algorithmic approach to laboratory testing of von willebrand … · 2018-08-02 · • 20 y/o male...

©2014 MFMER | slide-1 ©2014 MFMER | slide-1

Algorithmic Approach to Laboratory Testing of von Willebrand Disease and

Acquired von Willebrand Syndrome

Dong Chen M.D., Ph.D. Special Coagulation Laboratory

©2014 MFMER | slide-2

DISCLOSURE

No Relevant Financial Relationship(s)


Objectives:

•  Clinical and laboratory features of von Willebrand disease (VWD) and acquired von Willebrand syndrome (AVWS)

•  Algorithmic approach to VWD and AVWS laboratory testing

•  Exemplary cases of VWD and AVWS


VWD – Classification

•  Type 1 and 3 VWD

•  Type 2 VWD

•  Abnormal platelet adhesion: •  2A = selective deficiency of HMW multimers •  2B = increased platelet affinity, secondary loss of HMW multimers •  2M = decreased platelet or matrix binding, no selective deficiency of

HMW multimers

•  Normal platelet adhesion, low factor VIII: •  2N = normal multimers, decreased factor VIII binding

VWD NHLBI Guidelines (2008)

HMW: High molecular weight


AVWS-Associated Diseases Pathophysiologic Category Disease or Association

• Autoimmune: Antibodies to VWF MGUS, lymphoma, autoimmune disorders

• Shear-induced VWF proteolysis (ADAMTS13)

AS/R; MS/R; VSD; LVAD; HOCM; PH

• Thrombocytosis ET; and other MPNs. Blood. 1984 Nov;64(5):981-5.

• Aberrant VWF binding to tumor cells Wilm’s tumor; certain plasma cell or lymphoproliferative disorders

• Decreased VWF synthesis Hypothyroidism

• Drug-related AVWS Ciprofloxacin, valproic acid, hydryoxyethyl starch, griseofulvin

AS/R: aortic stenosis/regurgitation; ET: essential thrombocythemia; MS/R: mitral valve stenosis/regurgitation; HOCM = hypertrophic obstructive cardiomyopathy; LVAD: left ventricular assist device; MGUS: Monoclonal Gammopathy; MPN = myeloproliferative neoplasms; PH: pulmonary hypertension; VSD: ventricular septal defect.

Blood, 1968;31:806-12

NEJM,1958;196

Federici, et al. Thromb Haemost 2000 Kumar, et al. Am J Hem, 2003 Budde, et al. Sem Thromb Hemo, 2002


VWD NHLBI Guidelines (2008) VWD Testing - Laboratory

•  Initial Testing:

•  VWF:Ag; •  VWF:Act (e.g. Ristocetin) and VWF:Act/Ag ratio •  FVIII:C and FVIII/VWF:Ag ratio

•  Additional Testing: •  VWF multimer analysis •  VWF collagen binding activity and VWF:Col/Ag ratio •  VWF FVIII binding activity and VWF:FVIII binding/Ag ratio •  Ristocetin-induced (low concentration, 0.5 mg/mL) platelet aggregation

(RIPA)

VWD NHLBI Guidelines (2008)


Algorithmic Approach to Laboratory Testing of VWD and AVWS

FVIII:C/VWF:Ag

≥0.7 <0.7

VWD 2N Testing

VWF:activity/VWF:Ag ≥0.8 No AVWS Clinical Suspicion

Or AVWS Clinical Suspicion

Modified from Mayo Medical Laboratory VWD Testing Algorithm


Case 1: A Young Patient with Bleeding Diathesis


Patient’s Bleeding History

•  20 y/o male had significant bleeding after oral lesion excision requiring ED visit, surgical consultation and Amicar use.

•  Since childhood – frequent epistaxis, gum bleeding after brushing his teeth.

•  At age of 10 – large lower extremity hematoma after a sport injury

•  At age of 17 – large upper extremity hematomas after trauma

•  At age of 19 – 2 episodes of sport-related injuries resulting in large ecchymoses despite the use of DDAVP nasal spray

•  Physical Exam: Unremarkable.

•  ISTH-BAT score: 8 (normal cutoff: ≤3; Haemophilia. 2014 Nov;20(6):831-5)


Family History

•  Father – significant bleeding after surgery

•  Sister – severe menorrhagia

•  Mother – no abnormal bleeding history


Value Reference Blood type O CBC Normal INR 1.1 APTT 39 26-39 sec PFA-100 COL/EPI 131 78-206 sec FVIII 30 50-149% VWF:RCo 58 55-200% VWF:Ag 47 55-200% VWF:RCo/Ag 1.23 ≥ 0.7 FVIII/VWF:Ag 0.64 ≥ 0.7 VWF Multimer Normal Normal FVIII inhibor screen Negative Negative

Laboratory Results


DDAVP challenge test (0.01% DDAVP nasal spray)

Baseline 1 hour 2 hours 4 hours reference Factor VIII 26 22 22 25 (50-149) VWF:RCo 48 49 47 48 (55-200) VWF Ag 40 40 37 39 (55-200) FVIII/VWF:Ag 0.65 0.55 0.59 0.64 >0.7


