Coagulation for Dentists without pics2.ppt

1、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 Plate

2、let 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 pro

3、tease 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 b

4、y 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

5、 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 doesnt clot. My GP says my impartial throbbing time is over a hundred! Is that good?” No history of bleeding, surgical, minor trauma

6、, 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 rat

7、io 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,Conta

8、ct 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 c

9、an 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

10、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 exam

11、ination 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 lear

12、n that this is the result of a raucous party around a friends 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

13、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 procedur

14、e 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 GPs office was a bleeding time of over 15 minutes,vWF circulates with FVIII and binds with platelet,

15、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 t

16、he 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 hav

17、e 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

18、 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 abnormaliti

19、es Every other surgical procedure or trauma in this patient went badly, why shouldnt 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

20、 history of bleeding disorder Almost exanguinated at childbirth Disabling joint disorder, with bilateral knee replacements, special preparation for surgery Uncle Numo (mothers brother) bled to death after tooth extraction in a local pub (bar room fight) Preventive replacement program of Factor VIII

21、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 wate

22、r 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 di

23、d 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 inh

24、ibitors,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 F

25、actor 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

26、(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

27、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

28、 (mother carrier+father affected or early X inactivation),The Case of Mr. Ward (the Rat) Ferron,Rheumatic fever as a child, Mr. Ferrons 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

29、 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 Bo

30、nd movies He wants you to do the work now, and he makes you an offer you cant 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 inhibito

31、r 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 nutr

32、ition, antibiotics) Pharmacology of Warfarin Vitamin K necessary for addition of -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 regen

33、eration 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 affecte

34、d (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 se

35、rious, 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

36、 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 o

37、f 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 c

38、oag 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 overwhelmin

39、g 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 proco

40、agulant 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, kid

41、ney, 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 n

42、ot pass Go),The Case of Mrs. Purpura,Young, healthy, she arrives in your office feeling fine, but with a mouth that looks oddly like Dics (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 hav

43、e 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 Jacksons 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”,I