Coagulation (final) Flashcards
Describe Hemostasis
Normal hemostasis is a balance btw clot generation, thrombus formation, andcounter-regulatory mechanisms that inhibit uncontrolled thrombogenesis or premature thrombus degradation
Slide 2
3 Goals of Hemostasis
to limit blood loss from vascular injury
maintain intravascular blood flow
promote revascularization after thrombosis
Slide 2
What are the 2 stages of Hemostasis?
Describe each…
Primary: Immediateplatelet deposition at the endovascular injury site
Leads to the initial platelet plug formation
Only adequate for minor injury
Secondary: clotting factors activated
Stabilized clot formed and secured with crosslinked fibrin
Slide 3
What is the Vascular Endothelial Role?
Vascular endothelial cells have antiplatelet, anticoagulant, and profibrinolytic effects that inhibit clot formation
Slide 5
Describe the anti-clotting mechanisms of endothelial cells
-are negatively charged to repel platelets
-produce platelet inhibitors such as prostacyclin and nitric oxide
-excrete adenosine diphosphatase, which degrades -adenosine diphosphate (ADP), a platelet activator
-increase protein C, an anticoagulant
-produce Tissue Factor Pathway Inhibitor (TFPI), inhibiting factor Xa & TF-VIIa complex
-Synthesize tissue plasminogen activator (t-PA)
Slide 5
____ play a critical role in hemostasis and are derived from ____
Platelets and megakaryocytes
Slide 6
Nonactivated platelets circulate as ____ with a lifespan of ____
discoid anuclear cells and 8-12 days
Slide 6
normally, ~ ____ of platelets are consumed to ____ with ____ new platelets formed daily
10%
support vascular integrity
1.2-1.5 X10^11
Slide 6
2 important things about the platelet membrane
1) contains numerous receptors
2) has a surface canicular system, which increases membrane surface area
Slide 6
Describe the process of platelets undrgoing hemostasis
Damage to endothelium exposes the underlying extracellular matrix (ECM), which contains collagen, von Willebrands factor, and other platelet-adhesive glycoproteins
Upon exposure to ECM, platelets undergo 3 phases of alteration:
-adhesion
-activation
-aggregation
Slide 7
Describe Adhesion of platelets
Adhesion: occurs upon exposure to ECM proteins
Slide 8
Describe activation of platelets
What are 2 types of storage granules in platelets?
Activation: stimulated when platelet interacts w/collagen & tissue factor (TF), causing the release of granular contents
Plts contain 2 types of storage granules: alpha granules and dense bodies
-Alpha granules: contain fibrinogen, factors V & VIII, vWF, Plt-derived growth factor & more
-Dense bodies: contain ADP, ATP, calcium, serotonin, histamine, epinephrine
Slide 8
Describe aggregation of platelets
Aggregation: occurs when the granular contents are released, which recruit and activate additional platelets, propagating plasma-mediated coagulation. Activated glycoprotein IIb/IIIa receptors on plt surface bind fibrinogen, promoting fibrin crosslinking
Slide 8
Each stage of the platelet cascade requires what?
