Common Inherited Bleeding Disorders

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1 CAA 2015 Annual Conference Common Inherited Bleeding Disorders Bob Miller, A October 8, 2015 VWF has two jobs Loosely bound to protect FVIII and tether to site of injury All other coagulation factors also in circulation Injury to the blood vessel Contact with tissue factor and other subendothelial tissues 1

2 CAA 2015 Annual Conference Bleeding at site of injury with exposure to subendothelium with platelet activation VIII VWF tethers to exposed endothelium at site of injury VIII p vwf VIII Shear vwf vwf latelets are activated and adhere to VWF and then aggregate to form platelet plug VIII VIII vwf vfw vwf 2

3 CAA 2015 Annual Conference Activated coagulation proteins form fibrin strands VIII V IX VII X XIII I vwf vwf vwf II Fibrin Strands Fibrin Clot 3

4 CAA 2015 Annual Conference vwd Glanzmann s Thrombasthenia Bernard Soulier Syndrome G IIb/III a Fibrinogen Afibrinogenemia A representation of normal platelet responses and the congenital disorders of platelet function Deficiency of latelet Coagulant Activities Reproduced with permission from: Rao AK. Am J Med Sci. 1998;316:

5 CAA 2015 Annual Conference etechiae eter Maslak, ASH Image Bank 2011; Copyright 2011 American Societyof Hematology. Copyrightrestrictionsmay apply. atterns of Bleeding latelet type Coagulation type... mucous membrane epistaxis petechiae menorrhagia bruising soft tissue muscles joints latelet Function Evaluation IVY bleeding time lt Aggregation to : AD Epinephrine Collagen Ristocetin Arachidonic acid FA - latelet function analyzer 5

6 CAA 2015 Annual Conference Inherited Disorders Affecting latelets Low von Willebrand factor protein (common) von Willebrands Disease (VWD) Function defects in the platelet (rare) Glannsman s thrombasthenia Bernard-Soulier syndrome Vessel wall abnormalities (rare) Connective tissue disorders vwd Glanzmann s Thrombasthenia Bernard Soulier Syndrome G IIb/III a Fibrinogen Afibrinogenemia A representation of normal platelet responses and the congenital disorders of platelet function Deficiency of latelet Coagulant Activities Reproduced with permission from: Rao AK. Am J Med Sci. 1998;316: VWD.bleeding VWD Mucous membranes Epistaxis Menorrhagia Superficial (petechiae) Hemophilia Deep bruising Joints Muscles 6

7 CAA 2015 Annual Conference von Willebrand Disease Estimated 1% of population (autosomal) 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 VWD.diagnosis FVIII VWF:Ag RCof Type 1 All three partially decreased to similar levels 7

8 CAA 2015 Annual Conference Basic Bleeding Work-up CBC w/ platelet ct NL T 11.2 (10-12) TT 46 (31-43) Extra coag tube FVIII 38 (50-150) VWF Antigen 42 (50-150) Ristocetin (R cof.) 35 (50-150) Basic Bleeding Work-up CBC w/ platelet ct NL T 10.9 (10-12) TT 46 (31-43) Extra coag tube FVIII 32 (50-150) VWF Antigen 12 (50-150) Ristocetin (R cof.) 0 (50-150) von Willebrand Disease Type 2 Qualitative defects in function Type 2A Lacks HMW multimers Type 2B Gain of function Increased platelet binding = low plt ct 8

9 CAA 2015 Annual Conference von Willebrand Disease Type 2 Qualitative defects in function Type 2M Decreased binding to G1 Type 2N (Normandy) Normal amount of VWF (Ag & Rcof normal) Decreased binding to FVIII = low FVIII? Misdiagnosed as hemophilia A A Short Case # 1 MR is a 10 y/o Caucasian male scheduled for a tonsillectomy HX of excess bleeding beginning several hours after recent tooth extraction. Epistaxis has been rare and of short duration. Some minor bruising in the past usually after sports. No recent medications. Case #1 Initial Lab Values re-op lab values revealed: rolonged TT = 45 sec (24-38) Normal T = 11.5 sec (10-13) CBC normal except for a plt ct of 95,000 9

10 CAA 2015 Annual Conference Case #1 Lab Workup rolonged TT? Factor VIII level = 36% (50-150) Low platelet ct? VWD type 2B? VWF Ag = 38% (50-150) Rcof = 11% (50-150) Further confirming workup RIA increased Multimers = loss of HMW VWF Multimers von Willebrand Disease Type 3 VWF very low or absent Severe clinical features 10

