Coagulation for Dentists
Brian Dingle, M.Sc., M.D., F.R.C.P.(C)
Assistant Professor, Department of
Oncology
Thrombogenesis
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Vessel injury
Exposed collagen
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Platelets adhere to collagen via vWF and
aggregate (ADP) then activate
Thromboxane A2 promotes aggregation
Prostacyclin inhibits aggregation
Platelet plug formed
Stabilized by fibrin from the clotting cascade
Limited proteolysis
converts to active form
Stabilized within
hours by FXIII
On platelet
phospholipid
Hematology: Basic Principles and Practice,
Hoffman et. al. Churchill Livingston, 2000
Regulation of Coagulation
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Naturally occurring protease inhibitors of coagulation
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Antithrombin III (ATIII)
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Inhibits IIa, Xa
Heparin binds to ATIII
Protein C activated to Ca by protein S
Ca inactivates Va & VIIIa
Finbrinolysis is clot breakdown
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Plasminogen is converted to plasmin by tissue plasminogen
activator
This digests fibrin
Process ihibited by aminocaproic acid, tranexamic acid
Standard Laboratory Tests
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INR: International Normalized
Ratio
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aPTT: Activated Partial
Thromboplastin Time
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Prothrombin time (PT) divided
by normal taken to the power of
an exponent characteristic of the
reagent used
Measure of the “extrinsic”
pathway
VII, X, V, II
Measure of the “intrinsic”
pathway
XII, XI, IX, VIII
Bleeding Time
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Platelet-blood vessel interaction
abnormality
The Case of
Mr. Hageman Fitzgerald Fletcher
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“My blood doesn’t clot. My GP says my impartial
throbbing time is over a hundred! Is that good?”
No history of bleeding, surgical, minor trauma,
brushing teeth
DVT (blood clot) in leg after appendectomy, but
‘reacted badly’ to heparin
“Thirty eight teeth pulled in the last couple of years…
can I get the last one out?”
The Case of
Mr. Hageman Fitzgerald Fletcher
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A quick call to the GP. Yes, he did do some
coag studies:
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INR = 1.1 (this is a ratio of normal so close to 1.0
is good)
Bleeding time = 4 minutes (you too should stop
bleeding in under 8 mintues unless you take ASA)
aPTT = 107 seconds (using reagent insensitive to
Lupus anticoagulant, 110 seconds) Uh oh…
normal is 36 seconds, severe Haemophilia is 70
seconds!
Contact factors
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Contact Factor Deficiency
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Several factors are involved in contact activation of
the intrinsic pathway
Factor XII (Hageman) autoactivates when exposed to
a negatively charged surface
Prekallikrein (Fletcher) and High Molecular Weight
Kininogen (Fitzgerald) are all inolved
A curiousity, in that all three can result in marked
prolongation of the aPTT without clinical effect
Fletcher, the first described patient, actually had a
pulmonary embolus
The Case of
Mr. Hageman Fitzgerald Fletcher
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Learning points:
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Treat the patient, not the lab test
Admittedly rare, there are examples of seriously
abnormal lab tests which do not translate into
serious clinical abnormalities: contact factor
deficiencies, Lupus anticoagulant, dysfibrinogens
38 tooth extractions went without incident… the
thirty ninth (and hopefully last) should be a piece
of cake
The Case of
Miss Penelope von Willebrand
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As you enter the examination room, the sultry, seductive Miss
von Willebrand greets you with “Doctor, I have always just
loved…. Dentists!” The heavy makeup fails to cover the swollen
lip, fading black eye, and her inviting smile displays a fractured
front tooth.
While concerned about possible domestic violence, you learn
that this is the result of a raucous party around a friend’s pool.
But as you question Miss von Willebrand, you learn of
occasional nose bleeds, bleeding from the gums on brushing
teeth, bruising after minor trauma, near death experience from
tonsillectomy, swollen bruised neck and jaw after minor plastic
surgery
Mother also had ‘easy bruising’, serious bleeding after
hysterectomy
The Case of
Miss Penelope von Willebrand
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A quick call to the GP. Yes, he did do some
coag studies:
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INR = 1.0
aPTT = 35
Factor assays VII, VIII, IX and XI normal
Thrombin Time 8 seconds (normal)
A quick dental procedure ensues
The Case of
Miss Penelope von Willebrand
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You spend the rest of the afternoon trying to
stop the bleeding, cancelling all other
patients!
Your receptionist reports that the final fax
from the GP’s office was a bleeding time of
over 15 minutes
vWF circulates with
FVIII and binds with
platelet
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Von Willebrands Disease
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One of the few named after the doctor, instead of the
patient
Genetic disorder, qualitative or quanitative deficiency of
large glycoprotein vWF
Von Willebrand Factor
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Disulfide bonded polymers of 220 kD protein
Made in endothelial cells, stored there and in alpha
granules of the platelet
Chromosome 12
Binding site on the molecule for collagen, heparin,
platelet glycoprotiein (GP) Ib, areas for ristocetan
induced platelet aggregation
Three different subtypes (quantitative I, qualitative II,
and severe III) with sub-subtypes, A,B,C,..A1,A2… etc.
