Coagulation Flashcards
Exam 4
Normal hemostasis is a balance btw ______, ________, and _______ that inhibit uncontrolled thrombogenesis
clot generation, thrombus formation, andregulatory mechanisms
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:Immediateplatelet deposition at the endovascular injury site (initial platelet plug formation, minor injuries)
Secondary: clotting factors activated, stabilized clot formed, and secured with crosslinked fibrin
Vascular endothelial cells have ________, ________, and ________ effects to inhibit clot formation
antiplatelet, anticoagulant, fibrolytic
Anti-clotting mechanisms of the endothelial cells are _______ charged to repel ________
negatively, platelets
Anti-clotting mechanisms of the endothelial cells produce platelet inhibitors such as ________ and ________
prostacyclin and nitric oxide
Anti-clotting mechanisms of the endothelial cells excrete __________, which degrades adenosine diphosphate (ADP), a _______ activator
adenosine diphosphatase
platelet
Anti-clotting mechanisms of the endothelial cells increase ________, an anticoagulant, and synthesize ______
protein C, tissue plasminogen activator (t-PA)
Anti-clotting mechanisms of the endothelial cells produce Tissue Factor Pathway Inhibitor (TFPI), which inhibits factor___ & ______
Xa and TF-VIIa complex
Platelets are derived from
bone-marrow megakaryocytes
Inactive platelets circulate as disc-shaped _______ cells with a lifespan of _______
anuclear, 8-12 days
Approx __% of platelets are consumed to support vascular integrity with ________ new platelets formed daily
10%, 120-150 billion
The platelet membrane contains numerous receptors and a surface ________system, which increases membrane __________
canalicular, surface area
Damage to endothelium exposes the underlying extracellular matrix (ECM), which contains what 3 things?
collagen, von Willebrands factor, and other glycoproteins
Upon exposure to contents in the ECM, platelets undergo 3 phases of alteration:
- 1st: adhesion
- 2nd: activation
- 3rd: aggregation
______: occurs upon exposure to ECM proteins
Adhesion
_________:stimulated when platelet interacts w/collagen & tissue factor (TF), causing the release of granular contents
Activation
Which 2 types of storage granules do platelets contain?
alpha granules and dense bodies
________: occurs when the granular contents are released, which activate additional platelets, propagating plasma-mediated coagulation
Aggregation
Alpha granules contain
fibrinogen, factors V & VIII, vWF, Plt-derived growth factor
Dense bodies contain
ADP, ATP, calcium, serotonin, histamine, epinephrine
Each stage of the clotting cascade requires the assembly of membrane-bound activated tenase-complexes composed of
1) a substrate (inactive precursor)
2) an enzyme (activated coagulation factor)
3) a cofactor (accelerator or catalyst)
4) calcium
Factor 1 aka ______
fibrinogen
Factor 2 aka ______
prothrombin
Factor 3 aka ______
tissue thromboplastin
Factor 4 aka ______
calcium ions
Factor 5 aka ______
labile factor
Factor 7 aka ______
stable factor
Factor 8 aka ______
antihemophilic factor
Factor 9 aka ______
Christmas factor or plasma thromboplastin component (PTC)
Factor 10 aka ______
stuart-prower factor
Factor 11 aka ______
plasma thromboplastin antecedent (TPA)
Factor 12 aka ______
hageman factor
Factor 13 aka ______
fibrin stabilizing factor
The extrinsic pathway is the initiation phase of __________ hemostasis
plasma-mediated
What initiates the extrinsic pathway?
endothelial injury which exposes TF to plasma
Describe the order of the extrinsic pathway
TF exposed -> TF/VIIa complex -> activates X to Xa
TF/VIIa complex -> activates IX to IXa
The intrinsic pathway is an ___________ system to propagate ________ generation initiated by the extrinsic pathway
amplification, thrombin
Describe the steps and order of the intrinsic pathway
12 -> 11 -> 9+8 -> 10
- upon contact with (-) charged surface, factor 12 becomes activated
- factor 12a converts 11 to 11a
- factor 9a + 8a + plt membrane phospholipid + calcium converts 10 to 10a
Activated thrombin activates which factors?
