Mild Bleeding Disorder (MBD) and von Willebrand Disease
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- Terence Chambers
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1 Mild Bleeding Disorder (MBD) and von Willebrand Disease Chief of Medicine Rounds August 17, 2010 Michael Linenberger, MD, FACP Professor, Division of Hematology University of Washington
2 Bleeding Concerns in Adults with Normal Hemostasis (self-administered questionnaires) J Thromb Haemost 2007;5(Suppl 1):157
3 Primary Hemostasis Collagen vwf Granule Contents Platelet-Vessel Interactions
4 Secondary Hemostasis X Extrinsic TF VIIa II XIII Fibrin Thrombin Va Xa TF VIIa IXa VIIIa Coagulation Pathways X XIa Intrinsic
5 Suspected Bleeding Disorder 1 o Hemostatic Defect (platelet/vessel wall)_ Mucocutaneous (spontaneous) Immediate after trauma / surgery Petechiae, ecchymosis (> 3 cm) 2 o Hemostatic Defect (coagulation factors)_ Deep tissue / joints Delayed after trauma Ecchymosis, purpura, hematoma, hemarthrosis Consider mixed / multifactorial pathophysiology
6 Suspected Bleeding Disorder Screening Tests for 1 o Hemostasis (1) Platelet count and blood smear Plt satellites on PMNs Large platelets & ITP Chris Lawrence
7 Suspected Bleeding Disorder Screening Tests for 1 o Hemostasis (1) Platelet count and blood smear (2) Platelet function Bleeding time (BT)* * Low sensitivity/specificity (may cause keloid scar) Platelet function analyzer (PFA-100 )** ** Requires platelet ct > 100,000/µL & Hct > 28%
8 PFA Closure Time Plt Function ADP or Epi Collagen Platelet Research Laboratory; Coll/Epi & Normal Coll/ADP Aspirin effect Coll/Epi & Coll/ADP Platelet dysfunction
9 Acquired Platelet Function Disorders Drugs that affect platelet function Aspirin NSAIDs Clopidogrel (ticlopidine) Dipyridamole Abciximab Hetastarch Chronic renal failure (uremia) Intrinsic stem cell disorders Myeloproliferative (P vera, essential thrombocythemia) Myelodysplastic syndrome Cardiopulmonary bypass Dysproteinemias (myeloma)
10 Suspected Bleeding Disorder Screening Tests for 2 o Hemostasis (3) Activated partial thromboplastin time (aptt) (4) Prothrombin time (PT) / INR (5) Thrombin time (TT) or functional fibrinogen
11 Secondary Hemostasis TT PT/INR X Extrinsic TF VIIa II XIII Fibrin Thrombin Va Xa TF VIIa IXa VIIIa Coagulation Pathways X XII XIa appt Intrinsic
12 Normal PT & aptt: Further Evaluation by 1:1 Mix Correction of aptt in incubated 1:1 mixture Deficiency of factor activity level to < 50% Immediate aptt in 1:1 mix Lupus anticoagulant Unfractionated heparin Early correction but aptt at 1 2 hrs Acquired inhibitor (anti-factor VIII >> others)
13 aptt & Correction on 1:1 mix Specific factor deficiency Factor VIII (hemophilia A; X-linked) Factor IX (hemophilia B; X-linked) Factor XI (Ashkenazi; autosomal) von Willebrand disease (2 o to Factor VIII; autosomal) Factor XII (rare; not associated with bleeding) Liver disease (more severe; also PT) Warfarin (also PT)
14 PT/INR & Correction on 1:1 mix Warfarin [rodenticide: PT/INR; persistent] Vitamin K deficiency Malabsorption of fat Malnutrition Chronic antibiotics Antagonism by certain cephalosporins Liver disease (early) Factor VII deficiency (rare)
15 Suspected Bleeding Disorder: Additional Lab Tests aptt with 1:1 mix (incubated for 1-2 hours) von Willebrand disease screen vwf:ag (antigen level) Factor VIII coagulant activity vwf:rco (activity level) Specific factor assays (VIII, IX, XI) Platelet aggregation studies Fibrin degradation products (FDP) or D-dimer
