Exam 4 - Coags Flashcards
Normal hemostasis is a balance between ?
Clot generation, thrombus formation, and regulatory mechanisms that inhibit uncontrolled thrombogenesis
3 goals of hemostasis are
limit blood loss
maintain blood flow
promote revascularization after thrombosis
2 stages of hemostasis
Primary: immediate platelet deposition at endovascular injury site with initial platelet plug formation (only adequate for minor injury)
Secondary: clotting factors activated
Vascular endothelial cells have
antiplatelet, anticoagulant, and fibrolytic effects to inhibit clot formation
Anti-clotting mechanisms of the endothelial cells:
-negatively charged to repel platelets
-platelet inhibitors such as prostacyclin and nitric oxide
-ADP degradation, protein C, TFPI, t-PA
Platelets are derived from
bone-marrow megakaryocytes
Inactive platelets circulate as
disc-shaped anuclear cells with a lifespan of 8-12 days
Normally, approx ___% of platelets are consumed to support vascular integrity with ____ billion new platelets formed daily
10%; 120-150
Damage to endothelium exposes the _________, which contains collagen, von Willebrands factor, and other glycoproteins
underlying extracellular matrix (ECM)
Upon exposure to contents in the ECM, platelets undergo 3 phases of alteration
-adhesion: occurs upon exposure
-activation: stimulated when platelet interacts w collagen and TF, releases granular contents
-aggregation: the granular contents being released activates additional platelets.
Each stage of the clotting cascade requires assembly of
membrane-bound activated tenase-complexes
Each tenase-complex is composed of 4 things
1) a substrate (inactive precursor)
2) an enzyme (activated coagulation factor)
3) a cofactor (accelerator or catalyst)
4) calcium
The Extrinsic pathway is the initiation phase of ___________.
plasma-mediated hemostasis
Steps of the extrinsic pathway (long card…)
Endothelial injury –> Exposing TF to plasma –> TF forms an active complex with VIIa –> TF/VIIa complex binds to and activates factor X, converting it to Xa –> TF/VIIa complex also activates IX into IXa in the intrinsic pathway (IXa and calcium convert factor X to Xa in intrinsic pathway) ==> Factor Xa begins the final common pathway
For the intrinsic pathway, it was initially thought to occur only in response to ?
Endovascular contact with negatively charged substances such as glass and dextran
The current understanding of the intrinsic pathway is that it plays a minor role in the
initiation of hemostasis, and is more of an amplification system to propagate thrombin generation initiate by extrinsic pathway
Intrinsic pathway hemostasis initiation steps (another long one..)
Upon contact with neg 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
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.
Steps of 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 _________ from fibrinogen to generate ____, which polymerizes into strands to form ________.
fibrinopeptides; fibrin; basic clot
Finally, factor _____ crosslinks the fibrin strands to stabilize and make an insoluble clot, resistant to ________.
XIIIa; fibrinolytic degradation
___________ is the key-step in regulating hemostasis.
Thrombin generation
Both ___________ facilitate the formation of prothrombinase complexes
intrinsic and extrinsic tenase-complexes
Prothrombinase Complex converts PT (II) into ______.
thrombin (IIa)
the 4 major coag counter-mechanisms are
Fibrinolysis, TFPI, protein C, SERPINs
Fibrinolysis: endovascular TPA & urokinase convert ___________.
Plasmin breaks down clots enzymatically, and degrades factors _______.
plasminogen to plasmin
V & VIII
Tissue factor pathway inhibitor (TFPI): forms complex w/Xa that inhibits _______, along with Xa; thereby downregulating the extrinsic pathway
TF/7a complex; extrinsic pathway
Protein C system: inhibits factors ________________________. (3 of them)
2 (II), 5a (Va) & 8a (VIIIa)
3 SERPINs (Serine protease inhibitors)
Antithrombin, Heparin, Heparin cofactor II
Antithrombin (AT) inhibits thrombin, and what 4 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 ______ alone
thrombin
A carefully performed _______ is the most effective predictor of bleeding
bleeding hx
Inquire about frequent ______________. (3 things)
nose bleeds, bleeding gums, easy bruising
Ask about use of blood thinners: 6 examples
ASA, NSAIDS, Vitamin E, Ginko, Ginger, Garlic supps
These co-existing issues can affect bleeding, inquire about these in pre-op (4 examples)
Diseases related to renal, liver, thyroid & bone marrow disorders
If bleeding disorder suspected: ____ are standard first-line labs
PT, aPTT
Most common inherited bleeding disorder
Von Willebrand’s disease which affects 1% of the population
VWD is a deficiency in ___, causing defective plt adhesion/aggregation
vWF
Platelets & PT will be_____; aPTT might be prolonged d/t inreased level of ______.
