Coagulation - Assessment Exam 4 Flashcards
Normal hemostasis is a balance between what 3 things?
clot generation
thrombus formation
regulatory mechanisms that inhibit uncontrolled thrombogenesis
What are the 3 goals of hemostasis?
- to limit blood loss from vascular injury
- maintain intravascular blood flow
- promote revascularization after thrombosis
What are the 2 stages of hemostasis?
Primary
Secondary
Explain primary hemostasis
Immediateplatelet deposition at the endovascular injury site
- Leads to the initial platelet plug formation
- Only adequate for minor injury
Explain secondary hemostasis
clotting factors activated
- Stabilized clot formed and secured with crosslinked fibrin
Vascular endothelial cells have ____, _____, and _____ effects to inhibit clot formation
Antiplatelet
Anticoagulant
FIbrolytic
Explain 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), which inhibits factor Xa & TF-VIIa complex
- Synthesize tissue plasminogen activator (t-PA)
Platelets play a critical role in ______ and are derived from what?
Hemostasis
bone-marrow megakaryocytes
Inactive plts circulate as _____ - shaped _____ cells with a lifespan of ______ days
Disc-shaped anuclear cells
8-12 days
Normally, approx ___% of platelets are consumed to support vascular integrity with _____ billion new platelets formed daily
10%
120-150
T/F
The platelet membrane contains numerous receptors and a surface canalicularsystem, which increases membrane surface area
True
Damage to endothelium exposes the underlying _____ _____, which contains ______, ______, and other _____
Extracellular matrix
Contains
- collagen
- vWF
- other glycoproteins
Upon exposure to contents in the ECM, platelets undergo what 3 phases of alteration?
adhesion
activation
aggregation
When does adhesion occur?
occurs upon exposure to ECM proteins
When is activation stimulated?
when platelet interacts w/collagen & tissue factor (TF), causing the release of granular contents
Plts contain what 2 types of storage granules? What are they?
Alpha granules: contain fibrinogen, factors V & VIII, vWF, Plt-derived growth factor & more
Dense bodies: contain ADP, ATP, calcium, serotonin, histamine, epinephrine
When does aggregation occur?
when the granular contents are released, which activate additional platelets, propagating plasma-mediated coagulation
Each stage of the clotting cascade requires assembly of membrane-bound activated tenase-complexes
- each complex is composed of what 4 things?
1) a substrate (inactive precursor)
2) an enzyme (activated coagulation factor)
3) a cofactor (accelerator or catalyst
4) calcium
Clotting cascade picture
Other clotting cascade picture
The Extrinsic pathway is the initiation phase of what?
plasma-mediated hemostasis
Explain extrinsic pathway
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
With intrinsic pathway (beginning with factor ____), it was initially thought to occur only in response to endovascular contact with ___________ (glass, dextran)
XIIa
negatively-charged substances
Current understanding is the intrinsic pathway plays a minor role in _______ and is more an ______ system to propagate ______ generation initiated by the extrinsic pathway
Imitation of hemostasis
Amplification system
Thrombin generation
Explain Intrinsic pathway hemostasis initiation
- Upon contact with a negatively charged surface, factor XII becomes activated
- Factor XIIa converts XI to XIa
- (XIa + VIIIa +plt-membrane phospholipid + Ca++) converts factor X to Xa
- Xa initiates the final common pathway
Explain Intrinsic pathway propagation
- Activated Thrombin (IIa) activates factors V, VII, VIII, XI to amplify thrombin generation
- This process activates the platelets, leading to propagation of the FCP
Explain 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 from fibrinogen to generate fibrin, which polymerizes into strands to form basic clot
- Finally, factor XIIIa crosslinks the fibrin strands to stabilize and make an insoluble clot, resistant to fibrinolytic degradation
What does the common pathway depict?
Both intrinsic and extrinsic tenase-complexes facilitate the formation of _____________
thrombin generation and fibrin formation
prothrombinase complexes
prothrombinase complexes converts ______ into ______
PT (II) into thrombin (IIa)
What are the 4 major coagulation counter-mechanisms?