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Genetics
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Management
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1% of population have some type of defect
Of these, 80% type IA: no consistent genetic
abnormality while 15-20% type II localized to exon 28,
GPIb binding domain
Very rare type III is gene deletion (homozygous)
DDAVP (except in type IIB, contraindicated, or type
III, ineffective)
DDAVP raises factor VIII and vWF 3-5x
Test ahead of time to ensure levels of factor VIII, vWF,
bleeding time
Humate-P
Management by Dentists:
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Call the haematologist
The Case of
Miss Penelope von Willebrand
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Learning Points
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Treat the patient, not the lab test
Seriously normal tests can translate into serious clinical
abnormalities
Every other surgical procedure or trauma in this patient
went badly, why shouldn’t yours
Von Willebrands Disease is common, variable, easily
treatable, sometimes very difficult to diagnose, mostly
autosomal dominant, occasionally acquired rather than
inherited
The Case of Mr. Hema Foelia
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Life long history of bleeding disorder
Almost exanguinated at childbirth
Disabling joint disorder, with bilateral knee
replacements, special preparation for surgery
Uncle Numo (mother’s brother) bled to death after
tooth extraction in a local pub (bar room fight)
Preventive replacement program of Factor VIII
concentrates
Turia Family Tree
Great Uncle Beato “Beat”,
had similar problem to Hema
Sr but only after eating beets
Great Grandpa Turia
Polly, a carrier, was
a diabetic, until she
married into the
Foelia clan
Mr. Hema Foelia
Grandpa Turia
Aunt Vikki,
descended from
royalty
Uncle Numo, died of colovesicle fistula later in life
Uncle Hema (Sr.) Turia, the first
diagnosed in the Turia family when he
told his mother his ‘water’ had turned
into red wine!
Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company
The Case of Mr. Hema Foelia
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A quick call to the GP. Yes, he did do some coag
studies:
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INR = 1.0
aPTT = 62
Factor assays VIII 0.01 U/ml
Thrombin Time 8 seconds (normal)
The patient is referred to a local oral surgeon,
arrangements are made with his haematologist for
ongoing Factor VIII concentrate after tests are done
to establish responsiveness and lack of inhibitors
Hemophilia B: deficiency
in FIX
Hemophilia A:
deficiency in FVIII
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Haemophilia A (and a little bit about B)
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Genetics
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320 kD protein, made in liver
Stable complex with vWF (much larger, it is a polymer)
Activated by Xa, VIIIa acts as cofactor to accelerate activation
of X by IXa
Coagulant activity is Factor VIII activity, immunologic
quantitation is factor VIII antigen or VIII:Ag
1/10,000 of whole population is deficient in VIII (85%) or IX
(Haemophilia B:15%)
‘Christmas’ or my claim to infamy
X-linked recessive
Xq28, variety of different polymorphisms
Concordant VIII activity and VIII:Ag (rare discordance)
Manifestations
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Deep muscle and joint hemorrhage, easy bruising, CNS and
retroperitoneal bleeding
Chronic muscle and joint injury and fibrosis
Liver disease and AIDS from transfusions almost a thing of
the past (soon)
The Case of Mr. Hema Foelia
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Learning points
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Patients often know their own disease better than
anyone (Mr. Foelia knew his genetic problem was
a splice defect between exon 22 and 23, leading
to a truncated mRNA and totally absent protein…
fortunately, he tells you, he has not yet developed
an inhibitor to Factor VIII)
Female haemophilia is rare, but not impossible
(mother carrier+father affected or early X
inactivation)
The Case of Mr. Ward (‘the Rat’) Ferron
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Rheumatic fever as a child, Mr. Ferron’s mitral valve had to be
replaced in his forties, bringing his career as a hit man for the
Mafia to an early end (the loud clicking of the ball valve made
stealth and subsequent garrotting almost impossible)
He is moderately well controlled on Warfarin, except when he
drinks too much, which is pretty well everyday
Some of his teeth have been removed during the enforcement
of ‘Omerta’, but he wants one replaced with shining stainless
steel, like a villain in the Bond movies
He wants you to do the work now, and he makes you an offer
you can’t refuse!