5, 7, 8, 11
amplifies additional clotting
Describe the steps and order of the common pathway
- Factor 10 becomes 10a and binds with 5a to form “prothrombinase complex”
- prothrombinase complex rapidly convert prothrombin (2) to thrombin (2a)
- thrombin attaches to the platelets and converts fibrinogen (1) to fibrin (1a)
- fibrin molecules crosslink to form a mesh that stabilizes the clot
Thrombin cleaves ______ from _____ to generate _____, which polymerizes into strands to form basic clots
fibrinopeptides, fibrinogen, fibrin
What is the key-step in regulating hemostasis
thrombin generation
What converts prothrombin (2) to thrombin (2a)
prothrombin complexes (Xa +Va + calcium)
Both the intrinsic and extrinsic factors are initiated by a ________
catalyst (activator or tissue injury)
What are the 4 major coagulation counter-mechanisms
- fibrinolysis
- Tissue factor pathway inhibitor (TFPI)
- Protein C system
- Serine protease inhibitors (SERPINs)
How does fibrinolysis stop coagulation
inhibits conversion of plasminogen to plasmin
(plasmin breaks down clots enzymatically, and degrades factors 5 and 8)
How does tissue factor pathway inhibitor stop coagulation
forms complex between 10a and TF/7a that downregulates the extrinsic pathway
How does the protein C system inhibit coagulation
inhibits factors 2, 5a, 8a
What are the 3 examples of SERPINs and how do they work
- antithrombin (AT): inhibits factors thrombin (2a), 9a, 10a, 11a, 12a
- Heparin: binds to AT, causing conformational change that accelerates AT
- Heparin cofactor II: inhibits thrombin (2a) alone
What is the most common inherited bleeding disorder?
vWF disease, 1% of population
A deficiency of vWF causes what?
defective platelet adhesion/aggregation
vWF plays critical role in plt adhesion and prevents degredation of factor 8
What coagulation lab values would be expected for patient with vWF deficiency?
Routine coag labs generally not helpful
- Platelets normal
- PT normal
- aPTT might be prolonged (d/t level of factor 8)
Better tests would be vWF level, vWF-plt binding activity, factor 8 level, platelet function assasy
Mild vWF disease is often responsive to ______
DDAVP (↑ vWF)
Hemophilia A is caused by ______ deficiency; occurs 1 in ______ people
factor 8 deficiency; 1 in 5000
Hemophilia B is caused by _____ deficiency; occurs 1 in _____ people
factory 9 deficiency; 1 in 30,000
What coagulation lab values would be expected for patient with hemophilia
- normal PT, Plts, bleeding time
- prolonged PTT
What can be given prior to surgery for patient with hemophilia
DDAVP, factor 8 and/or factor 9
Which drugs commonly result in anticoagulation
- Heparin
- Warfarin
- Direct Oral Anticoagulants (DOAC)
- beta-lactam Abx
- Nitroprusside
- NTG
- NO
- SSRIs
Which supplements have anticoagulant effects
- Garlic
- Ginger
- Gingko
- Grapeseed oil
- Cayenne
- St. john’s wort
- Tumeric
- Vitamin E, large doses
Which coagulation factors are primary produced in the liver
5, 7, 9, 10, 11, 12, protein C & S, antithrombin
CKD patients display a baseline anemia d/t
- lack of EPO production
- Platelet dysfunction (due to uremic environment)
Treatment of platelet dysfunction includes
- Cryo (rich in vWF)
- DDAVP
- Conjugated estrogen given preop x5 days
DIC is a pathological hemostatic response to _______ causing excessive activation of the ______ pathway, which overwhelms anticoagulant mechanisms and generates ______ ________
TF/7a complex, extrinsic pathway, intravascular thrombin
DIC may be precipitated by what
- trauma
- amniotic fluid embolus
- malignancy
- sepsis
- incompatible blood transfusion
What lab findings would be expected in patient in DIC
- ↓ plts
- prolong PT/PTT/Thrombin time
- ↑ soluble fibrin & fibrin degredation products
Trauma induced coagulopathy (TIC) occurs due to what 3 things
- acidosis
- hypothermia
- hemodilution
thought to be related to activated protein C decreasing thrombin generation
The most common inherited prothrombotic diseases are caused by
mutation of factor 5 or prothrombin
Factor V Leiden mutation leads to _____ resistance
activated protein C
Prothrombin mutation causes a ______ in prothrombin concentration, leading to ________
increase, hypercoagulation
Thrombophilia generally manifests as ____
venous thrombosis
Thrombophilia is highly susceptible to _____
Virchow’s Triad
- blood stasis
- endothelial injury
- hypercoagulability
Antiphospholipid syndrome is an autoimmune disorder with antibodies against _______, and is characterized by recurrent _______ and ______
phospholipid-binding proteins, thrombosis and pregnancy loss
requires life-long anticoagulants
HIT occurs within ______ days after heparin tx
5-14 days
Risk factors for HIT include
- women
- pts receiving high heparin doses (cardiopulm bypass)
- heparin > LMWH
HIT diagnosis is confirmed with
HIT antibody testing
Antibodies for HIT are typically cleared from circulation in how long
3 months
Which pathways does prothrombin time (PT) measure? Which factors does it reflect?
extrinsic & common
factors 1,2,5,7,10
What is PT used to monitor?
