Coagulation
• 1) Vascular Phase
• 2) Platelet Phase
• 3) Coagulation Phase
Phases of Coagulation
• Cutting or damaging blood vessels leads to vascular
spasms of the smooth muscles. This produces a
vasoconstriction of the vessel which slows/stops blood
flow.
Vascular Phase
• Damaged endothelial cells releases von Willebrand’s
factors which causes platelets to adhere to the damage
area (glycoprotein Ib). Platelets also adheres to the
exposed collagen through glycoprotein Ia/IIa receptors.
Platelet Phase
• Activated platelets release Factor I (Fibrinogen), Factor V
(Prothrombin Activator), adenosine diphosphate (ADP),
thromboxane A2, vWF, calcium, and growth factors.
Platelet Phase
• ADP: Activates platelets through morphological changes
(“making them sticky”), and release of granules
• Thromboxane A2: vasoconstrictor, activates platelets,
cause glycoprotein IIb/IIIa receptors to be expressed.
• Glycoprotein IIb/IIIa: allows platelets to bind with
fibrin
• Calcium: activates Phospholipase A2 (arachidonic acid),
and helps express glycoprotein IIb/IIIa
Platelet Phase
• Thromboxane Inhibitor: Aspirin
• ADP Receptor Inhibitor: Clopidogrel (Plavix),
Prasugrel (Effient), Ticagrelor (Brilinta)
• Glycoprotein IIb/IIIa Receptor Inhibitor: Abciximab
(Reopro), Tirofiban (Aggrastat), Eptifibatide (Integrilin)
• Lower Intracellcular Ca: Dipyridamole (Persantine),
Cilostazole (Pletal)
Anti-platelet Medications
• Platelets adhere to damaged vessel walls, aggregate and
provide a core for which fibrin strands accumulate.
Arterial thrombi are white in appearance because they are
predominately platelets. They occlude arterial flow,
leading to ischemia and infarction of tissues.
Anti-platelet Medications
• Require patients to be on dual therapy anti-platelet
medication. Bare metal stents 6 months while drug
eluting stents require 6-12 months. This inhibits the initial
platelet adhesion/aggregation.
Coronary Artery
Disease/Stents
• Bleeding time is a medical test to assess platelet function
(adhesion/aggregation)
• All anti-platelet medication PROLONGS bleeding time
(initial bleeding time is prolong). This is because platelets
can NOT adhere or aggregate to the site of injury.
• Patients will initially bleed longer and take longer to
achieve initial hemostasis.
Bleeding Time?
• Platelet Rich Plasma are concentrated platelets
WITHOUT fibrin (due to the nature of a Calcium
chelating agent) (weaker clot)
• Platelet Rich Fibrin are concentrated platelets WITH
fibrin (stronger clot) – coagulation cascade
VS
PRP vs PRF?
• Concentrated platetlets that secrete essential growth
factors: transforming growth factor beta, fibroblast
growth factor, insulin like growth factor 1&2, platelet
derived growth factor, vascular endothelial growth
factor, epidermal growth factor, interleukin 8, and high
concentrations of leukocytes
• High angiogenesis potential (VEGF, IL-8), and essential
growth factors for RAPID HEALING
PRP/PRF
• Platelet Rich Plasma (PRP) is reactivated by mixing it
with Calcium for the platelets to degranulate and release
Platelet Rich Growth Factors (PRGF)
PRP vs PRGF
Coagulation Phase
• Factor VIII
• Factor V
• Both circulate in a active form all other factors circulate
in a inactive form
• Factor VIII binds to Platelet or collagen in presence of
Ca++ with Active Factor IX to activate Factor X
• Factor V binds to Platelet or Collagen in presence of
Active Factor X to activate Factor II
Active Co-Factors
Factor Ten
Coagulation Phase
Factor Five
Factor Ten
Coagulation Phase
• Active Factor V and Active Factor X activate Factor II (
(Prothrombin)
• Active Factor IIA polymerizes Factor I (Fibrinogen)into
Factor IA(Fibrin)
• Fibrin undergoes cross- linkage with Di-Sufide bonding
(Clot Retraction) in the presence of Factor XIII
Final Common Pathway
Factor Five
Extrinsic Pathway
Factor Ten
Coagulation Phase
Factor Five
TENET
Extrinsic Pathway
Intrinsic Pathway
Factor Ten
Coagulation Phase
Factor Five
TENET
Extrinsic Pathway
Intrinsic Pathway
Factor Ten
Thrombin
Fibrinogen
Coagulation Phase
Protein C and S
Factor Five
TENET
Extrinsic Pathway
Intrinsic Pathway
Factor Ten
Thrombin
Fibrinogen
Coagulation Phase
Protein C and S
Factor Five
TENET
Extrinsic Pathway
Intrinsic Pathway
Factor Ten
Thrombin
Fibrinogen
Coagulation Phase
• Where is factor IV and Factor VI???