Assembly of membrane-bound activation tenase-cmplexes
Each tenase complex is composed of
1) a substrate (inactive precursor)
2) an enzyme (activated coagulation factor)
3) 3) a cofactor (accelerator or catalyst)
4) 4) calcium
Slide 9
Describe the intrensic pathway
Beginning w/XIIa, it was initially thought to occur only in response to endovascular contact with negatively-charged substances (glass, dextran)
Current understanding is the intrinsic pathway plays a more minor role in theinitiation of hemostasis, and is more an amplification system to propagate thrombin generation initiated by the extrinsic pathway
Slide 13
Describe the extrensic pathway
The Extrinsic pathway is the initiation phase of plasma-mediated hemostasis
Begins endothelial injury, exposing TF to the plasma
TF forms an active complex with VIIa (TF/VIIa complex)
TF/VIIa complex binds to and activates factor X, converting it to Xa
TF/VIIa complex also activates IX→ IXa in the intrinsic pathway
IXaand calcium convert factor X to Xa (intrinsic pathway)
Factor Xa begins the final common pathway
Slide 12
Describe the intrinsic pathway hemostasis initiation
Upon contact with a negatively charged surface, factor XII becomes activated
Factor XIIa converts XI to XIa
(IXa + VIIIa +plt-membrane phospholipid + Ca++) converts factor X to Xa
Xa initiates the final common pathway
Slide 14
Describe intrinsic pathway propogation
Activated Thrombin (IIa) activates factors V, VII, VIII and XI to amplify extrinsic thrombin generation
This process activates the platelets, leading to propagation of the FCP(final common pathway)
Slide 14
Describe the common pathway
Factor X becomes Xa and binds with Va to form “prothrombinase complex”
Prothrombinase complex rapidly converts prothrombin (II) into thrombin (IIa)
Thrombin attaches to the platelets and converts fibrinogen (I) to fibrin (Ia)
Fibrin molecules crosslink to form a mesh that stabilizes the clot
Thrombin cleaves fibrinopeptides A & B from fibrinogen to generate fibrin monomers, which polymerize into fibrin strands to form basic clot
Finally, factor XIIIa crosslinks the fibrin strands to stabilize and make an insoluble clot, resistant to fibrinolytic degradation
slide 15 and 16
Vascular injury exposes ____, initiating ____ pathway. ____ pathway further amplifies thrombin and fibrin generation. Platelets adhere to ____, become activated and ____ additional platelets
TF
extrensic
intrinsic
collagen
recruit
Slide 16
What is the key step to regulating hemostasis?
Thrombin generation
Slide 15
What does the common pathway depict?
Thrombin generation and firbin formation
*both intrinsic and extrinsic tenase-complexes facilitate the formation of the prothrominase complexes
Slide 17
What is the function of prothrombinase complex?
Converts PT (II) into thrombin (IIa)
Slide 17
What are the 4 major Coagulation counter mechanisms?
Fibrinolysis
tissue factor pathway inhibitor (TFPI)
protein C system
Serine Protease inhibitors (SERPINs)
Slide 19
Describe fibrinolysis
endovascular TPA & urokinase convert plasminogen to plasmin
Plasmin breaks down clots enzymatically, and degrades factors V & VIII
Slide 19
Describe TFPI
forms complex w/Xa that inhibits TF/7a complex, along with Xa; Downregulating the extrinsic pathway
Slide 19
Describe the protein C system
inhibits factors 2 (II), 5a (Va) & 8a (VIIIa)
Slide 19
What are the SERPINs?
Antithrombin (AT) inhibits thrombin, factors 9a (IXa), 10a (Xa), 11a (XIa), 12a (XIIa)
Heparin binds to AT, causing a conformational change that accelerates AT activity
Heparin cofactor II inhibits thrombin alone
Slide 19
Preoperative assessment factors for coagulation
1) identify and correct hemostatic disorders
2) bleeding hx is more effective predictor of bleeding
3) inquire: frequent epistaxis, bleeding gums, easy bruising?
4) hx of excess bleeding with procedures or blood transfusion?
5) family hx
6) use of blood thinners (ASA, NSAID, Vit E, Ginko, Ginger, Garlic supp
7) coexisting disease (renal, liver, thyroid, bone marrow)
Slide 20
If a bleeding disorder is suspected in the preop assessment, what are the standard first-line labs?
PT, aPTT
Slide 20
Common bleeding disorders
Von Willebrand’s
Hemophilia
Drug-induced bleeding
Liver disease
Chronic renal disease
Disseminated Intravascular Coagulation
Trauma-induced coagulopathy
Slide 21
What is the most common inherited bleeding disorder? What percent of the population is affected?
Von Willebrand’s- effects 1% of the population
Slide 22
Describe the MOA of a deficiency in vWF
Deficiency in vWF, causing defective plt adhesion/aggregation
vWF plays critical role in plt adhesion & prevents degradation of factor 8 (VIII)
Slide 22
In vWF, are routine labs helpful?
how will labs look?
Which tests are more beneficial?
