von Willebrand’s Disease The Diagnosis of von Willebrand’s Disease Among Iranian Women with Gynaecological Bleeding Baghaipour Mohammad Reza, MD, Pediatrician, Hemophilia Fellow
history Dr Erik von Willebrand • 1870-1949
history • Bleeding from mucosal tissues • Significant bleeding in women • Prolonged BT • No X linked inheritance
history 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 Pool’s 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 Introduction of Haemate P in the market Epidemiology of vWD in general population 1st classification based on multimer Discovery of vWF gene by four laboratories First PK trials with FVIII/vWF concentrates 2nd Classification based on pathogenesis National guidelines for vWD management Molecular & clinical markers of vWD type 1 1981 1982 1984 1985 1992 1994 2002 2007
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
Genetics ↑ Adams13 The von Willebrand factor (vWF) protein sequence (amino acid 1–2813) is aligned with the cDNA sequence (nucleic acid 1–8439). The vWF signal peptide is the first 22 aa, the propeptide (vWFpp) aa 23–763, and mature vWFaa 764–2800. 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 Type Inheritance 1 Autosomal Dominant 2A Autosomal Dominant (recessive) 2B Autosomal Dominant 2M Autosomal Dominant (recessive) 2N Autosomal Recessive3 Autosomal Recessive
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 • Endoplasmic Reticulum • Dimerization • Golgi Apparatus • Multimerization
vWF Molecule • Plasma vWF has a half-life of approximately 12 hours (range 9–15 hours). • vWF is present as very large multimers that are subjected to physiologic degradation by ADAMTS13 • ADAMTS13 TTP • ADAMTS13 Type 2A
vWF Molecule 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
vWF Molecule Function • Hemostasis • (1) Vascular factors • (2) Platelet factors • (3) Plasma factors
vWF Molecule Function • Hemostasis • (1) Vasoconstriction • (2) Platelet plug formation • (3) Coagulation
vWF Molecule Function
vWF Molecule Function • A3 Collagen • A1 Gp I b • C1 Gp II b III a • A2 ADAMS 13 • Fibrinogen Gp II b
vWF Molecule Exposed sub- endothelium Collagen vWF Platelet GPIb GPIIb/IIIa Function • Platelet to exposed sub-endothelium (collagen & GPIb ) • Platelet to platelet ( GP IIb/IIIa ) • Carry FVIII ( protect from proteolysis)
Classification 1984 ( Multimer Based )
Classification 1994 , 2006 ( PathogenesisBased )
Classification 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.
Classification 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.
Classification Type 2 B • Mutations increase platelet–vWF 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.
Classification 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.
Classification 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 FVIII–vWF binding assay.
Classification Type 3 • Type 3 vWD is characterized by undetectable vWF protein and activity, and FVIII levels usually are very low.
Epidemiology • vWD , the most frequent inherited bleeding disorder. • 1% of General population • Clinically significant patients = 100-200 / milion • Mild form thought to be healthy
Epidemiology • vWD sub/type prevalence: • Type 1 , 55- 75 % • Type 2 , 10- 30 % • Type 3 , 5 – 20 % ( 0.5 – 6 / million )
Epidemiology • Non X-linked Disorder ( F ═ M ) • Type 1, 60% F • Type 2, 55% F • Type 3, 50% F
Diagnosis • Family History • Patient medical history • Physical exam • Laboratory findings • Genetics
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.
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 haemorrhagictelangiectasia), • Signs of anemia • Gynaecological examination.
Diagnosis 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 )
Diagnosis • 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.
Diagnosis 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.
Diagnosis Bleeding Score 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.
Diagnosis Bleeding Score TosettoA,et al,2006
Diagnosis Bleeding Score TosettoA,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.
Treatment • 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.
Treatment DDAVP: • 0.3 µg/kg , IV, (30–50 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
Treatment 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
Treatment DDAVP: • Complications: • Headache • Flushing • Tachycardia • Water intoxication ( only maintenance fluid for 24h) • DVT • MI • Release of tPA ( anti fibrinolytic agents ?)
Treatment Cryoprecipitate • Each bag contains about 100 IU vWF • Virally non safe • Volume overload • Not available always • Immunological reaction • Not reliable response
Treatment Replacement Therapy
Treatment Replacement Therapy
Treatment Other Therapies • Antifiibrinolytic agents • Aminocaproicacid (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