Coagulation Phase
• Calcium ++ ion is necessary to for Factor 2, 7, 9, 10 to
be activated
• 2,7,9,10 are activated by lysis of a serine molecule
• Factor V and Factor VIII are always active
Coagulation Phase
• Ultimately, Fibrins strands are made and Factor XIII
crosslinks fibrin to strengthen them. Platelets’
glycoprotein IIb/IIIa receptors binds to the fibrin
strands and you have a mixture of platelet/fibrin clot
for a strong hemostasis.
• A super strong mesh/net of fibrin
Coagulation Phase
• Protein C&S: Inactivates Factor Va and VIIIa
• Antithrombin III: Inactivates Xa and IIa
• Tissue Plasminogen Activator (tPA): converts
plasminogen to plasmin which lysis fibrin
Innate Anti-Coagulants
Protein C and S
Factor Five
TENET
Extrinsic Pathway
Intrinsic Pathway
Factor Ten
Thrombin
Fibrinogen
Innate Anti-Coagulants
• Hemophilia A, Factor VIII
• Hemophilia B, Factor IX
• Von Willebrand, Type 1 (asymptomatic) can be treated
with DDAVP which stimulates release of vwf from the
endothelial cells and increases factor VIII levels, 2(
DDAVP effective in some types of type 2 but not all and
is contrandicated in some, 3 ( DDAVP totally ineffective)
• Hemophila C, Factor XI (asymptomatic)
Inherited Coagulopathys
• Inhibits synthesis of multiple factors: Warfarin (2, 7, 9
10)
• Inhibits Factor IIa: Pradaxa
• Inhibits Factor Xa: Xarelto, Eliquis
Oral Anti-Coagulants
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Topical Thrombin , 5000units
Must be stored at 36-77 degrees F
Long shelf life
Reconstitute and apply topically only!!
Bypass intrinsic and extrinsic clotting cascade only
adequate Fibrinogen level needed to form clot
In office essential Items
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Some form of collagen
Either Avatine ( fibrillated collagen )
Collagen Plug
Platelet activation
In office essential items
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Saturate collagen with thrombin
Place thrombin saturated collagen in extraction site
Place chromic suture over extraction site
Both Bypass Coagulation Cascade and Directly Activate
Platelets
Collagen and Thrombin in
Combination
• Inhibits activity of multiple factors: Heparin (2, 9, 10, 11,
12)
• Inhibits IIa and Xa: Lovenox, Fragmin
• Inhibits Xa: Arixtra
• Inhibits IIa: Angiomax
IV Anti-Coagulants
• Warfarin, Heparin, Lovenox, Eliquis, Xarelto, Pradaxa,
etc… ALL PREVENT ACTIVATION OR INHIBIT
ACTIVATED Factor 10 or Factor 2!!!
Anti-Coagulants
Anti-Coagulants
• INR/PT (International Normalized
Ratio/Prothrombin time): Measures extrinsic pathway
• Normal INR is ~ 1.0
• Normal PT is ~ 11-13
• Example: INR of 3 is roughly 13x3 = 39 PT
INR/PT vs PTT
Extrinsic Pathway
Extrinsic Pathway
• aPTT (activated Partial Thromboplastin Time):
Measures Intrinsic Pathway
• Normal aPTT is ~ 30-36
aPTT
TENET
Intrinsic Pathway
Intrinsic Pathway
• Why does a patient on coumadin/warfarin usually bleed
A LOT after surgery and not during surgery?
Question???
• Coumadin/Warfarin has nothing to do with the initial
platelet plug (bleeding time). It affects the second part
(coagulation cascade)
• The platelet plug is weak and easily friable due to not
having any fibrin products.
Answer
• Coumadin inhibits the Vitamin K pathway (2, 7, 9, 10)
AND protein C and S. Protein C and S have shorter
half-life than Factor 2, 7, 9, 10. Protein C and S are the
body’s innate anti-coagulants. Therefore, you get an
initial paradoxical effect of thrombosis/embolism.
Coumadin Necrosis
• Vitamin K-1 and Vitamin K-2 are critical for the
Carboxalization of Key Proteins involved with CA++,
such as clotting Factors 2,7,9,10
• Vitamin K-1 from diet, Vitamin K-2 synthesized by Gut
bacteria such as E.coli
• Both are active in 2,7,9,10 Carboxalization
• Coumadin blocks the recycling of Vitamin K, therefore
depleting Vitamin K
• Broad Spectrum antibiotics can deplete E.coli therefore
depleting Vitamin K and therefore prolonging INR
Coumadin (Warfarin)
Only the prescribing physician can assess the risk of a
thrombotic event with the alteration of the patient’s anticoagulation routine
Only The Prescibing
Physician Should Advise
Patient to Alter Their AntiCoagulation Medication
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If INR is between 2-3
Minor surgery is planned
Routine exodontia
Treat wound with
Collagen and Topical
Thrombin
• Liquid diet and no
Brushing for 72 hours
• If major surgery is
planned
• Patient will need to
admitted pre-op and
bridged to heparin
Usually Not Necessary To
Discontinue Coumadin
• Standard for monitoring/ titrating the anticoagulation
effect of Coumadin
• INR is calculated by dividing the sample PT time by a lab
standard PT time
• PT time (Prothrombin Time) is done by collecting blood
in a citrated test tube ( Removes Calcium by chelation)
• The tube is spun down separating serum
• Serum placed in tube with calcium and tissue
thromboplastin
• Timed to form clot to measure extrinsic pathway
PT/INR
• Why do you bridge from one anti-coagulants to another
for surgery? – Half-life difference and smaller window of
NOT being anti-coagulated.