normal; factor 8
Better tests for VWD
vWF level, vWF-plt binding activity, Factor 8 level, Plt function assay
Mild vWD often responsive to
DDAVP (↑s vWF)
Hemophilia A: factor _____ deficiency; occurs 1 in 5,000
8 (VIII)
Hemophilia B: factor ___ deficiency; occurs 1 in 30,000
9 (IX)
What is normally prolonged in hemophilia?
PTT
Everything else normal
_________ are the most significant cause of intraoperative bleeding
Anticoag meds
Liver is primary source of factors __________________________ along with proteins C & S, and antithrombin
5, 7, 9, 10, 11, 12
(V, VII, IX, X, XI, XII)
In liver disease, lab findings often show prolonged ________
PT and possible PTT
What are valuable guides for bleeding in Liver disease?
TEG and ROTEM
CKD pts display a baseline anemia due to
Lack of erythropoietin
Platelet dysfunction (due to uremic environment)
__________ are both shown to shorten bleeding times
Dialysis and correction of anemia
Tx of platelet dysfunction includes:
Cryoprecipitate (rich in vWF)
DDAVP
Conjugated estrogens given pre-operatively x 5 days
DIC is a pathological hemostatic response to ____ causing excessive activation of the _______ pathway, which overwhelms the anticoagulant mechanisms and generates intravascular _______.
TF/7a complex; extrinsic; thrombin
DIC may be precipitated by
trauma, amniotic fluid embolus, malignancy, sepsis, or incompatible blood transfusion
Lab findings of DIC: (does what to platelets, PT/PTT/Thrombin time, soluble fibrin, and fibrin degradation products?)
↓Plts, prolonged PT/PTT/Thrombin time,↑soluble fibrin & fibrin degradation products
Coagulopathies in trauma occur due to: (3 things)
acidosis, hypothermia and/or hemodilution
Trauma Induced Coagulopathy (TIC): acute coagulopathy seen in trauma pts, which is thought to be related to _______ decreasing thrombin generation
activated protein C
__________ 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 _________
factor V or PT
Factor V Leiden mutation leads to ___________ and is present in 5% caucasian population
activated protein C resistance
What is this disease: inherited or acquired predisposition for thrombotic events.
Generally, manifests as venous thrombosis.
Highly susceptible to Virchow’s Triad (blood stasis, endothelial injury, hypercoagulability)
Thrombophilia
what is this disease: autoimmune disorder w/antibodies against the phospholipid-binding proteins in the coagulation system.
Characterized byrecurrent thrombosis and pregnancy loss
Often require life-longanticoagulants
Antiphospholipid Syndrome
Oral contraceptives, pregnancy, immobility, infection, surgery & trauma greatlyincrease the risk of thrombosis in ________
antiphospholipid syndrome
HIT occurs when?
occurs 5-14 days after heparintx
HIT results in _____ as well as activation of the remaining platelets and potential thrombosis
platelet count reduction
HIT: autoimmune response occurring in up to ___% pts receiving heparin
5%
Ifpt has received a prior heparin dose, thrombocytopenia or thrombosis may occurwithin ___ of subsequent dose
1 day
Risk factors for HIT: _____, pts receiving high heparin doses such as w/CPB
Unfractionated heparin carries_______ rx than LMWH
women; greater
Warfarin is contraindicated in HIT bc it decreases
protein C & S synthesis
HIT Antibodies are typically cleared from circulation in _____
3 months
Whats this lab: Plasma is mixed w/TF and the number of seconds is measured until a clot forms
Prothrombin Time (PT)
Whats this lab: Measures seconds until clot forms after mixing plasma w/phospholipid, Ca², and an activator of the intrinsic pathway
Activated Partial Thromboplastin Time (aPTT)
May be used to measure effect of Heparin
Whats this lab: Plasma combined w/Xa and an artificial substrate that releases a colorimetric signal after factor Xa is cleaved
Anti-factor Xa activity assay
Provides functional assessment of heparin’s anticoagulant effect
Can also be used to assess effect of LMWH, Fondaparinux, factor Xa inhibitors
Whats this lab: Standard component of coagulation testing
Platelet Count
Whats this lab: Variation of whole blood clotting time, with the addition of a clotting activator to accelerate clotting time
Activated Clotting Time (ACT)
What is a normal ACT?
