The Coagulation Workup In The Office Setting
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1 CAA Conference alm Springs 2012 The Coagulation Workup In The Office Setting CAA Conference alm Springs, October 2012 Robert Miller, A-C Henoch-Schoenlein urpura 1
2 CAA Conference alm Springs
3 CAA Conference alm Springs 2012 Types of Bleeding latelet problem Coagulation defect mucous membrane epistaxis petechiae menorrhagia bruising soft tissue muscles joints A Good History In addition to your good history, ask about potential challenges to hemostasis over the lifetime from birth to present Chronic symptoms or familial clues may suggest an inherited disorder Hx of epistaxis? Need specifics: frequency, duration, how do you stop them? complications? medications? 3
4 CAA Conference alm Springs 2012 LATELET... Evaluation Number Function latelet... Number CBC Count Morphology Bone marrow recursors Bone Marrow Aspirate / Bx latelet roduction latelets produced in bone marrow from megakaryocytes Average megakaryocyte produces 1,500 to 2,000 platelets in its lifetime Megakaryocyte illustration latelets illustration 4
5 CAA Conference alm Springs 2012 latelet Function Ivy bleeding time (Not a good test) Standardized incision (x2) Maintain 40 mm Hg No aspirin Qualitative & Quantitative latelet Function latelet Aggregation Aggregation to : AD Epinephrine Collagen Ristocetin Arachidonic acid latelet function analysis (FA-100) vwd Glanzmann s Thrombasthenia latelet Defects Bernard Soulier Syndrome G IIb/III a Fibrinogen Afibrinogenemi a Function Number Release/ storage Bernard- Soulier Syndrome Receptor Abnormalities in biochemical paths Glanzmann s Thrombasthenia Thrombocytopenia Decreased production Increased destruction Schematic representation of normal platelet responses and the congenital disorders of l t l t f ti Deficiency of latelet Coagulant Activities Reproduced with permission from: Rao AK. Am J Med Sci. 1998;316:
6 CAA Conference alm Springs 2012 latelet... Evaluation Number Function CBC Bone marrow Bleeding time Aggregation FA Coagulation The basic work-up Blood Vessel Blood flow latelets in circulation (unactivated) Unactivated platelets and coagulation factors Endothelial cells 6
7 CAA Conference alm Springs 2012 VWF loosely bound to FVIII (to protect FVIII) Bleeding at site of injury All other coagulation factors also in circulation Exposure to subendothelium Injury to the blood vessel Bleeding at site of injury with exposure to subendothelium with platelet activation VIII Contact with tissue factor and other subendothelial tissues 7
8 CAA Conference alm Springs 2012 VWF tethers to exposed endothelium at site of injury latelets are activated and adhere to VWF and then aggregate to form platelet plug VIII p vwf VIII Shear vwf vwf VIII VIII vwf vfw vwf Activated coagulation proteins form fibrin strands Fibrin Strands VIII V IX VII X XIII I vwf vwf vwf II 8
9 CAA Conference alm Springs 2012 Fibrin Clot Coagulation Cascade Made Easy Coagulation Testing (oversimplified) Factor deficiencies or defects may prolong the T, TT or both. att XII XI IX VIII VII X V rothrombin Thrombin Fibrinogen T Fibrin clot Coagulation Testing (oversimplified) att Greater than 50% deficiency of a single clotting factor may prolong the T or TT. Greater deficiency = longer prolongation XII XI IX VIII VII X V rothrombin Thrombin Fibrinogen T Fibrin clot 9
10 CAA Conference alm Springs 2012 Coagulation... Testing Coagulation... Testing TT - pt TT - con TT - 1:1 (mixing study: 50/50 mix to see if TT corrects) T-pt T-con INR TT T INR TT F-assays VWF Anti-Xa FDs drvvt Fibrinogen Inhibitors Anticoagulants Basic Bleeding Work-up Basic Bleeding Work-up CBC with platelet count CBC w/ platelet ct NL T TT, (1:1 mix) Extra coag tube FVIII c VWF Ag (antigen) R cof. Ristocetin cofactor (VWF) T 11.2 (10-12 sec) TT, (1:1 mix) 97 (42) (31-43 sec) Extra coag tube FVIII c ( %) VWF Antigen ( %) Ristocetin (R cof.) ( %) 10
11 CAA Conference alm Springs 2012 Coagulation Testing (oversimplified) Normal T with abnormal TT isolates the problem to these four factors Hemophilia? FXI? FXII? att XII XI IX VIII VII X V rothrombin Thrombin Fibrinogen T Fibrin clot Basic Bleeding Work-up CBC w/ platelet ct NL T 17 (10-12) TT, (1:1 mix) 40 (31-43) Extra coag tube FVIII c (50-150) VWF Antigen (50-150) Ristocetin (R cof.) (50-150) Coagulation Testing (oversimplified) Normal TT with abnormal T isolates your focus to factor VII Vitamin K? FVII deficiency? Liver? att XII XI IX VIII VII X V rothrombin Thrombin Fibrinogen T Fibrin clot Coagulation Testing (oversimplified) att XII XI IX VIII VII X Vitamin K V dependant rothrombin (FII) factors Thrombin Fibrinogen XIII T Fibrin Clot 11