Vit K antagonists s/a warfarin
aPTT measures seconds until clot forms after mixing plasma with _____ and ____ and an activator of the ____ pathway
phospholipid, calcium, intrinsic
Which pathways does aPTT assess? Which factors does it reflect?
intrinsic and common
factors 8 and 9
Which lab is used to measure effect of heparin?
aPTT and ACT, Anti-factor 10a activity assay
normal platelet count is
> 100,000 plts/microliter
ACT is used to asses which pathways? What is normal value?
intrinsic & common pathways
normal = 107 +/- 13 seconds (94-120)
1mg of protamine reverses ______ heparin
1mg
What does R time on TEG measure? What is normal value? Indicates a problem with what? Treament?
- Time to start of forming clot
- normal = 5-10min
- indicates problem with coagulation factors
- Tx= FFP
What does K time on TEG measure? What is normal value? Indicates a problem with what? Treament?
- Time until clot reaches a fixed strength
- normal = 1-3 min
- indicates problem with fibrinogen
- Tx= cryo
What does alpha angle on TEG measure? What is normal value? Indicates a problem with what? Treament?
- Speed of fibrin accumulation
- normal= 53-72 degrees
- indicates issue with Fibrinogen
- Tx= cryo
What does MA on TEG measure? What is normal value? Indicates a problem with what? Treament?
- highest vertical amplitude of TEG
- normal = 50-70mm
- indicates issue with platelets
- Tx= plts and/or DDAVP
What does LY30 on TEG measure? What is normal value? Indicates a problem with what? Treament?
- percentage of amplitude reduction 30min after max amplitude
- normal = 0-8%
- indicates excess fibrinolysis
- Tx= TXA or aminocaproic acid
ASA antiplatelet effects persist for how long after d/c
7-10 days
NSAIDs antiplatelet effect persists for how long after d/c
3 days
clopidogrel (plavix) antiplatelet effects persists how long after d/c
7 days
Ticlopidine antiplatelet effects persists how long after d/c
14-21 days
Ticagrelor & Cangrelor antiplatelet effects persists how long after d/c
<24hr
Which drugs are GIIb/IIIa antagonists? how do they work?
abciximab, eptifibatide, tirofiban
prevent vWF and fibrinogen from binding to GIIb/IIIa receptors
What are vitamin K dependent factors
2, 7, 9, 10, Protein C & S
Warfarin is the DOC for ____ and _____
afib & valve replacements
What is the 1/2life of warfarin
40hrs
Warfarin is frequently monitored with which lab? what is therapeutic?
PT/INR, therapeutic INR= 2-3
How does heparin act as anticoagulant
binds to antithrombin -> directly inhibits soluble thrombin and factor 10a
Protamine is ineffective at reversing which drug(s)
Fondaparinux, partially effective on LMWH
Examples of direct thrombin inhibitors are
- Hirudin: found in leeches
- Argatroban: reversibly binds to thrombin
- Bivalirudin: shortest HL of DTIs (DOC for liver and renal impairment)
- Dabigatran (Pradaxa): 1st DOAC - approved for CVA prevention and non-valvular afib
Which drugs are DOACs
- Dabigatran (pradaxa)
- rivaroxaban (xarelto)
- apixaban (eliquis)
- edoxaban (savaysa)
Most thrombolytics are ________ that convert ______ to ______ which breaks down ______ to ______
serine proteases, convert plasminogen to plasmin, which beaks down fibrinogen to fibrin
The two categories of thrombolytics are:
- Fibrin-specific: tPA, reteplase, tenecteplase
- Non-fibrin specific: strptokinase (not widely used d/t allergic reactions
Surgery is contraindicated for how long after thrombolytics are given
within 10 days
Absolute contraindications for thrombolytics include
- vascular lesions
- severe HTN
- recent cranial surgery or trauma
- brain tumor
- ischemic stroke < 3months prior
- active bleeding
Relative contraindications for thrombolytics include
- Ischemic stroke >3 months prior
- active peptic ulcer
- current use of anticoagulant drugs
- pregnancy
- prolonged/traumatic CPR <3 weeks prior
- Major surgery <3 weeks prior
2 classes of procoagulants are
antifibrinolytics and factor replacements
What are the 2 subclasses of antifibrinolytics
- Lysine analogues: epsilon-amino-caproic acid (EACA) and tranexamic acid (TXA)
- SERPIN: aprotinin (off market)
Preop guidelines for warfarin include
low risk: d/c 5 days prior, restart 12-24hr postop
high risk: d/c 5 days prior, bridge w/ UFH or LMWH
Preop guidelines for heparin include
UFH: d/c 4-6hrs preop, resume >12hr postop
LMWH: d/c 24hrs preop, resume 24hr postop
Preop guidelines for ASA include
mod/high risk: continue ASA
low risk: stop 7-10 days prior
Preop guidelines for coronary stent placement include
bare-metal stent: delay elective surgery for 6 weeks
drug-eluding stent: delay elective surgery for 6 months
Which is the only Direct Thrombin Inhibitor with a reversal agent/antidote
Dabigatran (pradaxa), reversal is Idadrucizumab
The reversal agent for DOAC Factor 10a inhibitors is
Andexanet (a derivative of factor 10a)
