platelets dont last long. Only a few days with fresh whole blood or PRP (which is a large volume) or about 15 min with lypholized platelets.
Thrombocytopathic patients, however, benefit from platelet transfusions because the transfused platelts will help initiate hemostasis and then the natural defective platelets are able to aid once the process begins
What breed of cat has a reported rare combined deficiency of vitamin k dependent coag factors (II, VII, IX, X)
Devon rex
Which coag (PT or APTT) will be prolonged in hemophilia A and B patients
prolonged APTT
what is the most common coag factor deficiency in cats?
factor XII
it is common but usually asymptomatic because it is involved in contact factor activation but is not essential for in vivo hemostasis - it will prolong APTT and usually is diagnosed incidentally
What enzyme helps recycle vitamin K
vitamin K epoxide reductase
Where does the body get its vitamin k
vitamin k is a fat soluble vitamin produced by colonic bacteriafrom ingeted vitamin K1
What factors increase the risk for percutaneous liver biopsy associated hemorrhage
in the dog, plt less than 86,000 and any prolongation of PT
in the cat, APTT prolongation more than 1.4 times
What is virchow’s triad
abnormalities of blood vessel (endothelial injury)
abnormalities of blood flow (vascular stasis)
abnormalities of blood constituents that promote hemostasis (hypercoagulability)
how does low protein lead to platelet hyperaggregability
hypoalbuminemia increases thromboxane synthesis
What is protein c role in hemostasis
The protein C system provides important control of blood coagulation by regulating the activities of factor VIIIa (FVIIIa) and factor Va (FVa), cofactors in the activation of factor X and prothrombin, respectively.
What conditions are associated with canine thromboembolism formation
PLN Neoplasia IMHA necrotizing pancreatitis Cushings or steroids cardaic disease (endocarditis and heartworm) sepsis diabetes mellitus
What do cancer cells express and produce that can increase the risk of a thromboembolism
tissue factor
cancer procoagulant which activates factor X
what is the westermark sign
it is a sign of regional oligemia which is an uncommon but reasonably specific finding for PTE
appears as areas of increased radiolucency representing hypovascular lung regions distal to the occlusion
what is the only laboratory marker with clinical utility in the diagnosis of PTE in humans
D dimers and we think it likely is helpful in dogs too
What is the mechanism of unfractionated heparin
5000 to 30,000 daltons
potentiation of antithrombin activity, which leads to inactivation of coag factors, especially thrombin and X
also releases tissue factor pathway inhibitor
decreases blood viscosity
decreases platelet function
increases vascular permeability
What is the mechanism of low molecular weight thrombin
4000 to 6500 dalton
will inhibit factor X far more than thrombin
must be assessed by anti factor X assay because APTT will not be reliable
lesser effects on platelet function
needs more frequent dosing than unfractionated
what is the mechanism of warfarin
vitamin k antagonist that alters the synthetsis of vitamin k dependent coag factors II, VII, IX, and X
also will alter proteins C and S synthesis
during the first 24-48 hours of administration, only short half life (VII and protein C) are affected
What kind of drug is rivaroxaban, apixaban, and edoxaban?
direct factor X inhibitors
WHat kind of drug is dabigatran
a direct thrombin inhibitor
what is the mechanism of aspirin
causes irreversible functional defect in platelets by inactivating COX 1 which then means that thromboxane production is decreased
But endothelial cells can still make new COX 1 and then can make more prostacyclin so overall effect may be blunted
What is the mechanism of clopidogrel
thienopyridine clopidogel requires hepatic metabolism to acquire antiplatelet activity
its active metabolies will irreversibly block ADP binding on the platelet surface
This then prevents activation of alphaIIbBeta3 integrin receptor, fibringogen binding, and sustained aggregation
onset of action takes 2 days and reaches staeady state after 5-7
also irreversible so it lasts for the life of a platelet
What inflammatory processes lead to increased risk of DIC
TNF alpha, IL 1, and IL 6 are initiators of DIC
cytokines damage microvascular endothelium and induce the expression of tissue factor which activates VII-TF pathway
protein c leves decline rapidly as a result of consumption
cytokines also stimulate plasminogen activator inhibitor 1 so that means the fibrinolytic system is also suppressed