16 von Willebrand Disease (vwd) Defects in 1 o & 2 o Hemostasis (1) vwf mediates plt adhesion: BT / abnl PFA Mucocutaneous bleeding: d with ASA / NSAID (2) vwf is carrier for FVIII: FVIII & aptt Delayed/deep tissue bleed (esp. type 3 vwd) vwd Prevalence: 0.1-1%; F > M; Frequent + FH Ethnic: Rare dx in E. Indians; U.S. blacks whites Mild vwd (< 30 IU/dL): Difficult to dx/confirm Normal vwf varies by ABO type: Type O 75%; AB 123% Ethnic: African/AA vwf:ag 125%, but vwf:rco 100% vwf d by: Stress/exercise, age, pregnancy, estrus May need repeated vwd lab screen w/strong 1 o suspicion
17 Bleeding Assessment Tool for MBD ** ** ** CNS Never Subdural, any intervention Intracerebral, any intervention **Score 1 if no bleeding with at least 2 risk exposures J Thromb Haemost 2006;4:766 J Thromb Haemost 2007;5(Suppl 1):157
18 Diagnosis of vwd in Children J Thromb Haemost 2010;8:950
19 Bleeding Score & Diagnosis of Type I vwd in Adults (N = 295) (N = 144) Female Male Female Male J Thromb Haemost 2006;4:766
20 Bleeding Sx s & Dx of Type I vwd in Affected Relatives J Thromb Haemost 2006;4:766 (N = 273)
21 von Willebrand Disease Diagnosis 1) Personal Hx &/or Family Hx &/or PE evidence of a MBD Bleeding assessment tool &/or targeted questions Exam: Truncal ecchymoses, hematomas, petechiae R/O other dz (telangiectasia, uterine fibroids, spider angiomata) 2) And Lab criteria for vwd (& r/o other disorder) CBC/plt ct PT; PTT; TT or quantitative Fbg level vwd screen (at 1 o visit if strong evidence) [Note: Not BT or PFA] vwf:ag vwf:rco Factor VIII activity Confirmatory testing (specialist) Repeat screen and assess vwf:rco/vwf Ag ratio vwf multimer study Other studies (binding to plts, collagen, FVIII) vwf:ag &/or vwf:rco: < 30 IU/dL vwf:rco/vwf:ag ratio: < (discern Type I from Type II) *NHLBI von Willebrand Disease Expert Panel, NIH Publ # ; 2007; Haemophilia 2008;14:171
22 Von Willebrand Disease Subtypes Type 1 Type 2A Type 2B Type 3 Auto Dom. Auto Dom. Auto Dom. Auto Rec. 80% cases 15% < 5% Rare vwf:ag / vwf:rco < 30 IU/dL: (+) mutation IU/dL: ( ) mutation FVIII; Nl multimer vwf:rco Nl/ FVIII Abnl multimer vwf:rco plt Abnl multimer vwf FVIII DDAVP + (with mild/mod) DDAVP (25% response) DDAVP No! ( Plts) vwf infusion
23 vwd: Management Minor surgery/dental: DDAVP + Amicar DDAVP (IV or nasal): Release of vwf; t ½ = 12 hr Aminocaproic acid (Amicar ): Antifibrinolytic (VTE risk) Mod-high risk surgery/bleeding: Replacement Tx Intermediate-purity factor VIII/vWF concentrates Humate-P or Alphanate SD/HT Cryoprecipitate (if no concentrate) Plt Transfusion Follow: Clinical effect, vwf:rco & FVIII levels NHLBI von Willebrand Disease Expert Panel, NIH Publ # ; Mannucci NEJM 2004;351:683
24 Congenital Bleeding Disorders vwd Frequency ~ 1% (F > M) Hemophilia A FVIII deficiency Hemophilia B FIX deficiency 1 / 5000 males 1 / 25,000 males Genetics AD X-Linked X-Linked Severe (< 1 IU/dL) Frequent, deep Type III 2 / 3 Cases 1 / 2 Cases bleeds from birth Mod. (1-5 IU/dL) Mod + Mild: Mod + Mild: Rare spont; 2 o bleed Most = 1 / 3 Cases 1 / 2 Cases Mild (> 5 IU/dL) Mild (mild carrier 2 o trauma/surgery females)
25 Mild Bleeding Disorders: Menorrhagia & Children with Epistaxis Disorder vwd (mild > mod) Incidence 13-16% (Cauc, +FH) Congenital platelet defect 1-10% FXI deficiency 4% (Ashkenazi) FVIII def (rare hemizygous females) 1-2% No diagnosis 70% Lancet 1998;351:485 Obstet Gynecol 2001;97:630 Blood Coagul Fibrinol 2002;13:89 J Pediatr Hematol Oncol 2002;24:47
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