Coagulation Flashcards
Test 4
What is normal hemostasis a balance between?
Balance between:
-clot generation
-thrombus formation
-regulatory mechanisms
All of these should inhibit uncontrolled thrombosis
What are the goals of hemostasis? (3)
- Limit blood flow from vascular injury.
- Maintain intravascular blood flow.
- Promote revascularization after thrombosis.
What are the two different stages of hemostasis? Describe them.
Primary: initial platelet plug formation at the endovascular injury site
-only adequate for minor injuries
Seconday: clotting factors activated
-clot form, stabilized and secured with cross-linked fibrin
Vascular endothelium cells have _________ (3) affects. What do these effects do? What are the mechanisms of the endothelial cells to achieve these effects? (6)
Anti platelet, anticoagulant, fibrolytic effects –> inhibit clot formation
- Negatively charged –> repel platelet.
- Produce prostacyclin & Nitric Oxide = platelet inhibitors
- Excrete adenosine diphosphatase –> degrades ADP (platelet activator)
- Increases protein C (anticoagulant)
- Produces tissue factor pathway inhibitor (TFPI) –> inhibits factor Xa & TF-VIIa complex
- Synthesizes. tPA
Platelets are derived from bone marrow ________
megakaryocytes
Inactivated platelet circulate as ____-shaped _______ cells. What is their lifespan?
disc-shaped
anuclear cells
8-12 days
___% a platelets are consumed to support vascular integrity
10%
_______billion new platelets are formed daily
120-150 billion
T/F: the surface area membrane of a platelet can increase
T
What does a platelet have on its surface?
Receptors and a canalicular system (channel & ducts)
Damage to endothelium exposes the underlying __________ which contains what? (3)
Extracellular matrix (ECM)
- Collagen.
- Von Willebrand’s factor (vWBF).
- Glycoprotein.
When platelets are exposed to contents in the extracellular matrix (ECM) what three phases do they undergo?
- Adhesion.
- Activation.
- Aggregation.
Adhesion of platelets occurs when exposed to _______
ECM proteins
Activation of platelets occurs when platelets interact with _____ & _______. What does this cause?
collagen
tissue factor (TF)
release of granular contents
What are the two types of platelet storage granules? What do they contain?
Alpha granules: fibrinogen
Factors V & VIII (5 & 8)
vWF
Platelet derived growth factors
Dense bodies: ADP
ATP
Calcium
Serotonin
Histamine
Epinephrine
When does aggregation of platelets occurs?
Granular contents are released –> additional platelets are activated
Each stage of the clotting cascade requires assembly of membrane bound activated ___________. What does this consist of?(4)
Tenase-complexes:
-A substrate (inactivated precursor)
-an enzyme (activated coagulation factor)
-a cofactor (accelerator/catalyst)
-calcium
Clotting factors: Factor I (1)
Fibrinogen
Clotting factors: Factor II (2)
Prothrombin
Clotting factors: Factor III (3)
Tissue thromboplastin
Clotting factors: Factor IV (4)
Calcium ions
Clotting factors: Factor V (5)
Labile factor
Clotting factors: Factor VII (7)
Stable factor
Clotting factors: Factor VIII (8)
Anti-hemophilic factor
Clotting factors: Factor IX (9)
Christmas factor
Plasma thromboplastin component (PTC)
Clotting factors: Factor X (10)
Stuart-Prower Factor
Clotting factors: Factor XI (11)
Plasma thromboplastin antecedent (PTA)
Clotting factors: Factor XII (12)
Hageman factor
Clotting factors: Factor XIII (13)
Fibrin stabilizing factor
Describe the extrinsic pathway of the clotting cascade
- Trauma activates factor VII (7)
- factor VII (7)–> factor VIIa –> bind to Tissue Factor
- factor VIIa/TF –> factor X (10) –> factor Xa (common pathway)
- Prothrombin (F II) –> Thrombin –> activates plates & converts fibrinogen of fibrin
The extrinsic pathway is the initiation phase of __________ homeostasis
Plasma mediated
Factor ______ begins the final common pathway
Xa (10a)
What initiates the intrinsic pathway of the clotting cascade?
Damage to the endothelial; contact with negatively charged surface –> factor XII becomes activated
Describe the intrinsic pathway of the clotting cascade
- Factor XII (12) –> factor XIIa
- Factor XIIa –> FXI (11) –> F XIa
- F XIa –> F IX (9) –> F IXa
- F IXa –> F X (10) –> F Xa (common pathway)
- Prothrombin (F II) –> Thrombin –> activates plates & converts fibrinogen of fibrin
What additional factors does Thrombin (F IIa) activate?
V - 5
VII - 7
VIII - 8
XI - 11
What forms the prothrombinase complex? What does this do?