Fibrinolysis
Tissue factor pathway inhibitor (TFPI)
Protein C systen
Serine Protease Inhibitors (SERPIN)
Explain fibrinolysis
endovascular TPA & urokinase convert plasminogen to plasmin
- Plasmin breaks down clots enzymatically, and degrades factors V & VIII
Explain TFPI
forms complex w/Xa that inhibits TF/7a complex, along with Xa; thereby downregulating the extrinsic pathway
Explain protein C system
inhibits factors 2 (II), 5a (Va) & 8a (VIIIa)
Explain 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
What is the most effective predictor of bleeding during preop?
A carefully performed bleeding hx
What are the bleeding disorders?
Von Willebrand’s
Hemophilia
Drug-induced bleeding
Liver disease
Chronic renal disease
Disseminated Intravascular Coagulation
Trauma-induced coagulopathy
What is the most common inherited bleeding disorder??
It effects __% of the population
vWF
1%
What is vWF disease?
Deficiency in vWF, causing defective plt adhesion/aggregation
- vWF plays critical role in plt adhesion & prevents degradation of factor 8 (VIII)
What will labs look like in vWF?
Platelets & PT will be normal; aPTT might be prolonged d/o level of factor 8
Hemophilia A is factor ____ deficiency and occurs in what ratio?
8
1 in 5,000
Hemophilia B is factor ____ deficiency and occurs in what ratio?
9
1 in 30,000
Hemophilia frequently presents in ______ as spontaneous ____ involving what 2 things?
Childhood
Hemorrhage
Joints/muslces
What do labs look like in hemophilia?
Labs show normal PT, Plts, bleeding time
PTT normally prolonged
What may be indicated in hemophilia prior to surgery?
DDAVP and Factors 8 and/or 9 may be indicated before surgery
What are the most significant cause of intraop bleeding?
Anticoagulant meds
Anticoagulant meds include what? What about herbal supplements?
Heparin
Warfarin
Direct Oral Anticoags (DOACs)
Beta-Lactam Abx
Nitroprusside
NTG
NO
SSRIs
The liver is the primary source of what factors?
What other 3 things come from the liver?
5, 7, 9, 10, 11, 12
proteins C & S, and antithrombin
What are the 3 reasons that liver disease leads to multifactorial hemostatic issues?
Impaired synthesis of coagulation factors
Quantitative and qualitative platelet dysfunction
Impaired clearance of clotting and fibrinolytic proteins
What do coagulation labs look like in liver disease?
Lab findings often show prolonged PT and possible prolonged PTT
CKD pts display baseline anemia due to what 2 things?
Lack of erythropoietin
Platelet dysfunction (due to uremic environment)
_____ and _____ are both shown to shorten bleeding times
Dialysis
Correction of anemia
Treatment of plt dysfunction in CKD pts includes?
Cryoprecipitate (rich in vWF)
DDAVP
Conjugated estrogens given pre-operatively x 5 days
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
DIC may be precipitated by?
trauma, amniotic fluid embolus, malignancy, sepsis, or incompatible blood transfusion
Lab findings in DIC
↓Plts, prolonged PT/PTT/Thrombin time,↑soluble fibrin & fibrin degradation products
_____ is a common cause of trauma-related death
Uncontrolled hemorrhage
Coagulopathies occurs due to:
acidosis, hypothermia and/or hemodilution
What is TIC?
Trauma Induced Coagulopathy
- acute coagulopathy seen in trauma pts, which is thought to be related to activated protein C decreasing thrombin generation
- The endothelial glycocalyx, which contains proteoglycans, degrades
- Proteoglycan-shedding results in “auto-heparinization”
- Platelet dysfunction contributes to the increased bleeding
What is thought to be the driving factor for protein C activation in TIC?
Hypoperfusion
The most common inherited prothrombotic diseases are caused by a mutation in what 2 things?
Factor V
PT
Factor V Leiden mutation leads to what?
activated protein C resistance
Prothrombin mutation causes what?
↑PT concentration, leading to hypercoagulation
What is thrombophilia?
inherited or acquired predisposition for thrombotic events
- generally manifests as venous thrombosis
- highly susceptible in virchow’s
What is antiphospholipid syndrome?
autoimmune disorder w/antibodies against the phospholipid-binding proteins in the coagulation system
- Characterized byrecurrent thrombosis and pregnancy loss
- Often require life-longanticoagulants
In pts in prothrombic states, what things greatly increase the risk of thrombosis?