11 CAA 2015 Annual Conference 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 3 (50-150) VWF Antigen <12 (50-150) Ristocetin R cof. <6 (50-150) VWD... lab tests VIII VWF:Ag RCof Bleeding time VWF multimers Blood group RIA latelet count von Willebrand Disease Diagnosis Repeated testing may be needed Bleeding history important Family history / inheritance Autosomal dominant / recessive 11

12 CAA 2015 Annual Conference Basic Bleeding Work-up CBC w/ platelet ct NL T 11.1 (10-12) TT 43 (31-43) Extra coag tube FVIII c 60 (50-150) VWF Antigen 41 (50-150) Ristocetin (R cof.) 52 (50-150) von Willebrand Disease Treatment DDAV (desmopressin) intranasal or IV Most Type 1 respond, some Type 2, no Type 3 Contraindicated in Type 2B Factor VIII concentrates which include VWF may be needed in some cases Inherited Defects of Coagulation Factors 12

13 CAA 2015 Annual Conference Coagulation Testing (oversimplified) att XII Fibrinogen XI IX VIII VII X V rothrombin Thrombin XIII T Fibrin Clot (not tested by T/TT) Thromboelastograph (TEG) T & TT measures clot initiation 90% of clot dynamics occur after clot initiation Coagulation Testing (oversimplified) Normal T with abnormal TT isolates the problem to these four factors att XII XI IX T VIII VII X V rothrombin Thrombin Fibrinogen Fibrin clot 13

14 CAA 2015 Annual Conference Queen Victoria Hemophilias Classic hemophilia A Factor VIII deficiency Hemophilia B Factor IX deficiency Christmas disease 14

15 CAA 2015 Annual Conference Hemophilia Severity Circulating FVIII or FIX level Normal = % Severe < 1 % Moderate 1-5 % Mild 6-50 % 15

16 CAA 2015 Annual Conference 16

17 CAA 2015 Annual Conference 17

18 CAA 2015 Annual Conference 18

19 CAA 2015 Annual Conference Hemophilia Treatment revent bleeding! Consider prophylactic FVIII or IX (2-3 x wk) Treat bleeding early - replace the missing factor VIII or IX (given IV) Monitor for complications such as orthopedic, viral and inhibitors 19

20 CAA 2015 Annual Conference Hemophilia rophylaxis IV rophylaxis given 2 to 3 times a week can prevent most bleeding episodes Regimen based mostly on half-life Hemophilia Treatment Donor derived factor concentrates in the 70 s and 80 s led to viral complications HBV, HCV, HIV MMWR July 16, 1982 Epidemiologic Notes and Reports neumocystis carinii neumonia among ersons with Hemophilia A Hemophilia Treatment Safer plasma derived concentrates are now used Newer products using recombinant technology New products with a longer half-life DDAV used in mild hemophilia A 20

21 CAA 2015 Annual Conference A Recombinant Technology Mammalian cells are provided with genetic information to produce a target protein. Cell lines may include CHO, BHK, HEK Mammalian CELLS produce a protein rotein is purified Lyophilized product Hemophilia Inhibitors Antibodies inhibitors develop in ~ 20% of persons with severe hemophilia A Antibodies neutralize the infused coagulation factor May require an activated concentrate to control bleeding Coagulation Testing (oversimplified) Normal TT with abnormal T isolates the problem to factor VII att XII XI IX T VIII VII X V rothrombin Thrombin Fibrinogen Fibrin clot 21

22 CAA 2015 Annual Conference Coag Factor Deficiencies Factor VII deficiency Autosomal Rare 1:500,000 Bleeding variable Bleeding does not correlate with level Treat with rfviia Factor XI deficiency Autosomal Rare > 1:100,000 Ashkenazi Jews (8%) Bleeding variable Treat with FF or rviia (No FXI available) Factor Deficiencies Factor XII deficiency Autosomal Rare rolongs the TT but does not result in clinical bleeding Surgery is OK Factor XIII deficiency Autosomal Rare T / TT normal Excess bleeding from umbilical stump Federal Regional Hemostasis & Thrombosis Centers (HTCs) (Hemophilia Treatment Centers) 22

23 CAA 2015 Annual Conference Captain Morgan, The Rescue Dog 23

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