Unit 9 - Coagulation Flashcards
tunica media is thicker in arteries or veins?
arteries
thinnest vascular layer in veins
tunica externa
how does the body attempt to prevent hemorrhage with vascular injury?
- vascular spasm
- formation of platelet plug
- coagulation and fibrin formation
- fibrinolysis when clot no longer needed
4 steps of homeostasis
primary step of homeostasis
formation of platelet plug
function of von willebrand factor
platelet adhesion
function of collagen
tensile strength
function of fibronectin
cell adhesion
function of thrombomodulin
regulates naturally occuring anticoagulants
function of protein C
degrades factor 5a & 8a
degrades factor 5a & 8a
protein C
cofactor for protein C
protein S
degrades factors 9a, 10a, 11a, 12a
antithrombin
function of antithrombin
degrades factors 9a, 10a, 11a, 12a
precursor to plasmin
plasminogen
activates plasmin
tPA
urokinase
inactivates tPA & urokinase
alpha-antiplasmin
inhibits plasmin
plasmin activator inhibitor
vasoactive mediators responsible for vascular smooth muscle constriction
thromboxane A2
ADP
serotonin
vasoactive mediators responsible for vascular smooth muscle relaxation
nitric oxide
prostacyclin
produces platelets in bone marrow
megakaryocytes
where are platelets produced
bone marrow
by megakaryocytes
normal platelet value
150-300k
lifespan of a platelet
8-12 days
how are platelets cleared
by macrophages in reticuloendothelium & spleen
what organ can sequester up to 1/3 of all circulating platelets for later use
spleen
why are plts pushed towards vessel wall close to site of action
smaller size
where do glycoproteins adhere
injured endothelium, collagen, and fibrinogen
2 components of platelet external membrane
glycoproteins
phospholipids
7 components inside the plts
- actin/myosin
- thrombosthenin
- ADP
- calcium
- fibrin-stabilizing factor
- serotonin
- growth factor
function of actin & myosin inside platelet
help contract to form plt plug
function of thrombosthenin inside the platelet
help with platelet activation & aggregation
function of ADP inside platelet
plt activation & aggregation
function of calcium inside platelet
multiple functions in coagulation cascade (factor 4)
function of serotonin inside plts
activates nearby plts
function of growth factor inside platelet
helps repair damaged vessel walls
what keeps blood as a liquid when there’s no injury
- coagulation proteins circulate in inactive form
- glycocalyx repels clotting factors
- smooth endothelium prevents activation of plts/coagulation
- activated factors removed by brisk blood flow/circulating anticoagulants
how does the endothelium inhibit plt function in the absence of vascular injury
secretes prostaglandin 12 & nitric oxide
substrate for prostaglandin synthesis
phospholipids
what produces thromboxane A2
phospholipids
what does the GpIIb complex do
- attaches activated platelet to vWF
- links platelets together to form plug
how does nitric oxide inhibit platelet function
inhibits thromboxane A2 receptor
how does prostaglandin 12 help inhibit plt function
- inhibits vWF adherence
- thromboxane A2 activation
- release of storage granules
common sources of endothelial injury
- surgery
- trauma
- plaque dislodgment
- spontaneous micro-injury (occur daily)
what part of the vessel contracts immediately following injury
tunica media
tunica media contraction with injury is the result of what 3 functions
- SNS reflexes
- myogenic response
- release of vasoactive substances
2 functions of vascular spasm
- reduces blood loss
- helps procoagulants remain in affected area
3 steps of primary homeostasis
- adhesion
- activation
- aggregation
how long does the process to form a plt plug take
about 5 min
what happens in step 1 of platelet plug formation
adhesion
plts immediately adhere to exposed collagen with help of vWF
endothelial injury exposes collagen
how do plts adhere to collagen in step 1 of primary homeostasis
via Gp Ia/IIa and Gp VI receptors