No
normal: platelets and PT, prolonged: aPTT d/t deficiency in factor 8
better tests: vWF level, vWF plt-binding activity, factor 8 level, plt function assay
Slide 22
What treatment is vWF responsive to?
DDAVP in mild cases (it increases vWF)
Slide 22
for patients with vWF, intraoperative bleeding may require administration of what?
vWF, and factor 8 concentrates
Slide 22
What are the 2 types of Hemophilia?
is this inherited or not?
A: factor 8 (VIII) deficiency; occurs in 1 in 5,000
B: factor 9 (IX) deficiency; occurs in 1 in 30,000
2/3 of cases are inherited, 1/3 present as new mutation w/o family hx
Slide 23
How does hemophlia commonly present?
in childhood as spontaneous hemorrhage involving joints and muscles
Slide 23
Labs in hemophilia
Normal PT, plts, bleeding time
PTT is prolonged
Slide 23
In patients with bleeding disorders, especially hemophilia, who should be consulted?
Hematology
Slide 23
What may be indicated pre-operatively for patients with hemophilia?
DDAVP and factors 8 and/or 9
Slide 23
What is the most significant cause of intraoperative bleeding?
Anticoagulant medications
Heparin
Warfarin
Direct Oral Anticoags (DOAC
Beta lactam ABx
Nitroprusside
NTG
NO
SSRI
Slide 24
What are common supplements that increase the risk of bleeding?
Cayenne, Garlic, Ginger, Ginkgo Biloba, grapseed oil, st johns wart, Turmeric, Vitamin E
Good Grief Girls, St. John’s Grape’s Turned Very Crimson
Slide 24
When should common herbal supplements be stopped prior to surgery?
Slide 24
The ____ is the primary source of which factors?
- Liver
- 1,2,5,7, 9, 10, 11, 12 (I, II, V, VII, IX, X, XI, XII)
along with proteins C & S, and antithrombin
Slide 25
How can liver disease lead to hemostatic issues?
Impaired synthesis of coagulation factors
Quantitative and qualitative platelet dysfunction
Impaired clearance of clotting and fibrinolytic proteins
Slide 25
Lab findings in liver disease
-Prolonged PT and PTT
***lab values only reflect the lack of pro-coagulation factors, NOT accounting for concurrent lack of anti-coagulation factors
TEG and ROTEM are valuable guidelines
Slide 25
Chronic liver patents often display a ________ ________ as well as ________ amount of ________ production
What should we still consider with these patients?
rebalanced hemostasis, sufficient, thrmobin
although rebalanced, they are very susceptible to disruption in coagulation
Slide 25
CKD patients have baseline ______ d/t what 2 things?
Anemia!
-lack of erythropoietin
-platelet dysfunction
Slide 26
what 2 things can shorten bleeding times in CKD?
dialysis and correction of anemia
Slide 26
Tx of platelet dysfunction includes
Cryoprecipitate (rich in vWF)
DDAVP
Conjugated estrogens given pre-operatively x 5 days
Slide 26
What is DIC
Disseminated Intravascular Coagulation
Pathological hemostatic response to TF/7a complex causing excessive activation of the extrinsic pathway, which overwhelms the anticoagulant mechanisms and generates intravascular thrombin
Coagulation factors & platelets become depleted during widespread microvascular thrombotic activity, causing multi-organ dysfunction
Slide 27
DIC may be precipitated by
trauma, amniotic fluid embolus, malignancy, sepsis, or incompatible blood transfusion
slide 27
Lab findings in DIC
↓Plts, prolonged PT/PTT/Thrombin time,↑soluble fibrin & fibrin degradation products
Slide 27
How to manage DIC
correct underlying condition, administration of appropriate blood products
Slide 27
What is trauma induced coagulopathy?
Independent acute coagulopathy seen in trauma pts, which is thought to be related to activated protein C decreasing thrombin generation
-Hypoperfusion: driving factor for protein C activation
-The endethelial glycocalyx, which contains proteoglycans, degrades. Proteoglycan-shedding results in “auto-heparinization”
Platelet dysfunction contributes to the increased bleeding
Slide 28
What is a common cuase of trauma-related death?
