The Diagnosis of von Willebrand’s Disease Among Iranian Women with Gynaecological Bleeding...
Preview:
Citation preview
- Slide 1
- 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
- Slide 11
- Genetics 11
- Slide 12
- Type Inheritance 1 Autosomal Dominant 2A Autosomal Dominant
(recessive) 2B Autosomal Dominant 2M Autosomal Dominant (recessive)
2N Autosomal Recessive 3 Autosomal Recessive 12 Genetics
- Slide 13
- 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
- Slide 17
- Function Hemostasis (1) Vascular factors (2) Platelet factors
(3) Plasma factors 17 vWF Molecule
- Slide 18
- Function Hemostasis (1) Vasoconstriction (2) Platelet plug
formation (3) Coagulation 18 vWF Molecule
- Slide 19
- Function 19
- Slide 20
- 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
- Slide 32
- 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
- Slide 35
- Diagnosis Physical exam Ecchymoses, Haematomas, Petechiae
Evidence of liver disease (e.g. jaundice), Splenomegaly Arthropathy
Joint and skin laxity (e.g. Ehlers-Danlos syndrome), Telangiectasia
(e.g. hereditary haemorrhagic telangiectasia), Signs of anemia
Gynaecological examination. 35
- Slide 36
- 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
- Slide 52
- Menorrhagia in women with bleeding disorders
- Slide 53
- Pictorial Blood Assessment Chart score 100 = 80ml blood
- Slide 54
- 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!