Oral contraceptives, pregnancy, immobility, infection, surgery & trauma
HIT occurs _____ after heparin treatment
5-14 days
Explain HIT
Mild-moderate thrombocytopenia associated w/Heparin
- Results in platelet count reduction as well as activation of the remaining platelets and potential thrombosis
Risk factors for HIT
women, pts receiving high heparin doses such as w/CPB
- Unfractionated heparin carries greater rx than LMWH
What do you do if HIT is suspected?
D/C heparin, convert to an alternative anticoagulant
- Warfarin is contraindicated bc it decreases protein C & S synthesis
HIT diagnosis is confirmed with?
Antibodies are typically cleared from circulation in ____
HIT antibody testing
3 months
Coagulation labs include
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
Anti-factor Xa activity assay
Platelet Count
Activated Clotting Time (ACT)
Heparin Concentration Measurement
Viscoelastic Coagulation Tests
- TEG (Thromboelastogram)
- ROTEM (Rotational Thromboelastometry)
Explain a prothrombin time
Plasma is mixed w/TF and the number of seconds is measured until a clot forms
- Assesses integrity of extrinsic & common pathways
A PT (lab) reflects deficiencies in what factors?
What is this used to monitor?
1, 2, 5, 7, 10
Used to monitor vit K antagonists s/a Warfarin
- (factors 2, 7 & 10 are vit K dependent)
Explain aPTT
Measures seconds until clot forms after mixing plasma w/phospholipid, Ca², and an activator of the intrinsic pathway
- Assesses integrity of intrinsic and common pathways
What factors are looked at with aPTT?
What is this used to monitor?
More sensitive to deficiencies in factor 8 & 9
May be used to measure effect of Heparin
Explain Anti-factor Xa activity assay
Plasma combined w/Xa and an artificial substrate that releases a colorimetric signal after factor Xa is cleaved
What do you use a Anti-factor Xa activity assay for?
Provides functional assessment of heparin’s anticoagulant effect
- Can also be used to assess effect of LMWH, Fondaparinux, factor Xa inhibitors
Explain plt count lab with normal values
Standard component of coagulation testing
- Normal = Plt count >100,000 plts/microliter
Explain ACT
Variation of whole blood clotting time, with the addition of a clotting activator to accelerate clotting time
- Addresses intrinsic and common pathways
What is ACT used for?
What is normal?
Used to measure responsiveness to heparin
Normal = 107 +/- 13 seconds
What is a Heparin Concentration Measurement?
___ mg of protamine will inhibit ___ mg of heparin
determines perioperative heparin concentration
- As increasing amts of protamine are added to heparinized blood, time to clot decreases until protamine concentration > heparin concentration
1 mg protamine : 1 mg heparin
Explain viscoelastic coagulation test
Measures all aspects of clot formation from early fibrin generation to clot retraction & fibrinolysis. Coagulation diagrams generated
- Allows for more precise blood product administration
TEG picture
Antiplatelet agents inhibit what?
platelet aggregation and/or adhesion
What are the 3 main classes of anti platelets?
Cyclooxygenase inhibitors
P2Y12 receptor antagonists
Platelet GIIb/IIIa R antagonists
What do COX inhibitors do?
Examples of this with length of anti platelet effects?
Block Cox 1 from forming TxA₂, which is important in plt aggregation
ASA: anti-plt effects x 7-10 days after d/c
NSAIDS: anti-plt effect x 3 days
What do P2Y12 receptors agonist do?
Examples of this with length of anti platelet effects?
Inhibit P2Y12-R→preventing GIIb/IIIa expression
Clopidogrel: anti-plt effects x 7 days after d/c
Ticlopidine: anti-plt effects x 14-21 days after d/c
Ticagrelor & Cangrelor: Short-acting, <24h activity
What do Platelet GIIb/IIIa R antagonists do?
Examples?
prevent vWF & fibrinogen from binding to GIIb/IIIa-R
Abciximab, Eptifibatide, Tirofiban
Anticoagulants include:
Vitamin K antagonists
Heparin
Direct thrombin inhibitors
Direct oral antiocagulants
Direct Xa inhibitors
What do vitamin K antagonist do?
Example of this?
Who is this the DOC for?
