Coagulation for Dentists

Brian Dingle, M.Sc., M.D., F.R.C.P.(C)

Assistant Professor, Department of Oncology

Thrombogenesis

Vessel injury Exposed collagen

– 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

Hematology: Basic Principles and Practice, Hoffman et. al. Churchill Livingston, 2000

Limited proteolysis converts to active form

On platelet phospholipid

Stabilized within hours by FXIII

Regulation of Coagulation

Naturally occurring protease inhibitors of coagulation– Antithrombin III (ATIII)

Inhibits IIa, Xa Heparin binds to ATIII

Protein C activated to Ca by protein S Ca inactivates Va & VIIIa Finbrinolysis is clot breakdown

– Plasminogen is converted to plasmin by tissue plasminogen activator

– This digests fibrin– Process ihibited by aminocaproic acid, tranexamic acid

Standard Laboratory Tests

INR: International Normalized Ratio

– 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 aPTT: Activated Partial

Thromboplastin Time– Measure of the “intrinsic”

pathway– XII, XI, IX, VIII

Bleeding Time– Platelet-blood vessel interaction

abnormality

The Case of Mr. Hageman Fitzgerald Fletcher

“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

A quick call to the GP. Yes, he did do some coag studies:– 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

Contact Factor Deficiency– 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

Learning points:– 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

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

A quick call to the GP. Yes, he did do some coag studies:– 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

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

Von Willebrands Disease– 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– 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.

Genetics– 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)

Management– 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:– Call the haematologist

The Case of Miss Penelope von Willebrand

Learning Points– 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

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

Goldman: Cecil Textbook of Medicine, 21st ed., Copyright © 2000 W. B. Saunders Company

Mr. Hema Foelia

Uncle Numo, died of colo-vesicle fistula later in life

Aunt Vikki, descended from royalty

Uncle Hema (Sr.) Turia, the first diagnosed in the Turia family when he told his mother his ‘water’ had turned into red wine!

Grandpa Turia

Great Uncle Beato “Beat”, had similar problem to Hema Sr but only after eating beets

Polly, a carrier, was a diabetic, until she married into the Foelia clan

Great Grandpa Turia

Turia Family Tree

The Case of Mr. Hema Foelia

A quick call to the GP. Yes, he did do some coag studies:

– 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 A: deficiency in FVIII

Hemophilia B: deficiency in FIX

Haemophilia A (and a little bit about B)– 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

Genetics– X-linked recessive– Xq28, variety of different polymorphisms– Concordant VIII activity and VIII:Ag (rare discordance)

Manifestations– 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

Learning points– 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

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!

Chronic Warfarin Anticoagulation– 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

– 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

Reversal of Warfarin– 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– 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

Learning points– 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

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

A quick call to the GP. Yes, he did do some coag studies:

– 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

Disseminated Intravascular Coagulation– 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)

Two components of DIC:– 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– 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

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

A quick call to the GP. Yes, he did do some coag studies:– 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…”

Idiopathic Thrombocytopenic Purpura– 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– 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

Learning points– 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 Guideby 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