Factor Xa & Factor Va
Converts prothrombin –> thrombin
Describe the common pathway
- Factor Xa & Factor Va –> Prothrombin to thrombin
- Thrombin attaches to platelet –> converts fibrinogen to fibrin
- Fibrin cross link –> stabilize clot
_________ is the key step in regulating hemostasis
Thrombin generation
What are the 4 major anticoagulation mechanisms? Describe them
- Fibrinolysis: TPA & Urokinase
Convert plasminogen to plasmin
Breaks down clots
Degrades factors V & VIII - Tissue factor pathway inhibitor (TFPI): forms complex with Xa –> inhibits VIIa/TF complex & Xa
Down regulates the extrinsic pathway - Protein C system: inhibits factors II, Va, VIIIa
- Serine Protease inhibitors (SERPINs):
-antithrombin (AT): inhibits thrombin, factors IXa, Xa, XIa, XIIa,
-Heparin: Bonds to antithrombin –> confirmational change that accelerates antithrombin activity
-heparin cofactor II: inhibits thrombin alone
_______ are first line labs if bleeding disorder is suspected
PT, aPTT
Pinpoint important things from vWBF disease
Most common bleeding disorder
Deficiency in vWBF –> defective platelet adhesion/aggregation
vWBF prevents degradation of Factor 8 –> decreased Factor 8
aPTT prolonged (platelets/PT normal)
Mild cases will respond to DDAVP
Tx: vWBF & Factor 8 concentrates
Describe Hemophilia
Hemophilia A: Factor 8 deficiency (1/5000)
Hemophilia B: Factor 9 deficiency (1/30000)
2/3 genetic
1/3 present as a new mutation w/o family hx
Presents in childhood as spontaneous hemorrhage involving joints & muscles
Labs: PTT prolonged
Normal PT & bleeding time
Tx: DDAVP
Factors 8/9 concentrates before Sx
What drugs induce bleeding?
Heparin
Warfarin
PO anticoags
Beta-lactam abx
Nitroprusside
Nitroglycerin
NO
SSRIs
What herbs induce bleeding?
Cayenne
Garlic
Ginger
Ginkgo Biloba
Grapeseed oil
St. John wort
Turmeric
Vitamin E
The liver is the primary source of what factors? How does liver disease affect this?
Factors:
5
7
9
10
11
12
Protein C & S
Antithrombin
Hemostatic issues:
-Impaired synthesis of coagulation factors
-quantitative and qualitative platelet dysfunction
-impaired clearance of clotting in fibrinolytic proteins
Labs: prolonged PT/PTT
How does Chronic Kidney Disease affect coagulation? How do we Tx this?
CKD –> anemia at base dt:
-lack of erythopoietin
-platelet dysfunction dt uremic environment
Tx: Dialysis
Correction of anemia
(Both shorten bleeding time)
Cryo
DDAVP
Conjugated estrogen preop x5days
(these are for platelet dysfunction only)
Describe DIC
Disseminated intravascular coagulation
Pathologic hemostatic response to TF/7a complex –> excessive activation of extrinsic pathway
Coagulation factors & platelets become depleted –> widespread microvascular thrombosis –> multiorgan dysfunction
causes: trauma, amniotic fluid in embolus, malignancy, sepsis, incompatible blood transfusion
labs: decreased platelets,
Prolonged PT/PTT/TT/Soluble fibrin/fibrin degration products
Tx: correct underlying condition
Administer appropriate blood products
Coagulopathies occur dt ______ (3)
Acidosis
Hypothermia
Hemodilution
What is trauma induced coagulopathy?
Acute coagulopathy scene and trauma patient thought to be related to activated protein C decreasing thrombin generation
Hypoperfusion is thought to be the driving factor for protein C activation
Decribe the Prothrombotic disorders (4). Which are most common?
Inherited/genetic
Factor V Leiden mutation: activated, protein C resistance
-present 5% Caucasian population
Prothrombin mutation: increase prothrombin concentration –> hypercoagulation
Thrombophilia: can be inherited or acquired
-highly susceptible to Virchow’s triad (blood stasis, endothelial injury, hypercoagulability)
Antiphospholipid syndrome: autoimmune disorder with antibodies against phospholipid binding proteins in the coagulation system
-recurrent thrombosis and pregnancy loss
Requires lifelong anticoagulant
PO contraceptives, pregnancy, and mobility, infection, surgery and trauma, greatly increased the risk of thrombosis
Describe HIT
Heparin induced thrombocytopenia
Occurs 5 to 14 days after heparin treatment
Platelet count reduction –> potential thrombosis
Auto immune response in 5% patient receiving heparin
Response can occur within 1 day if previously had heparin before
Infraction heparin»_space; LMWH risk
Cannot bridge to warfarin
Dx confirmed with HIT antibody testing
Antibodies cleared within 3 months
Labs: PT
Second until clot forms
extrinsic/common
Deficiencies in factors: 1, 2, 5, 7, 10
Used for Warfarin
Labs: aPTT
Second until clot forms after mixing plasma with phospholipid, Ca++, and an activator of the intrinsic pathway
intrinsic/ common
Deficiencies in factors: 8, 9
Used for Heparin
Labs: Anti-factor Xa
Functional assessment of heparins anticoagulant effects
Labs: platelet count
Normal: >100,000plts/microliter
Labs: activated clotting time (ACT)
Normal: 107 +/- 13seconds
Addition of clotting activator to accelerate clotting time
intrinsic/common
Measure responsiveness to heparin
Labs: heparin concentration measurements
Determines preoperative heparin concentration
1mg protamine will inhibit ____ heparin
1mg
What are my Viscoelastic coagulation test?