Inhibit synthesis of Vit-K dependent factors 2, 7, 9, 10, Protein C & S
Warfarin
Valvular a-fib and valve replacement
Warfarin has a ____ half life (___hrs) and can take ______ days to reach therapeutic INR
Usually requires what med until therapeutic effect achieved?
40 hr
3-4 days
Heparin
What does heparin do?
Binds to antithrombin→ directly inhibits soluble thrombin and Xa
Describe differences in unfractionated heparin and LMWH
Unfractionated Heparin
- Short HL, given IV
- Fully reversable w/Protamine
- Close monitoring required
LMWH
- Longer HL, dosed BID SQ
- No coag testing needed
- Protamine only partially effective
What is the half life of Fondaparinux?
Is protamine effective?
17-21 hr
No
What do direct thrombin inhibitors do?
Examples?
bind/block thrombin in both soluble & fibrin-bound states
- Hirudin
- Argatroban
- Bivalirudin
- Dabigatran (Pradaxa)
Where is hirudin naturally found?
Leeches
Agratroban info
synthetic, reversibly binds to thrombin. HL 45 min.
- Monitored intraop w/PTT or ACT
Bivalirudin info
DOC for which pt?
synthetic, shortest HL of DTI’s
DOC for renal or liver impairment
What was the first DOAC?
It was approved for what?
Dabigatran (Pradaxa)
- direct thrombin inhibitor approved for CVA prevention and non-valvular A-fib
What are DOACs?
Direct Oral Anticoagulants
- Have more predictable pharmacokinetics/dynamics
- Fewer drug interactions
- Dosed daily w/o lab monitoring
DOAC have an efficacy similar to ____, but a much shorter half life
It has fewer _____, _____, and lower _____ than this drug.
Warfarin
Fewer embolic events, intracranial hemorrhages, and lower mortality than warfarin
What are direct Xa inhibitors?
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
What are thrombolytics used for?
Used to dissolve blood clots
- Most are serine proteases that convert plasminogen to plasmin, which breaks down fibrinogen to fibrin
What are the 2 categories of thrombolytics?
Fibrin-Specific: Altepase (tPA), Reteplase, Tenecteplase
Non-Fibrin-Specific: Streptokinase * not widely used d/t allergic reactions
Surgery is contraindicated within ______ days of thrombolytic treatment
10 days
Absolute and relative contraindications for thrombolytics picture
What are procoagulants used for?
What are the 2 classes?
Used to mitigate blood loss
Antifibrinolytics & Factor Replacements
What are the 2 subclasses of antifibrinolytics?
Lysine analogues: Epsilon-amino-caproic acid (EACA) & Tranexamic Acid (TXA)
Binds & inhibits plasminogen from binding to fibrin→impairing fibrinolysis
SERPIN: Aprotinin (removed from market d/t renal & cardio toxicity)
What are the 4 types of factors replacements (procoagulant)?
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
Preop guidelines for warfarin
low rx pts should d/c 5 days prior to surgery & restart 12-24h postop
high rx pts should stop 5 days prior & bridge w/UFH or LMWH
Preop guidelines for heparin
UFH should be d/c’d 4-6h prior to surgery & resumed (no bolus) ≥12h postop
LWMH should be d/c’d 24h prior to surgery & resumed 24h postop
Preop guidelines for aspirin
mod/high rx pts- current recommendation is to continue ASA
low rx pts- stop 7-10 days prior to surgery
Pts post coronary stent placement anticoagulant pre op guidelines
Bare-metal stents→ delay elective surgery 6 weeks after placement
Drug-eluding stents→ delay elective surgery 6 months after placement
Neuraxial anesthesia on anticoags chart
Why would emergent reversal of warfarin be required?
What does this include?
excessive bleeding or emergent surgery
Prothrombin Complex Concentrates: DOC for emergent coumadin reversal
- Vit K to restore liver carboxylation of vit K-dep factors for more sustained correction
Is there a reversal for direct thrombin inhibitors?
What is the exception?
Noreversal for most, however, HL relatively short
The DOAC Dabigatran (Pradaxa) does have an antidote –Idarucizumab
What can you use to reverse DOAC factor Xa inhibitors?
Andexanet, a derivative of factor Xa
Common anticoags with lab monitoring chart