12 CAA Conference alm Springs 2012 Coagulation Defects Liver Disease Liver function & diagnostic testing T part of your liver panel? Factor VII short half-life 4-6 hr Basic Bleeding Work-up CBC w/ platelet ct NL T 17 (10-12) TT, (1:1 mix) 67 (40) (31-43) Extra coag tube FVIII c (50-150) VWF Antigen (50-150) Ristocetin (R cof.) (50-150) Coagulation Testing (oversimplified) If both the T and TT are prolonged Focus on the common pathway or multiple defects (or poor processing) att XII XI IX VIII VII X V rothrombin Thrombin Fibrinogen T Fibrin clot rocessing The Specimen Correct tube Drawing the blood Transit to lab Shipping Lab standards Equipment 12
13 CAA Conference alm Springs 2012 Coagulation Testing (oversimplified) Coagulation Testing (oversimplified) att Factor deficiencies may result in bleeding Except FXII a FXII deficiency does not result in bleeding. XII XI IX VIII VII X V rothrombin Thrombin Fibrinogen T Fibrin clot Factor XIII is not measured by the T/TT. att FXIII stabilizes the clot by cross linking XII XI IX VIII VII X V rothrombin Thrombin Fibrinogen T Fibrin clot FXIII Coagulation... Defects Acquired anticoagulants Inhibitors (antibodies) in Hemophilia usually specific to FVIII or FIX Spontaneous inhibitors (antibodies) usually specific to FVIII Lupus-type (lupus-like) anticoagulants nonspecific antibodies affect testing von Willebrand Disease (VWD) The most common inherited bleeding disorder Affecting ~ greater than 1% of population Autosomal VWF = von Willebrand Factor 13
14 CAA Conference alm Springs 2012 VWD.bleeding VWD Mucous membranes Epistaxis Menorrhagia Superficial (petechiae) Hemophilia Deep bruising Joints Muscles latelets are activated and adhere to VWF and then aggregate to form platelet plug VIII VIII vwf vfw vwf von Willebrand Disease Type 1 mild / most common Type 2 mild to moderate Type 3 severe von Willebrand Disease Type 1 Reduced quantity of VWF VWF normal, just reduced Mild and most common > 80% of all VWD 14
15 CAA Conference alm Springs 2012 VWD.diagnosis latelets are activated and adhere to VWF and then aggregate to form platelet plug VIII:C VWF:Ag RCof Type 1 All three partially decreased in parallel levels VIII VIII vwf vfw vwf Basic Bleeding Work-up CBC w/ platelet ct NL T 11.2 (10-12) TT, 1:1 mix 46 (31-43) Extra coag tube FVIII c 38 (50-150) VWF Antigen 42 (50-150) Ristocetin (R cof.) 35 (50-150) von Willebrand Disease Type 2 Qualitative defects in function Type 2A Lacks HMW multimers Type 2B Qual.variants / platelet binding 15
16 CAA Conference alm Springs 2012 Basic Bleeding Work-up CBC w/ platelet ct NL T 10.9 (10-12) TT, 1:1 mix 46 (31-43) Extra coag tube FVIII c 32 (50-150) VWF Antigen 12 (50-150) Ristocetin (R cof.) 0 (50-150) von Willebrand Disease Type 3 VWF very low or absent Severe clinical features Basic Bleeding Work-up CBC w/ platelet ct NL T 11.0 (10-12) TT, 1:1 mix 59 (31-43) Extra coag tube FVIII c 3 (50-150) VWF Antigen <12 (50-150) Ristocetin R cof. <6 (50-150) VWD... lab tests VIII:C Bleeding time VWF:Ag VWF multimers RCof Blood group RIA latelet count 16
17 CAA Conference alm Springs 2012 VWF Multimers von Willebrand Disease Diagnosis Repeated testing may be needed Bleeding history important Family history / inheritance Autosomal dominant / recessive Basic Bleeding Work-up CBC w/ platelet ct NL T 11.1 (10-12) TT, 1:1 mix 43 (31-43) Extra coag tube Questions? FVIII c 60 (50-150) VWF Antigen 41 (50-150) Ristocetin (R cof.) 52 (50-150) 17
18 CAA Conference alm Springs 2012 atient Hx Medications Hospitalizations Surgeries Transfusions ROS Family Hx Bleeders Easy bruising Chronic diseases Deaths Bleeding Disorder? Bleeding Hx Hx from birth Circumcision Teething Extractions Bruising Epistaxis frequency / duration Sutures / FXs Trauma Menstruation regnancies Coagulation... Defects Vitamin K deficiency Synthesis of Factors II VII IX X Factor VII has short half-life Dietary - reduced intake Chronic antibiotics - reduced absorption Consider giving Vit K and re-test Hemorrhagic disease of the newborn Coag Factor Deficiencies Factor VII deficiency Autosomal Rare 1:500,000 Bleeding variable Bleeding does not correlate with level Treat with rfviia Coag Factor Deficiencies Hemophilia A & B A Classic hemophilia Factor VIII Deficiency B Christmas Disease Factor IX Deficiency X-linked Severity: severe / mod. / mild 18
19 CAA Conference alm Springs 2012 Coag Factor Deficiencies Factor XI deficiency Autosomal Rare > 1:100,000 Ashkenazi Jews (8%) Bleeding variable Treat with FF or rviia (No FXI available) Coag Factor Deficiencies Factor XII deficiency Autosomal Rare rolongs the TT but does not result in clinical bleeding Surgery is OK Factor XII Deficiency If you isolate this diagnosis, give them a note / card Inherited Factor XII deficiency will prolong the TT but does not result in clinical bleeding Coag Factor Deficiencies Factor XIII deficiency Autosomal Rare T / TT normal Excess bleeding from umbilical stump 19
20 CAA Conference alm Springs 2012 Inherited Thrombophilia A redisposition to Hypercoagulation Factor V Leiden rothrombin G20210A mutation Antithrombin III deficiency rotein C deficiency rotein S deficiency High homocysteine level 20
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