how long does it take for platelets to adhere to collagen after vascular injury
within seconds
where is von Willebrand factor synthesized and released from
endothelium
where does vWF bind to platelet to bind to subendothelium
to GpIb receptor
step 2 of primary homeostasis
(formation of plt plug)
plts contract and release series of compounds that attract other plts to site
how are platelets activated in step 2 of primary homeostasis
exposed collagen at site of injury activates plts
2 substances released by activated platelets
ADP
thromboxane A2
responsible for adhering platelet to damaged vessel
von willebrand factor
what do activated plts release in step 2 of primary homeostasis
contents of alpha granules
* fibrinogen
* fibronectin
* vWF
* platelet factor 4
* platelet growth factor
2 glycoproteins expressed on surface of activated platelets
GpIIb
GpIIIa
links activated platelets together to form platelet plug
GpIIb/IIIa receptor complex
step 3 of primary homeostasis
aggregation
plt plug forms
required to configure GpIIb and GpIIIa
Thromboxane A2
ADP
what is needed to mesh wound in micro-injuries
a platelet plug is all that’s needed
(activation of coagulation cascade not needede)
primary purpose of coagulation cascade
form fibrin
in the classic coagulation model, when is the extrinsic pathway activated
when coagulation initiated outside intravascular space
in the classic coagulation model, when is the intrinsic pathway activated
when coagulation initiated inside intravascular space
how is coagulation activated in the cell based model
by extrinsic pathway as injured endothelium releases tissue factor 3
endpoint of classic model of coagulation
2 distinct pathways
each arrives st final common pathway
function of intrinsic pathway in cell based model
amplifies thrombin generating effect of extrinsic pathway
factors in coagulation cascade
1 fibrinogen
2 prothrombin
3 tissue factor
4 calcium ions
5 labile factor
7 stable factor
8 antihemophilic factor
9 christmas factor
10 stuart-prower factor
11 plasma thromboplastin antecedant
12 hageman factor
13 fibrin stabilizing factor
Foolish People Tty Climbing Long Slopes After Christmas Some People Have Fallen
factors in coagulation cascade
1 fibrinogen
2 prothrombin
3 tissue factor
4 calcium ions
5 labile factor
7 stable factor
8 antihemophilic factor
9 christmas factor
10 stuart-prower factor
11 plasma thromboplastin antecedant
12 hageman factor
13 fibrin stabilizing factor
Foolish People Tty Climbing Long Slopes After Christmas Some People Have Fallen
where are factors in coagulation cascade synthesized
liver
except tissue factor (vascular wall) & calcium (diet)
lab test for intrinsic pathway
PTT, ACT
lab tests for extrinsic pathway
PT/INR
vitamin-k dependent clotting factors
2, 7, 9, 10
1st coagulation factor activated in extrinsic pathway
tissue factor
activates extrinsic pathway
tissue factor
factors of extrinsic pathway
3 & 7
first factor to become deficient in liver failure, vitamin K deficiency, and pts on warfarin
factor 7
coagulation factor with the shortest half life
factor 7
(4-6 hours)
how much time does extrinsic pathway take
~15 seconds
collective coagulation factors that lead to thrombin activation (2a)
prothrombin activator
aka prothrombinase
how is factor 10 activated in extrinsic pathway
- tissue trauma activates tissue factor
- tissue factor activates factor 7
- factor 7 activates factor 10 in presence of 4 calcium
positive feedback mechanism that accelerates continued production of prothrombin activator in extrinsic pathway
factor 5
factors specific to classical intrinsic pathway
8, 9, 11, 12
steps of extrinsic pathway
- tissue factor release
- factor 10 activation
- prothrombin activator
steps of intrinsic pathway
- blood trauma exposure to collagen
- factor 11 activation
- factor 9 activation
- factor 10 activation
- prothrombin activator
time for intrinsic pathway to form a clot
6 minutes
what happens in first step of intrinsic pathway