Uncontrolled hemorrhage
Slide 28
Why do coagulopathies occur?
acidosis, hypothermia, and/or hemodilution
Slide 28
What are the most common inherited prothrombotic diseases caused by?
A mutation in factor V or PT
Slide 27
___________ mutation leads to _____________ resistance.
What popualtion is this present in?
Factor V Leiden mutation, activated protein C
***present in 5% caucasion population
Slide 29
___________ mutation causes _______ Concentration, leading to _____________
Prothrombin, increased PT, hypercoagulation
Slide 29
What is Thrombophilia?
How does is manifest?
Inherited or acquired predisposition for thrombotic events
Manifests as venous thrombosis
Highly susceptible to Virchow’s triad
Slide 29
What is Virchow’s Triad?
Blood stasis, endothelial injury, hypercoagulability
Slide 29
what is anti-phospholipid syndrome?
Characterized by?
autoimmune disorder w/antibodies against the phospholipid-binding proteins in the coagulation system.
Characterized byrecurrent thrombosis and pregnancy loss
Often require life-longanticoagulants
Slide 30
What are other common prothrombotic states?
Oral contraceptives, pregnancy, immobility, infection, surgery & trauma greatlyincrease the risk of thrombosis in thesepopulations
Slide 30
HIT is a mild to moderate ____ associated with ____
thrombocytopenia
heparin
Slide 31
When does HIT occur?
5-14 days after heparin treatment
Slide 31
HIT results in a ____ count reduction as well as activation of the ____ platelets and potential thrombosis
platelet
remaining
Slide 31
autoimmune-mediated response occurring in up to ____ pts receiving heparin
5%
Slide 31
Ifpt has received a prior heparin dose, thrombocytopenia or thrombosis may occurwithin ____ day of subsequent dose
1
Slide 31
Which patients are at higher risk of HIT?
What type of heparin carries a greater risk of HIT?
women, pts receiving high heparin doses such as w/CPB
unfractionated
Slide 31
If HIT is suspected what needs to happen?
What is contraindicated?
D/C heparin, convert to alternative anticoag
Warfarin: contraindicated b/c it decreasse Protein C and S synthesis
Slide 31
How is HIT diagnosis confirmed?
HIT antibody testing
When are antibodies from HIT typically cleared from the circulation?
3 months
Slide 31
To find PT, ____ is mixed with ____ and the number of seconds is measured until a clot forms
Plasma and TF
Slide 32
What does PT assess? What does it reflect? What is it used to monitor?
Assesses integrity of extrinsic & common pathways.
Reflectsdeficiencies in factors 1, 2, 5, 7, 10 (II, V VII, X)
Used to monitor vit K antagonists s/a Warfarin
—>(factors 2, 7 & 10 are vit K dependent)
Slide 32
aPTT measures seconds until clot forms after mixing ____ with ____, ____, and ____ of the intrinsic pathway
plasma
phospholipid
Ca
activator
Slide 32
aPTT assesses what?
which factors is it more sensitive to?
aPTT is used to measure the effect of ____
Assesses integrity of intrinsic and common pathways
More sensitive to deficiencies in factor 8 & 9 (VIII, IX) than others
May be used to measure effect of Heparin
Slide 32
anti-factor Xa activity assay is also known as what?
____ is combined wth ____ and an ____ substrate that releases a colorimetric signal after factor ____ is cleaved
Factor Xa inhibition test
plasma
Xa
artificial
Xa
Slide 33
Anti-factor Xa activity assay provides functional assessment of ____’s anticoagulant effect
can also be used to assess effect of ____, ____, and factor ____ inhibitors
Heparin’s
LMWH, fondaparinux, factor Xa
Slide 33
Platelet count is a standard component of ____ testing
Normal plt count?
Is POC testing available?
coagulation
greater than 100,000plts/microliter
yes
Slide 33
Activated clotting time: variation of ____ blood clotting time, with the additiona of ____ activator to accelerate clotting time
whole
clotting
Slide 33
ACT addresses which pathway?
What is it used to measure?
what is normal?