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Chronic Warfarin Anticoagulation
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Heart valves, mitral worse than aortic, require anti-coagulants to
prevent stroke due to blood clots around valve
atrial fibrillation
Often ASA used, as well, as a platelet inhibitor
Chronic anitcoagulation may be required for high risk DVT
patients (repeated DVT, known thrombophilia such as protein S
or C deficiency, Factor V Leiden mutation [activated protein C
resistance], antiphospholipd antibody syndrome, with varying
degrees of risk
Remember Vitamin K deficiency (poor nutrition, antibiotics)
Pharmacology of Warfarin
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Vitamin K necessary for addition of γ-carboxy-glutamic acid
residues to factors II, VII, IX, and X (and proteins C and S: skin
necrosis)
When number of residues reduces to 9 (usually 12), 70%
activity, when reduced to 6, 2% activity
Warfarin inhibits regeneration of Vitamin K
99% bound to albumin, t1/2 40 hours
Factor VII (t1/2 5 hours) falls quickly
Vitamin K dependant
factors
II, IX, X
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Reversal of Warfarin
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Factor VII governs the INR
Patients with congenital Factor VII deficiency have variable
bleeding manifestation, and only homozygotes are affected
(warfarin therapy rarely forces VII down to these levels)
Anitcoagulant effect of warfarin is due to largely II, IX, and X
INR can be corrected quickly, long BEFORE anticoagulation is
corrected
Similarly, loading doses of warfarin probably not wise
Minor procedures while anticoagulated
For more serious, reverse warfarin and bridge with heparin
(LMW)
Drug Interaction and Dose
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99% protein bound, only 1%, the free drug is active
Easily displaced by many other drugs
Pharmacogenomics: CYP 2C9 variants
The Case of Mr. Ward (‘the Rat’) Ferron
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Learning points
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Patients on warfarin with normal INR after Vitamin
K can still bleed
Patients with therapeutic INR when returning to
warfarin may still clot
Stable doses of warfarin can be drastically altered
by additional drugs/alcohol
Remember II, VII, IX, and X
The Case of Mr. Richard Richards
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Dic, as he was known to his friends, had 60+
pk-yr history of smoking, now has chronic
cough, haemoptysis, and shortness of
breath, worse over the last three months
Before he opens his mouth, you see bruising
on his arms, purpura
Small hematomas are seen in the mucosa of
his mouth
The Case of Mr. Richard Richards
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A quick call to the GP. Yes, he did do some coag
studies:
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INR = 1.5
aPTT = 47
Factor assays VII 95%, V 23%, VIII 31%
FDP (D-dimer) strongly positive
Platelets 18,000
Fibrinogen level 1.1 (N 2-4)
“Oh, by the way, he is being seen at LRCC, not sure
why”
Factors consumed in
coagulation
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Disseminated Intravascular Coagulation
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Two components of DIC:
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Usually an overwhelming disease only seen in the critically ill (sepsis,
toxemia of pregnancy, meningitis) i.e. not your typical outpatient dental
Occasionally seen as a chronic disorder in patients with malignancy,
often just with bruising, petechiae, or briefly before the catastrophic
event
Due to slow leakage of procoagulant enzymes out of damaged tissues
and cancer (often adenocarcinomas)
Often presents with thrombotic tendency (recurrent, unresponsive
DVT)
Consumption of coagulation factors (I, II, V, VIII) and platelets
Microthrombi leading to progressive organ failure (lung, heart, kidney,
liver)
Most physicians only remember the first, but the second is probably
more important
Mild component of hemolytic anemia
Management
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Treat the underlying disease
Must anticoagulate before ‘fanning the fire’
Keep your instruments out of his mouth
Run to your local haematologist/oncologist (do not pass ‘Go’…)
The Case of Mrs. Purpura
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Young, healthy, she arrives in your office feeling fine, but with a
mouth that looks oddly like Dic’s (you wonder briefly if they
know each other)
Three days ago she had the sniffles, but they passed
This morning she noticed a ‘blood blister’ in her mouth (“…must
have been the tomatoes…”)
No medications, no previous illness, no bleeding after minor
surgery, no history of anything
Mother had thyroid disorder, grandmother had diabetes and
vitiligo (Michael Jackson’s illness without the cognitive
features)
Noticed some red spots on her legs
The Case of Mrs. Purpura
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A quick call to the GP. Yes, he did do some
coag studies:
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INR = 1.0
aPTT = 32
Platelets 18,000 (normal 150,000 to 400,000)
“Funny, now that you mention it, the platelets
look a little off…”
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Idiopathic Thrombocytopenic Purpura
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Idiopathic = ‘Patient is pathetic and the doctor is an idiot’
Two diseases (that I know of) where a physician has given himself the
disease in order to prove the pathophysiology: ITP and Duodenal
ulcers (H. Pylorii)
Autoimmune disorder: platelet membrane component serves as a
target for auto or allo-antibodies, IgG
Petechiae, skin, mucous membrane bleeding
Adult vs childhood, relatively common
In adults, female>male, often young teens or early twenties
Occasional trigger, SLE, AIDS, Evan’s,
Distinguish from TTP, HUS, E. Coli 0157, HIT
Management
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Keep platelet count over 20,000 (normal 150,000 to 400,000)
Avoid ASA
Steroids vs IVIG vs. Rho-Gam
Unpredictable relapses
Splenectomy (with prior vaccination, 1/200 overwhelming sepsis)
Often ‘burn themsleves out’
In twenty five years of practice, only one died, and he refused all
treatment (and was actually my colleague’s patient)
The Case of Mrs. Purpura
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Learning points
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ITP is common, HUS-TTP is rare
ITP is common, DIC is rare
Remember HIT can look the same, but risk of arterial
thrombus is serious in this disease, and it can occur with
Low Molecular Weight Heparins (1-3% receiving regular
Heparin, 1/3 that getting LMWH)
Disorders of Hemostasis and Thrombosis: A Clinical Guide
by William E., Hathaway, Scott H., Goodnight Jr. for those who want to learn
everything even a hematologist doesn’t know, a very readable text of 500+
pages, but small, so it goes quickly