blood trauma exposure to collagen = factor 12 activation
how is factor 11 activated in intrinsic pathway
factor 12a
what is required for factor 12a to activate factor 11 in intrinsic pathway
HMW kininogen
what acceperates factor 12a activation of factor 11
prekallikrein
what activates factor 9 in intrinsic pathway
factor 11
how is factor 10 activated in intrinsic pathway
by factor 9a & 8
what factor is missing in hemophilia A
8
how is thrombin (factor 2a) activated in intrinsic pathway
prothrombin activator & tissue phospholipids
identical to last step of extrinsic pathway
how is thrombin (factor 2a) activated in intrinsic pathway
prothrombin activator & tissue phospholipids
identical to last step of extrinsic pathway
factors involved in final common pathway
5, 10, 1, 2, 13
“The final common pathway can be purchased at the five (5) and dime (5) for 1 or 2 dollars on the 13th of the month”
factors involved in final common pathway
5, 10, 1, 2, 13
“The final common pathway can be purchased at the five (5) and dime (5) for 1 or 2 dollars on the 13th of the month”
factors involved in final common pathway
5, 10, 1, 2, 13
“The final common pathway can be purchased at the five (5) and dime (5) for 1 or 2 dollars on the 13th of the month”
primary goals of intrinsic and extrsinic pathway in final common pathway
produce prothrombin activator
when does final common pathway begin
when prothrombinase (complex of 10z + 5a + 4) converts prothrombin (2) to thrombin (2a)
proteolytic enzyme that changes fibrinogen to fibrinogen monomer
thrombin (2a)
when is fibrin incorporated into platelet plug in final common pathway
after platelets aggregate
facilitates cross-linkage of fibin fibers to complete clot in final common pathway
factor 13a
activated fibrin-stabilizing factor
4 mechanisms that counterbalance clot formation
- vasodilation/washout of ADP & TXA2
- anththrombin actions
- tissue factor pathway inhibitor
- protein C & S
how does antithrombin counterbalance clot formation
inactivates thrombin (2a), 9a, 10a, 11a, & 12a
how do proteins C & S counterbalance clot formation
inhibit factors 5a and 8a
where is plasminogen synthesized
liver
function of plasminogen
proenzyme incorporated into clot as it’s being formed (dormant until activated)
what is plasmin
proteolytic enzyme that degrades fibrin into fibrin degradation products
2 enzymes that convert plasminogen to plasmin
tPA
urokinase
major mechanism of plasmin activation
injured tissue releases tissue plasminogen activator (tPA) over a period of days
minor mechanism of plasmin formation
urokinase produced by kidneys and released into circulation
where is urokinase produced
kidneys
how are plasmin activators used therapeutically
to dissolve thrombi and restore blood flow
inhibits conversion of plasminogen to plasmin
tPA inhibitor (tPAI)
inhibits action of plasmin on fibrin
alpha-2 antiplasmin
3 phases of contemporary cell-based coagulation cascade
- initiation
- amplification
- propagation
when does the initiation phase of the contemporary coagulation cascade begin
when tissue factor is expressed
what factors begin the initiation phase of contemporary coagulation cascade
3 & 7
thrombin levels during initiation phase of contemporary coagulation cascade
remain low bc tissue factor pathway inhibitor limits amount of tissue factor released
why isn’t fibrin activated in the initiation phase of the contemporary coagulation cascade
quantity of thrombin produced is insufficient to activate thrombin
lays groundworn for large-scale thrombin production in amplification phase of contemporary coagulation cascade
platelets and cofactors
how does the small amount of thrombin produced on TF-bearing cells amplify the coagulation response
(contemporary coagulation cascade)
by activating platelets, factor 5, and factor 11
what happens in the propagation phase of the contemporary coagulation cascade
Large quantities of thrombin are produced on the surfaces of platelets
when does propagation phase begin (contemporary coagulation cascade)
