Mild Bleeding Disorder (MBD) and von Willebrand Disease

Chief of Medicine RoundsAugust 17, 2010

Michael Linenberger, MD, FACPProfessor, Division of Hematology

University of Washington

Bleeding Concerns in Adults with Normal Hemostasis

(self-administered questionnaires)

J Thromb Haemost 2007;5(Suppl 1):157

Primary Hemostasis

Collagen vWF

GranuleContents

Platelet-Vessel Interactions

Secondary Hemostasis

Thrombin

Coagulation Pathways

FibrinXIII

VIIIa

VIIa

IXa

XIa

TF

XaVa

TFVIIa

X

XExtrinsic Intrinsic

II

Suspected Bleeding Disorder1o Hemostatic Defect__(platelet/vessel wall)_• Mucocutaneous

(spontaneous)• Immediate after

trauma / surgery• Petechiae,

ecchymosis (> 3 cm)

2o Hemostatic Defect__(coagulation factors)_• Deep tissue / joints• Delayed after trauma• Ecchymosis, purpura,

hematoma, hemarthrosis

Consider mixed / multifactorial pathophysiology

Suspected Bleeding DisorderScreening Tests for 1o Hemostasis(1) Platelet count and blood smear

Plt “satellites” on PMNs

Large platelets & ITP http://www.healcentral.org/index.jsp;

©Chris Lawrence

Suspected Bleeding DisorderScreening Tests for 1o 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%

PFA – Closure Time ≈ Plt Function

Platelet Research Laboratory; www.platelet-research.org

CollagenADP or

Epi

↑ Coll/Epi & Normal Coll/ADP → Aspirin effect↑ Coll/Epi & ↑ Coll/ADP → Platelet dysfunction

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)

Suspected Bleeding Disorder

Screening Tests for 2o Hemostasis

(3) Activated partial thromboplastin time (aPTT)

(4) Prothrombin time (PT) / INR

(5) Thrombin time (TT) or functional fibrinogen

Secondary Hemostasis

Thrombin

Coagulation Pathways

FibrinXIII

VIIIa

VIIa

IXa

XIa

TF

XaVa

TFVIIa

X

XExtrinsic Intrinsic

II

PT/INR

TT

aPPT

XII

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)

↑ 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 (2o to ↓ Factor VIII; autosomal)– Factor XII (rare; not associated with bleeding)

• Liver disease (more severe; also ↑PT)• Warfarin (also ↑PT)

↑ 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)

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

von Willebrand Disease (vWD)Defects in 1o & 2o 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 + FHEthnic: Rare dx in E. Indians; U.S. blacks ≈ whites

• Mild vWD (< 30 IU/dL): Difficult to dx/confirmNormal 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 1o suspicion

Bleeding Assessment Tool for MBD

J Thromb Haemost 2006;4:766 J Thromb Haemost 2007;5(Suppl 1):157

CNS Never Subdural, any intervention Intracerebral, any intervention

**Score −1 if no bleeding with at least 2 risk exposures

****

**

Diagnosis of vWD in Children

J Thromb Haemost 2010;8:950

Bleeding Score & Diagnosis of Type I vWD in Adults

J Thromb Haemost 2006;4:766

(N = 144)

FemaleMale

(N = 295)

FemaleMale

Bleeding Sx’s & Dx of Type I vWD in Affected Relatives

J Thromb Haemost 2006;4:766

(N = 273)

von Willebrand Disease Diagnosis1) 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)

*NHLBI von Willebrand Disease Expert Panel, NIH Publ #08-5832; 2007; Haemophilia 2008;14:171

2) And…Lab criteria for vWD (& r/o other disorder)– CBC/plt ct − PT; PTT; TT or quantitative Fbg level– vWD screen (at 1o 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: < 0.5 – 0.7 (discern Type I from Type II)

Von Willebrand Disease Subtypes

Type 1 Type 2A Type 2B Type 3Auto Dom. Auto Dom. Auto Dom. Auto Rec.80% cases 15% < 5% Rare

↓vWF:Ag / ↓vWF:RCo< 30 IU/dL: (+) mutation30-50 IU/dL: ( ) mutation

↓ FVIII; Nl multimer

↓ vWF:RCoNl/↓ FVIIIAbnl multimer

↓ vWF:RCo ↓ pltAbnl multimer

↓ ↓ vWF↓ ↓ FVIII

DDAVP + (with mild/mod)

DDAVP (25% response)

DDAVP – No ! (↓ Plts)

vWF infusion

vWD: Management• Minor surgery/dental: DDAVP + Amicar®

– DDAVP (IV or nasal): ↑ Release of vWF; t½ = 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 levelsNHLBI von Willebrand Disease Expert Panel, NIH Publ #08-5832; Mannucci NEJM 2004;351:683

Congenital Bleeding Disorders

vWDHemophilia A

FVIII deficiencyHemophilia BFIX deficiency

Frequency ~ 1% (F > M)

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 Casesbleeds from birth

Mod. (1 - 5 IU/dL) Mod + Mild: Mod + Mild:Rare spont; 2o bleed Most = 1 / 3 Cases 1 / 2 Cases

Mild (> 5 IU/dL) Mild (mild carrier2o trauma/surgery females)

Mild Bleeding Disorders:Menorrhagia & Children with Epistaxis

Disorder IncidencevWD (mild > mod) 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