TEG
ROTEM
TEG values/Tx: R time
Time to start forming clot
Normal: 5-10minutes
> 10min –> FFP
TEG values/Tx: K time
Time until clot reaches a fixed strength
Normal: 1-3 mins
> 3min –> cryo
TEG values/Tx: Alpha angle
Speed of fibrin accumulation
Normal: 53 - 72 degrees
Tx: cryo
TEG values/Tx: maximum amplitude (MA)
Highest vertical amplitude of the TEG
Normal: 50 - 70 mm
Tx: Platelets
DDAVP
TEG values/Tx: LY30
Percentage of amplitude reduction 30 minutes after maximum amplitude (percentage of clot dissolved after 30 minutes)
Normal: 0-8%
> 8% –> TXA or Aminocaproic acid
What are the three classes of anti-platelets? How do they work? How long do their anti-platelet effects last after stopping the drug?
- Cyclooxygenase inhibitors: Block COX1 from forming TXA2
-ASA: 7-10 days
-NSAIDS: 3 days - P2Y12-Receptor antagonists: Inhibit those receptors & prevent IIb/IIIa granulation/aggregation
-Clopidogrel: 7 days
-Ticopidine: 14-21 days
-Ticagrelor & Cangrelor: 24 hrs - Platelet GIIb/IIIa antagonists: prevents vWF & fibrinogen from binding to those receptors
-Abciximab, Eptifibatide, Tirofiban
What are the vitamin K dependent factors?
2
7
9
10
Protein C & S
Anticoagulants: Warfarin
Long 1/2 life (40h)
3-4 days to reach therapeutic INR (2-3)
Reversible with vitamin K
Anticoagulants: Heparin
MOA: binds to ANTITHROMBIN!!!! –> inhibits thrombin & Xa
(indirect thrombin inhibitor)
UFH:
Short 1/2 life
fully reversable w/ protamine
Close monitoring required
LMWH:
Longer HL
Dose BID SQ
Partially reversed w/ protamine
Fondaparinux:
Much longer half life (17-21h)
Dose once a day
Not reversible
Anticoagulants: direct thrombin inhibitors
MOA: bind/block thrombin
Hirudin: found in leeches
Argatroban: reversible
Bivalirudin: shortest half life
Dabigatran (Pradaxa): 1st DOAC (PO)
DOAC =
Direct Oral anticoagulants
What are the benefits of DOAC? What drugs are they?
More predictable pharmacokinetics/ pharmacodynamics
-fewer drug interactions
-does daily without lab monitoring
-shorter half life
-fewer embolic events
-lower mortality
Direct thrombin inhibitors: Dabigatran (Pradaxa)
Direct Xa inhibitors: Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
What are the 2 categories of thrombolytics?
Fibrin-Specific: tPA, Reteplase, Tenecteplase
Non-Fibrin-Specific: Streptokinase (has allergic reactions sometimes)
Surgery is contraindicated within _______ of thrombolytic treatment
10 days
What are absolute contraindications for thrombolytic treatment?
Vascular lesions
-severe uncontrolled hypertension (SBP >185; DBP >110)
-recent cranial surgery or trauma
-brain tumor
-ischemic stroke <3 months
-Active bleeding
What are relative contraindications for thrombolytic treatment?
Ischemic stroke >3 months
-Active Pepcid ulcer
-current use of anticoagulant drug drugs
-pregnancy
-prolonged or traumatic CPR <3 weeks prior
-major surgery <3 weeks prior
What are the 2 Procoagulant classes? Describe them. What is included in them?
Antifibrinolytics:
-Lysine analogues: Epsilon-amino-caproic acid (EACA) & Tranexamic acid (TXA) - inhibits plasminogen from binding to fibrin –> impairs fibrinolysis
-SERPIN: Aprotinin - removed from market dt renal/cardio toxicity
Factor Replacements:
-Recombinant VIIa
-prothrombin complex concentrates (PCC): has vit K factors
-fibrinogen concentrates
-cryoprecipitate & FFP: more coag factors but less specific
When should you stop/start taking this med for Sx: Warfarin
low risk:
stop: 5 days prior
start: 12-24 h
high risk:
Stop: 5 days prior & bridge to heparin
When should you stop/start taking this med for Sx: Heparin
UFH:
Stop: 4-6h
Start: 12h
LMWH:
Stop: 24h
start: 24h
When should you stop/start taking this med for Sx: aspirin
mod/high risk: continue
low risk:
stop: 7-10 days
We delay elective Sx for _____ with bare metal stents & ______ for drug eluding stents
6 weeks
6 months
What are the reversals for warfarin?
Prothrombin complex concentrates (PCC) = for emergent reversal
vitamin K = more sustained reversal (slower)
The reversal for DOAC Dabigatran (Pradaxa) is ________
Idarucizumab
The reversal for DOAC factor Xa inhibitors is __________
Andexanet