factor 10 is activated by factors 4 (Ca+2), 8, and 9 on the surface of the platelet
which phase of contemporary coagulation cascade is a positive feedback mechanism
propagation phase
produces enough thrombin to activate fibrin
which phase of contemprary coagulation cascade is a positive feedback mechanism
propagation phase
produces enough thrombin to activate fibrin
what coagulation pathways does aPTT assess
intrinsic
final common
best predictor of bleeding during surgery
history & physical
what does aPTT measure
time it takes to form a clot using phospholipid, calcium, and an activator
Monitors therapeutic response to unfractionated heparin (not LMWH)
aPTT
factors included in intrinsic pathway
12
11
9
8
coagulation pathway inhibited by heparin
intrinsic
what is the role of thrombin
converts fibrinogen to fibrogen monomer
what must be present to convert fibrogen monomer to fibrin fibers
calcium (factor 4)
converts fibrin to fibrin degredation products
plasmin
measures fibrin degradation products
D-dimer
inhibits conversion of plasminogen to plasmin
tPA
normal aPTT value
25-32 seconds
why is normal aPTT longer than normal PT
the intrinsic pathway is slower than extrinsic
at what point will a change in aPTT occur
factors must be reduced by > 30%
what pathways does PT assess
extrinsic & final common
what 2 enzyme inhibitors turn off the fibrinolytic process
- tPAI
- alpha 2 antiplasmin
how are plasmin activators used therapeutically
dissolve thrombi to restore flow
what does PT measure
time it takes to form a clot using tissue factor and calcium
which lab test monitors therapeutic response to warfarin
PT
normal PT
12-14 seconds
when will a decrease in PT be seen
Factors must be reduced by > 30% before a change in PT is observed
calculation that standardizes PT results
INR
what is INR based on
ratio between patient’s PT and the standard mean PT
normal INR in healthy pts
~1
target INR for pts on warfarin
2-3x control
lab that guides heparin dosing
ACT
normal ACT
90-120 seconds
Should be > 400 seconds before going on CPB
normal ACT
90-120 seconds
Should be > 400 seconds before going on CPB
when is ACT measured
before heparin admin, 3 minutes after it’s given, and every 30 min thereafter
what lab tends to be more accurate when large doses of heparin are given
ACT > PTT
factors that affect ACT
- hypothermia
- thrombocytopenia
- deficiency of fibrinogen
- deficiency of factor 7
- deficiency of factor 12
plt count that indicates inc surgical bleeding risk
< 50,000
plt count that indicates inc surgical bleeding risk
< 50,000
plt count that indicates increased spontaneous bleeding risk
<20,000
plt count that indicates increased spontaneous bleeding risk
<20,000
lab test that monitors platelet function
bleeding time
normal bleeding time value
2-10 minutes
what drugs prolong bleeding time
aspirin
NSAIDs
what does D-dimer monitor for
fibrinolysis (fibrin degradation products)
what does increased d-dimer indicate
fibrinolysis
if increased, likely a thrombus present
differential with increased D-dimer
DVT
PE
DIC
Provides a “real time” visual representation of disorders of coagulation & fibrinolysis
TEG
TEG: R time
time to begin forming clot
normal R time (TEG)
6-8 minutes
treatment for prolonged R time
(TEG)
FFP
TEG: K time
time until clot has achieved fixed strength
normal value of K time (TEG)
3-7 minutes
treatment for prolonged K time (TEG)
cryo
what is the alpha angle in a TEG result
speed of fibrin accumulation
treatment of increased alpha angle (TEG)
cryo
normal alpha angle (TEG)
50-60 degrees
what is maximum amplitude of TEG
highest verticle amplitude
measures clot strength
what is A60 on TEG
height of verticle amplitude 60 min after max amplitude
normal A60 value (TEG)
MA - 5
what does an increased A60 in TEG indicate
excess fibrinolysis
treatment of increased A60
TXA
Amicar
produces endogenous heparin
basophils, mast cells, and the liver
what is exogenous heparin derived from