Bridging Anti-Coagulants
• Example: Coumadin -> Heparin -> Coumadin
• Mean half-life of Coumadin: 2-3 days
• Mean half-life of Heparin: 60-90 mins
• Patient has a mechanical valve with an INR of 3.0 and
needs extraction of three teeth. Patient can NOT stop
anti-coagulants due to be high risk of stroke.
Bridging Anti-Coagulants
• Bridge: INR 3.0 is roughly 3X normal PT. Patient will
start heparin and build up an aPTT of 90 (3X normal
aPTT). Once aPTT goal is reached. Patient will stop
Coumadin for 2-3 days and continue heparin while
maintaing aPTT of 90. Once Coumadin levels have
dropped close to normal, discontinue heparin for roughly
1-2 hours before surgery. Do surgery. Re-start heparin
AND Coumadin after surgery. Build up INR of 3.0 and
discontinue Heparin.
• Coumadin -> Heparin -> Coumadin
Bridging Anti-Coagulants
Platelets/Coagulation
Disorder
• HITT (Heparin induced Thrombocytopenia and
Thrombosis): IgG antibodies against heparin/platelet
factor4 causes platelet activation (thrombosis) and usage
(thrombocytopenia)
HITT
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Bone Wax (Wax/paraffin – tamponade)
Gelfoam (Gelatin – physical scaffold)
Surgicel (Cellulose – tamponade and physical scaffold)
Collaplug/Collatape (Collagen – platelets)
Avitene (Collagen – platelets)
Quikclot (Kaolin – dehydration and Factor XII)
Arista – (microporous polysaccharide hemospheres –
dehydration)
• Floseal – (thrombin and granules – scaffold and Factor 2)
• Tisseal (Factor 1, 13, thrombin, and CaCl)
• Thrombin – (Factor 2)
Local Agents Hemostasis
• Phase 1: Pressure/Tamponade
• Phase 2: Platelet Activation
• Phase 3: Coagulation Cascade
• Example 1: Avitene (platelets) + thrombin (coagulation
cascade)
• Example 2: Floseal (platelets) + thrombin (coagulation
casecade)
Local Agents – “The Key”
• Tranexamic acid (8x) /Aminocaproic Acid – inhibits
plasminogen from breaking down fibrin
Anti-fibrinolytics
• Platelets – 1 unit increase roughly 10,000 platelets
• FFP – fresh frozen plasma (contains all the coagulation
factors)
• Cryoprecipitate – contains Factor VIII, Von Willebrand
Factor, Factor 2, Factor XIII
IV Meds
• 30 y/o female
• PMH: anemia, CVA, bladder incontinence, cerebral palsy,
mild mental retardation
• Surgery: 4X wisdom teeth (poppers) under GA
• Meds: Plavix (anti-platelets = prolong initial bleeding)
Case Study: WV
• Nonstop bleeding from all 4 extractions sites 1, 16, 17, 32
• Unable to be controlled with local measures
• Why???
Case Study: WV
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INR 1.1
aPTT 43.5
Liver Panel: ALT 32 (6-45), AST 41 (10-35)
Factor VIII: 121 (48-177)
Platelets: 190
Fibrinogen 160 (152-337)
Von Willebrand Activity: 181 ( 42-200)
Calcium 8.3 (8.5 – 10.5)
Patient is on anti-platelets and has prolong PTT = double
whammy!!!
Case Study WV Day 1
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Fibrinogen: 134
Platelets: 125 -> 94 -> 82
D-Dimer: .25 ( <.50)
Calcium 7.3
INR: 1.3
aPTT: 30.1
Case Study: WV Day 2
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Factor 2: 68 (75-130)
Factor 5: 83 (60-140)
Factor 8: 181 (50-150)
Von Willenbrand 113 (50-150)
Factor 9: 38 (55-150)
Factor 11: 53 (60-135)
Factor 12: 155 (5-150)
Factor 10: 93 (65-140)
Case Study: WV Final Day
• Patient was on anti-platelets (prolong bleeding) and had
prolong PTT (similar to taking anti-coagulation meds)
• Should have packed the patient in the OR with Avitene
(collagen) and thrombin (factor 2) ?
• Only controlled after 4 units of FFP !!
• Does she have undiagnosed Hemophilia C ? Or is it
purely a problem secondary to Hepatitis C ?
Case Study – WV
• Thank you! Questions?
The End