IS POC analyzation available?
both intrinsic and extrensic
responsiveness to heparin
107 +/- 13 seconds
Yes
Slide 33
Heparin Concentration Measurement: ____-concentration is the most popular POC method to determine perioperative heparin concentration
Protamine
Slide 34
With heparin concentration measurement:
1mg protamine will inhibit ____ heparin
as increasing amounts of protamine are added to heparinezed blood, time to clot ____ until protamine concentration>heparin concentration
it estimates plasma ____concentration
1mg
decreases
heparin
Slide 34
____ Coagulation Tests: Measures all aspects of clot formation from early fibrin generation to clot retraction & fibrinolysis. Coagulation diagrams generated.
Viscoelastic
Slide 34
Viscoelastic Coagulation Tests:
allows for more precise ____ ____ administration
Examples: ____ and ____
blood product
TEG (thromboelastogram)
ROTEM (rotational thromboelastrometry)
Slide 34
Picture of a TEG
Slide 35
____ Inhibit platelet aggregation and/or adhesion
What are the 3 main classes?
Anti-platelet agents
cyclooxygenase inhibitors
P2Y12 receptor antagonists
platelet GIIb/IIIa R antagonists
Slide 36
Cyclooxygenase Inhibitors: Block ____ from forming ____, which is important in plt aggregation
what are 2 examples and how long do their anti-plt effects last?
cox1
TxA₂
ASA, 7-10 days after d/c
NSAID’s 3 days
Slide 36
P2Y12 receptor antagonists: Inhibit ____→preventing ____ expression
What are 3 ex’s and how long do their anti-plt affects last?
P2Y12-R
GIIb/IIIa
clopidogrel: 7days after d/c
ticlodipine: 14-21 days after d/c
ticagerelor & cangrelor <24h activity
Slide 36
Platelet GIIb/IIIa R antagonists: prevent ____ & ____ from binding to GIIb/IIIa-R
Examples?
vWF
Fibrinogen
Abciximab, Eptifibatide, Tirofiban
Slide 36
Vitamin K antagonists: Inhibit synthesis of Vit-K dependent factors…which are?
2, 7, 9, 10, Protein C & S
Slide 37
What is the most common vitamin K antagonist?
its the DOC for ____ and ____
It has a long half life of ____, can take ____ days to reach therapeutic INR of ____
usually requires ____ until therapeutic effect achieved
Frequent lab monitoring required such as ____ and ____
Reversable with ____
warfarin
afib and valve replacements
40h, 3-4d
2-3
heparin
PT and INR
vitamin K
Slide 37
Heparin: Binds to antithrombin→ ____ inhibits soluble thrombin and Xa
What are 3 examples?
directly
unfractionated heparin
LMWH
Fondaparinux
Slide 38
Unfractionated Heparin
____ HL, given IV
Fully reversable w/____
Close monitoring required
short
protamine
Slide 38
LMWH
____HL, dosed BID SQ
No coag testing needed
Protamine only ____ effective
Longer
partially
Slide 38
Fondaparinux
Much ____ HL ( ____-____hrs), dosed once/day
Protamine ____ effective
Longer (17-21hrs)
not
Slide 38
direct ____ inhibitors: bind/block ____ in both soluble and fibrin-bound states
What are some examples?
thrombin, thrombin (hehe)
hirudin, argatroban, bivalirudin, and dabigatran (pradaxa)
Slide 39
Hirudin is naturally found in ____
Leeches
Slide 39
Argatroban: synthetic, reversibly binds to thrombin. HL 45 min.
Monitored intraop w/____ or ____
PTT or ACT
Slide 39
____ is a synthetic direct thrombin inhibitor with the shortest HL of DTI’s
It is the DOC for ____ impairment
Bivalirudin
renal or liver
Slide 39
Dabigatran is the ____ DOAC
It is approved for ____ prevention and non-valvular ____
1st
CVA and afib
Slide 39
What is DOAC
Direct Oral Anti-coagulants
Slide 40
DOAC’s are a newer class introduced over the last ____ years
have ____ pharmacokinetics/dynamics
____ drug interactions
dosed ____ w/o lab monitoring
efficacy is similar to ____ but much shorter ____
fewer ____ events, ____, and lower mortality than warfarin
10
predictable
fewer
daily
warfarin, half life
embolic events, intracranial hemorrhage
Slide 40
Direct thrombin inhibitor that is a DOAC: ____
Direct Xa inhibitors that is a DOAC: ____, ____, and ____
Dabigatran (Pradaxa)
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
Slide 40
thrombolytics are used to ____ blood clots
can be given ____ or directly into ____
most are ____ ____ that convert plasminogen to plasmin, which breaks down fibrinogen to fibrin
dissolve
IV, site of blockage
serine proteases
Slide 41
What are 2 categories or thrombolytics? examples of each?