bovine lung and pig GI mucosa
naturally occurring anticoagulant that circulates in plasma
antithrombin
pathways inhibited by heparin
intrinsic
final common
MOA of heparin
- binds to AT and greatly accelerates its anticoagulant ability (1000-fold)
- heparin-AT complex neutralizes thrombin & activated factors 9, 10, 11, and 12
also inhibits platelet function
MOA of heparin
- binds to AT and greatly accelerates its anticoagulant ability (1000-fold)
- heparin-AT complex neutralizes thrombin & activated factors 9, 10, 11, and 12
also inhibits platelet function
MOA of heparin
- binds to AT and greatly accelerates its anticoagulant ability (1000-fold)
- heparin-AT complex neutralizes thrombin & activated factors 9, 10, 11, and 12
also inhibits platelet function
what should be considered if heparin fails to adequately anticoagulate
AT deficiency
Vd of heparin
small
how is heparin metabolized
heparinase
2 pathways for heparin elimination
- degradation by macrophages
- renal excretion
is heparin safe in pregnancy
yes - does not cross placenta
1 unit heparin =
the volume of heparin-containing solution that prevents 1 mL of citrated sheep blood from clotting for one hour following the addition of 0.2 mL of 1:100 CaCI
heparin dosing. for cardiac surgery
300-400 units/kg IV
heparin dosing for VTE prophylaxis
5,000 U SQ BID or TID
heparin dosing for active VTE
5,000 U IV then infusion of ~ 1,250 U/hr to maintain aPTT 1.5 - 2.5x normal
heparin dosing for unstable angina & MI
5,000 U IV then infusion of 1,000 U/hr
aPTT that indicates therapeutic heparinization
1.5-2.5x normal
(normal = 25-35 sec)
Side effects of heparin
- hemorrhage
- heparin-induced thrombocytopenia (HIT)
- allergic reaction
- hypotension
- decreased antithrombin concentration
heparin contraindications
NSGY
HIT
regional anesthesia
MOA of protamine
highly alkaline, strong positive charge + negative charge of heparin = neutralization reaction that stops heparin’s anticoagulant
dosing protamine
1 mg protamine for every 100 U heparin predicted to be in circulation
how is the heparin-protamine complex cleared
Reticuloendothelial system
function of protamine when given alone
anticoagulant
3 side effects of protamine
- hypotension
- pulmonary HTN
- allergic reaction
what causes hypotension with protamine
histamine release
give over > 5 min
what causes pulmonary HTN with protamine
thromboxane A2 and serotonin release
factors that increase risk of allergic reaction to protamine
- sensitization to NPH insulin
- fish allergy
- vasectomy
- multiple allergies
MOA of warfarin
Inhibits the enzyme vitamin K epoxide reductase complex 1 (VKOR c1)
factors indirectly inhibited by warfarin
responsible for converting inactive vitamin K to active vitamin K
vitamin K epoxide reductase complex 1 (VKOR c1)
inhibited by warfarin
factors indirectly blocked by warfarin
vitamin-K dependent (2, 7, 9, 10)
proteins c and s
protein binding of warfarin
highly protein bound
how long required to achieve therapeutic concentration of warfarin
36-72 hours
warfarin antidote
Vitamin K and FFP
how to reverse warfarin for emergent or high-risk procedures
1-2 units FFP, recombinant factor 7a, or prothrombin complex concentrate
high risk = NSGY procedures
how to reverse warfarin for non-emergent minor surgical procedures
10-20 mg vitamin K
how is plasminogen converted to plasmin
by tPA
what is required for absorption of vitamin K
presence of fat and bile for absorption
risk factors for vitamin K deficiency
- poor dietary intake
- antibiotics
- malabsorption d/t obstructive biliary tract disease
- Hepatocellular disease
- Neonates
what is phyntonadione
exogenously administered vitamin K
required for exogenous vitamin K admin
a functional liver
how long does it take for exogenous vitamin K to restore concentration of vitamin K-dependent clotting factors in blood
4-8 hours
phytonadione dose
10-20 mg IV, IM, PO
risk assoc with IV phytonadione
life threatening anaphylaxis
avoid IV or give max. 1mg/min