Differential Diagnosis

Type 1 VWD in conjunction with

Mild hemophilia A

Type 2N VWD


FVIII/VWF:Ag Ratios

0.7

Leger RR, et al. J Thromb Haemost. 2015 Jun; 13:497


VWF:FVIII Binding Activity (%) %

Leger RR, et al. J Thromb Haemost. 2015 Jun; 13:497


Additional VWD 2N Testing

•  VWF FVIII binding activity: 16% (normal >20%)

•  Genetic test for type 2N VWD: Heterozygous for Arg854Gln


Case Summary and Diagnosis

•  Positive personal and family bleeding history

•  Persistently decreased VWF:Ag and VWF:Act

•  Normal VWF multimer pattern

•  Factor VIII / VWF Ag ratio < 0.7

•  VWF Factor VIII binding assay < 20%

•  Heterozygous for Arg854Gln

Diagnosis: Compound heterozygous type 1 and 2N VWD


Compound Heterozygous Type 1 and 2N VWD: Mayo Clinic Experience

Age/Sex Clinical presentation Blood

type

VWF:Ag (IU/mL) 55-200

VWF:RCo (IU/mL) 55-200

FVIII:C (IU/mL) 55-205

FVIII:C/VWF:Ag

ratio >0.7

VWF:FVIII binding (> 20%)

FVIII binding/ VWF:Ag

2N mutations

Case 1 44 F

Lifelong spontaneous hematomas, menorrhagia and post-surgical bleeding

O 47% 50% 16% 0.34 7% 0.15 Het. Arg854Gln

Case 2 25 F

Extensive bruising, epistaxis, menorrhagia and post-partum bleeding.

A 48% 53% 25% 0.52 Not performed

Het. Arg854Gln

Case 3 19 F Easy bruising and menorrhagia O 14% 15% 10% 0.71 Not

performed

Het. Arg854Gln

Case 4 23 M

Hemarthrosis in his teens and delayed bleeding after tonsillectomy

NA 35% 32% 1 to 12% 0.34 Not performed

Het. Arg854Gln

Case 5 65 M Easy bruising and bleeding after oral surgery

A 41% 29% 31% 0.75 12% 0.29 Het.

Arg854Gln

Case 6 20 M Epistaxis and post-trauma bleeding O 34% 24% 24% 0.71 16% 0.47

Het. Arg854Gln

Modefied from Perez Botero J. et al. Br J Haematol 2016.



FVIII:C/VWF:Ag

≥0.7 <0.7

VWD 2N Testing





Case 2: A Patient with Persistent GI Bleeding


CASE PRESENTATION

§  64 year old, African American male

§  Recurrent overt gastrointestinal bleeding §  7 year history of episodic melena and

occasional bright red blood per rectum §  Received over 50 units of pRBCs

§  EGD/colonoscopy: fern-like vascular ectasia in gastric body, proximal duodenum, cecum, ascending and transverse colon

§  Treated with Argon plasma coagulation several times


CASE PRESENTATION

§  Exertional syncope of 13 years duration §  Orthostatic syncope 7 years prior to presentation, during an

episode of melena §  Diagnosed with obstructive variant of hypertrophic

cardiomyopathy - asymmetric septal hypertrophy

Brockenbrough - Braunwald - Morrow sign

Cardiac Catheterization


Lab Results

§  CBC: Hb 15.1, WBC 7.3, PLT 172 §  PT 13.2 (11.6 - 14.7) §  aPTT 31.7 (22.7 - 36.1)

§  VWF:Ag 159% §  VWF:RCo 116% §  FVIII:C 119% §  VWF:Rco/Ag 0.73 §  FVIII/VWF:Ag 0.75

DIAGNOSIS: Acquired von Willebrand’s Syndrome (AVWS), Type 2


Management

§ Offered cardiac surgery but opted medical treatment § Over the next 12 months - 3 episodes of GI bleeding § Underwent extended septal myomectomy


Cardiac pressure gradient tracings vWF multimers Echocardiogram

PRE-OPERATIVE

POST-OPERATIVE

Patient Control

Patient Control

Brockenbrough - Braunwald - Morrow sign


Diagnosis of AVWS •  Clinical history is crucial in making the diagnosis of AVWS

•  Bleeding onset: new •  Bleeding pattern: typically mucocutaneous, GI or postoperative •  AVWS-associated diseases

•  Abnormal VWF:Ag, VWF:Act and/or multimer patterns •  Type 1 AVWS •  Type 2 AVWS

•  Selective loss of VWF high molecular weight multimers •  VWF:Act/Ag < 0.8: limited sensitivity and specificity



FVIII:C/VWF:Ag

≥0.7 <0.7

VWD 2N Testing





Summary:

•  Clinical and laboratory features of von Willebrand disease (VWD) and acquired von Willebrand syndrome (AVWS)

•  Algorithmic approach to VWD and AVWS laboratory testing

•  Exemplary cases of VWD and AVWS


Thank You

algorithmic approach to laboratory testing of von willebrand … · 2018-08-02 · • 20 y/o male...

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