Fibrin-Specific: Alteplase (tPA), Reteplase, Tenecteplase
Non-Fibrin-Specific: Streptokinase * not widely used d/t allergic reactions
Slide 41
Surgery is contraindicated within ____ days of thrombolytic treatment
10
Slide 41
Absolute and relative contraindications for thrombolytics
Slide 42
procoagulants are used to ____ blood loss
What are the 2 classes?
mitigates
anti-fibrinolytics
factor replacements
Slide 43
antifibrinolytics have 2 subclasses: ____ and ____
Lysine analogues
SERPIN
Slide 43
Lysin analogues: ____ and ____
MOA?
Epsilon-amino-caproic acid (EACA) & Tranexamic Acid (TXA)
Binds & inhibits plasminogen from binding to fibrin→impairing fibrinolysis
Slide 43
What are the factor replacements (4)? and how does each one work?
Recombinant VIIa (RfVIIa): ↑’s thrombin generation via intrinsic & extrinsic paths
Prothrombin Complex Concentrate (PCC): contain vitamin-K factors
Fibrinogen Concentrate: derived from pooled plasma. Standard concentration.
Cryoprecipitate & FFP: Cheaper & contain more coag factors, but less specific composition
Remember:Factor Replacements R Put Forth Carefully
Slide 43
pre-op guidelines: warfarin
low risk patients should d/c ____ prior to surgery and restart ____ post-op
high risk patients should stop ____ prior and bridge w/ ____ or ____
5d, 12-24hrs post op
5d, UFH or LMWH
Slide 44
Pre-op guidelines: heparin
UFH dc ____ prior to surgery and resumed ( ____ ) greater than or equal to 12 hours post op
LMWH should be dc’d ____hr prior to surgery and resumed ____ postop
4-6hr, no bolus
24hrs prior, 24h postop
Slide 44
Pre-op guidelines: ASA (not as defined)
mod/high risk: ____
low risk: stop ____ prior to surgery
continue
7-10d
Slide 44
pts post-coronary stent placement
bare-metal stents–> delay elective surgery ____ after placement
drug-eluding stents–> delay active surgery ____ after placement
6 weeks
6 months
Slide 44
Neuraxial anesthesia on anti-coags
Slide 45
warfarin reversal may be required for excessive ____ or ____
what is the DOC for emergent coumadin reversal (even though HL is short)?
Concurrent ____ required to restore carboxylation of vit-k dep factors by the liver for more sustained correction
bleeding, emergent surgery
PCC: prothrombin complex concentrates
vit k
Slide 46
What is the reversal for direct thrombin inhibitors?
Half life is ____
no reversal
half life is relatively short
Slide 46
We just said direct thrombin inhibitors do not have a reversal, but there is 1 exception! which drug has a reversal and what is the reversal?
dabigatran (pradaxa)–>antidote: idarucizumab
Slide 46
DOAC factor Xa inhibitors may be reversed by ____ which is a derivative of Xa
Andexanet
Slide 46
Which labs are required to monitor for each drug and possible reversal for each
Pic
Slide 47
What are the names of each Factor?
I: fibrinogen
II: prothrombin
III: tissue thromboplastin (tissue factor, TF)
IV: Ca ions
V: labile factor
VII: stabile factor
VIII: antihemophillic factor
IX: plasma thromboplastin component
X: stewart prower factor
XI: plasma thromboplastin antecedent
XII: hageman factor
XIII: fibrin stabilizing factor
Slide 10
