The Diagnosis of von Willebrand’s Disease Among Iranian Women with Gynaecological Bleeding...
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The Diagnosis of von Willebrand’s Disease Among Iranian Women with Gynaecological Bleeding Baghaipour Mohammad Reza, MD, Pediatrician, Hemophilia Fellow
The Diagnosis of von Willebrands Disease Among Iranian Women
with Gynaecological Bleeding Baghaipour Mohammad Reza, MD,
Pediatrician, Hemophilia Fellow
Slide 2
history 2
Slide 3
Dr Erik von Willebrand 3 1870-1949 history
Slide 4
4
Slide 5
5
Slide 6
Bleeding from mucosal tissues Significant bleeding in women
Prolonged BT No X linked inheritance 6
Slide 7
1926 1928 1951 1964 1971 1973 1977 First description by Erik
von Willebrand 5 patients described in Boston by Minot Cross
transfusion by HA plasma in vWD Pools cryoprecipitate in vWD
Immunologic difference of HA and vWD Synthesis of vWF by cultured
EC First report on the use of DDAVP in vWD history 7
Slide 8
1981 1982 1984 1985 1992 1994 2002 2007 Introduction of Haemate
P in the market Epidemiology of vWD in general population 1 st
classification based on multimer Discovery of vWF gene by four
laboratories First PK trials with FVIII/vWF concentrates 2 nd
Classification based on pathogenesis National guidelines for vWD
management Molecular & clinical markers of vWD type 1 history
8
Slide 9
Genetics vWF gene is located near the tip of the short arm of
chromosome 12, at 12p13.3 approximately 178 kb of DNA and contains
52 exons. Mutations causing vWD have been identified throughout the
vWF gene ( >500 mutations) good correlation between the location
of mutations in the vWF gene and the subtype of vWD 9
Slide 10
The von Willebrand factor (vWF) protein sequence (amino acid
12813) is aligned with the cDNA sequence (nucleic acid 18439). The
vWF signal peptide is the first 22 aa, the propeptide (vWFpp) aa
23763, and mature vWF aa 7642800. Type 2 mutations are primarily
located in specific domains (regions) along the vWF protein. Types
2A, 2B, and 2M vWF mutations are primarily located within exon 28
that encodes for the A1 and A2 domains of vWF. The two different
types of 2A are those that have increased proteolysis (2A2) and
those with abnormal multimer synthesis (2A1). Type 2N mutations are
located within the D and D3 domains. Ligands that bind to certain
vWF domains are identified, including FVIII, heparin, GPIb
(platelet glycoprotein Ib complex), collagen, and GPIIb/IIIa
(platelet glycoprotein IIb/IIIa complex that binds to the RGD
[arginine-glycine-aspartate] amino acid sequence in vWF). Genetics
10 Adams13
vWF Molecule Vascular endothelium Stored in secretory granules
(Weibel-Palade bodies) Released by stress or DDAVP Bone marrow
megakaryocyte Stored in alpha-granules Released by platelet
activation. DDAVP does not release platelet vWF 13 Endoplasmic
Reticulum Dimerization Golgi Apparatus Multimerization
Slide 14
14 vWF Molecule
Slide 15
Plasma vWF has a half-life of approximately 12 hours (range 915
hours). vWF is present as very large multimers that are subjected
to physiologic degradation by ADAMTS13 ADAMTS13 TTP ADAMTS13 Type
2A 15 vWF Molecule
Slide 16
vWF blood level Blood type O (25%) Hypothyroidism Valproate Old
age African-American black Exercises, Surgery, Trauma Pregnancy
Hyperthyroidism Renal failure Diabetes Liver disease
Atherosclerosis Inflammatory state and cancer 16 vWF Molecule
A3 Collagen A1 Gp I b C1 Gp II b III a A2 ADAMS 13 Fibrinogen
Gp II b 20 vWF Molecule Function
Slide 21
Platelet to exposed sub-endothelium (collagen & GPIb )
Platelet to platelet ( GP IIb/IIIa ) Carry FVIII ( protect from
proteolysis) 21 vWF Molecule
Slide 22
1984 ( Multimer Based ) 22 Classification
Slide 23
1994, 2006 ( Pathogenesis Based ) 23 Classification
Slide 24
Type 1 Level of vWF in plasma is low. vWF mediates platelet
adhesion and binding FVIII normally. FVIII is normal or mildly
decreased. vWF multimer gels are normal. 24 Classification
Slide 25
Type 2 A Platelet adhesion is decreased because the proportion
of large vWF multimers is decreased. Levels of vWF:Ag and FVIII may
be normal or modestly decreased. vWF:Rco is markedly decreased. 25
Classification
Slide 26
Type 2 B Mutations increase plateletvWF binding and leads to
the proteolytic degradation and depletion of large vWF multimers.