Normal = 107 +/- 13 seconds
Whats this lab: determines perioperative heparin concentration
Heparin Concentration Measurement
1mg protamine will inhibit ___mg of heparin
1mg
Whats this lab: Measures all aspects of clot formation from early fibrin generation to clot retraction & fibrinolysis. Coagulation diagrams generated
Viscoelastic Coagulation Tests (TEG, ROTEM)
Allows for more precise blood product administration
What drug class: 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
Cyclooxygenase Inhibitors
What drug class is clopidogrel, ticlopidine, and ticagrelor, and cangrelor?
P2Y12 receptor antagonists
What drug class: prevent vWF & fibrinogen from binding to GIIb/IIIa-R
Abciximab, Eptifibatide, Tirofiban
Platelet GIIb/IIIa R antagonists
Vitamin K antagonists:
Inhibit synthesis of Vit-K dependent factors ___________
2, 7, 9, 10, Protein C & S
Warfarin is the DOC for ____ & ______. It has a half life of ____ and can take ______ days to reach therapeutic INR of ______.
Valvular Afib and valve replacements
40 hours
3-4 days
2-3
what drug: Binds to antithrombin→ directly inhibits soluble thrombin and Xa
Heparin
What drug class: bind/block thrombin in both soluble & fibrin-bound states
Direct Thrombin Inhibitors
Hirudin: naturally found in _______
leeches
Direct Oral Anticoagulants (DOACs): Newer class, introduced over the past 10 yrs
What drugs are these?
Dabigatran, rivaroxaban, apixaban, edoxaban
Direct thrombin inhibitors and direct Xa inhibitors
2 categories of thrombolytics
Fibrin-specific: What drugs?
Non-fibrin-specific: What drugs?
Fibrin-specific: tPA, Reteplase, Tenecteplase (all the plase’s!!!)
Non-fibrin-specific: Streptokinase (not widely used d/t allergic reactions
Surgery is contraindicated if thrombolytics have been used within _____
10 days
Absolute contraindications to thrombolytics include
Stroke <3 months prior
Brain tumor
severe uncontrolled HTN (SBP >185 or DBP >110)
Vascular lesions
2 classes of procoagulants are
antifibrinolytics & factor replacements
Antifibrinolytics has 2 subclasses which are
lysine analogues and SERPIN
These are all considered to be what type of therapy?
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
Factor replacements
Preop guidelines for warfarin
low rx pts should d/c __ days prior to surgery & restart ____ postop
high rx pts should stop __ days prior & bridge w/________
5; 12-24 hours
5; UFH or LMWH
Preop guidelines for heparin
UFH should be d/c’d ___ prior to surgery & resumed (no bolus) ___ postop
LWMH should be d/c’d ___ prior to surgery & resumed ___ postop
4-6h; >12h
24h; 24h
Preop guidlines for aspirin
not as defined
mod/high rx pts- current recommendation is to _______
low rx pts- stop ______ prior to surgery
continue ASA
7-10 days
Pts post coronary stent placement:
Bare-metal stents→ delay elective surgery __ weeks after placement
Drug-eluding stents→ delay elective surgery __ months after placement
6; 6
What drug is this: DOC for emergent coumadin reversal
though HL is short
Prothrombin complex concentrates
What drug is this: Noreversal for most, however, HL relatively short
Direct Thrombin Inhibitors
What drug is this: may be reversed by Andexanet, a derivative of factor Xa
DOAC Factor Xa inhibitors
fucking long ass chart with common anticoags