Patients have thrombocytopenia that is exacerbated by surgery,
pregnancy, or other stress. RIPA is increased at low concentrations
of ristocetin. 26 Classification
Slide 27
Type 2 M Reduced interaction of vWF with platelet GPIb or with
connective tissue. Screening laboratory results are similar with
type 2A vWD and the distinction between them depends on multimer
gel electrophoresis. 27 Classification
Slide 28
Type 2 N Impaired binding to FVIII, lowering FVIII levels. Type
2 N masquerade as an autosomal recessive H.A. The FVIII level is
low but vWF:Ag and vWF:Rco are normal. Discrimination from
hemophilia A needs FVIIIvWF binding assay. 28 Classification
Slide 29
Type 3 Type 3 vWD is characterized by undetectable vWF protein
and activity, and FVIII levels usually are very low. 29
Classification
Slide 30
vWD, the most frequent inherited bleeding disorder. 1% of
General population Clinically significant patients = 100-200 /
milion Mild form thought to be healthy 30 Epidemiology
Slide 31
vWD sub/type prevalence: Type 1, 55- 75 % Type 2, 10- 30 % Type
3, 5 20 % ( 0.5 6 / million ) 31 2A2B2M2M 2N France3028834
Italy1714663 Germany7410133 Average30 10
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Epidemiology Non X-linked Disorder ( F M ) Type 1, 60% F Type
2, 55% F Type 3, 50% F 32
Slide 33
Diagnosis Family History Patient medical history Physical exam
Laboratory findings Genetics 33
Slide 34
Diagnosis Family History Although a positive family history of
documented vWF is useful for diagnosis of vWD, such a history is
frequently not present. But a family history of bleeding symptoms
is not helpful. 34
Common Bleedings Nose 60% ( common in kids ) Gyn/Obs 60% ( 15%
have vWD ) Teeth 50% Ecchymosis 50% Post surgical 25% GI Tract 15%
Musculoskeletal 10% ( type 3 ) 36 Diagnosis
Slide 37
Mild bleeding symptoms are very common in healthy populations.
Menorrhagia has good sensitivity but low specificity. Three
findings that predict abnormal menstrual blood loss of >80 mL
include: Clots greater than approximately 1 inch in diameter Low
serum ferritin Changing a pad or tampon more than hourly. 37
Diagnosis
Slide 38
Bleeding Score The bleeding symptoms are very Important. The
bleeding score (BS) is a quantitative index summarizing both the
number of episodes and their severity. The BS has shown good
sensitivity and specificity for the diagnosis of type 1 VWD. 38
Diagnosis
Slide 39
Bleeding Score 39 Diagnosis Rodeghiero et al,2005 A score of
>3 in a male or >5 in a female is 99% specific and 64%
sensitive in identifying obligate carriers of VWD.
Slide 40
40 Diagnosis Tosetto A,et al,2006 Bleeding Score
Slide 41
41 Diagnosis Bleeding Score Tosetto A,et al,2006 Positive BS (4
or more) has a sensitivity of 100% and a specificity of 87%. The
positive predictive value is 0.20 and the negative predictive value
is 1.
Slide 42
42 Diagnosis
Slide 43
DDAVP : release endogenous VWF stores through stimulation of
endothelial cells Plasma-derived, viral-inactivated concentrates.
Agents that promote hemostasis and wound healing but do not
substantially alter the plasma concentration of VWF. 43
Treatment
Slide 44
DDAVP: 0.3 g/kg, IV, (3050 mL of N/S) over 30 min, peak
increments of FVIII and VWF 30 to 90 min post infusion. Sub
cutaneous way is usually identical to IV. Nasal DDAVP ( Simate, 150
micro/g / dose ) >50 kg: 2 puffs 44 Treatment
Slide 45
DDAVP: Use with caution: Under 3 years vWD type1 with low PLT
vWD type 3 vWD type 2B ( some physicians recommend DDAVP) Pseudo
platelet vWD Older age with atherosclerosis Uremia Major surgery (
long term prophylaxis is needed ) Several doses Brain, ocular, and
coronary artery surgeries 45 Treatment
Slide 46
DDAVP: Complications: Headache Flushing Tachycardia Water
intoxication ( only maintenance fluid for 24h) DVT MI Release of
tPA ( anti fibrinolytic agents ?) 46 Treatment
Slide 47
Cryoprecipitate Each bag contains about 100 IU vWF Virally non
safe Volume overload Not available always Immunological reaction
Not reliable response 47 Treatment
Slide 48
Replacement Therapy 48 Treatment
Slide 49
Replacement Therapy 49 Treatment
Slide 50
Other Therapies Antifiibrinolytic agents Aminocaproic acid
(25-50 mg/kg/dose QID )and Tranexamic acid (5-10 mg/kg/dose TDS),
PO or IV or topically in oral cavity. DIC and U.T bleeding are
contraindications. Topical agents Topical bovine thrombin Fibrin
sealant Topical collagen sponges Women Bleedings OCP, IUD,
hysterectomy 50 Treatment
Slide 51
Other therapies Platelet transfusion : may control bleeding
that is non- or poorly responsive to replacement therapy with VWF
concentrate. 51 Treatment
Women with inherited bleeding disorders 116 women studied at
Royal Free Hospital 66 vWd 30 carriers of hemophilia 20 with factor
XI deficiency
Slide 55
Prevalence rates of von Willebrand disease in 988 women
presenting with menorrhagia 13% (5-24%)
Slide 56
Frequency of inherited bleeding disorders in women with
menorrhagia 12% general gynecology referrals are for menorrhagia
150 women with PBAC score > 100 Frequency of VWD 13% compared
with 0.1 to 1% in the normal population
Slide 57
The frequency of bleeding symptoms in the normal population
compared with 264 Scandinavian patients with VWD
Slide 58
Predictive value of bleeding symptoms in diagnosis of type 1
VWD
Slide 59
< 10% 10-30% 30-50% Type 1 Type 2 Type 3 RCof: VWD 0.82%
(480.000 patients?)
Slide 60
Please Reffer : Women with menorrhagia whom surgical and
Endocrinal abnormalities have been ruled out. Thank you for your
attention!
