vin willebrand factor, disease and Hemophilia

Pathophysiology & Management
of-
Haemophilia
Von Willebrand Disease
Presenter- Dr. Shiny
Moderator- Dr. Nidhi Bansal

6
Often called ‘the disease of kings’ because it was carried
by many members of Europe’s royal family.
Queen Victoria of England was a carrier of Hemophilia
HEMOPHILIA

TYPES
Disease Factor deficiency Inheritance
Hemophilia A VIII X linked recessive
Hemophilia B IX X linked recessive
Hemophilia C XI Autosomal recessive
Parahemophilia V Autosomal recessive
7

8
Distribution Clotting factor
activity
Severe hemophilia 50% <1%
Moderate hemophilia 10% 1-5%
Mild hemophilia 30-40% 5-40%
Severity of Hemophilia is defined by measured level of
clotting factor activity

Haemophilia A
• Haemophilia A (classical haemophilia)- most common hereditary coagulation
disorder.
• occurs in approximately 1:10,000 individuals.
• caused by hereditary deficiency or dysfunction of Factor VIII.
• In India, about 1300 haemophilics are born every year and currently there are
about 50,000 patients with severe disease.

Inheritence
• Positive family history is not obtained in about 30% of patients with haemophilia.
These cases probably arise from spontaneous mutation.
• The disease manifests only in males because they lack the complementary normal
X chromosome.
• Majority of female carriers of haemophilia A do not suffer from haemorrhagic
diathesis. This is because F VIII synthesised by complementary gene on the
normal X chromosome is adequate to achieve haemostasis.
• However, haemophilia may develop in carrier females when there is lyonisation
predominantly of normal X chromosomes during embryogenesis or in Turner’s
Syndrome (XO)

Laboratory Features
Coagulation Profile
• Tests for primary haemostasis (platelet count, bleeding time) and for extrinsic and
common coagulation pathway (prothrombin time) are normal.
• The only abnormality in coagulation profile is prolongation of activated partial
thromboplastin time (APTT), i.e. a measure of intrinsic and common pathways.
• Thromboplastin generation test (TGT) is a second-line test and is abnormal
• The combination of normal PT, prolonged APTT, and abnormal TGT are highly
suggestive of F VIII deficiency.

Prenatal analysis
• Two methods of prenatal diagnosis are available—foetal blood sampling and
genotypic analysis.
• Foetal sex is determined by amniocentesis around 14 to 15 weeks of gestation.
• Foetal blood is obtained at 18 to 20 weeks by foetoscopy.
• For genotypic analysis, foetal DNA can be obtained either by amniocentesis (14-15
weeks) or by chorionic villus biopsy (9–12 weeks).
• Various methods of genetic analysis are outlined under “Detection of carriers”.
• Prenatal diagnosis by genetic analysis using chorionic villus sampling is possible in
the 1st trimester while foetal blood sampling can be applied only in the 2nd trimester.

Hemophilia B
• Haemophilia B (also known as Christmas disease) is a hereditary F IX deficiency
state with X-linked recessive mode of inheritance.
• The incidence is about 1:60,000 populations.
• Clinical features and inheritance pattern are similar to haemophilia A.
• It is essential to distinguish between haemophilia A and B in the laboratory
because of different therapeutic products required.

• Coagulation profile shows selective prolongation of activated partial thromboplastin
time (APTT).
• In mild cases APTT may be normal and in such cases if clinical features are
suggestive then specific F VIII and IX assay should be performed (F VIII assay
should always be performed first).
• About 1 to 2% of patients with severe hemophilia B develop inhibitor antibodies
against F IX.

Haemophilia B Leiden: In this form of haemophila B, F IX levels in blood increase
at the time of puberty followed by resolution of bleeding manifestations.
It is seen in 3% of haemophilia B patients and results from specific F IX promoter
mutations.

21
• Bleeding can happen
anywhere in the body.
• Following an
injury / surgery or
rarely spontaneous.
CLINICAL MANIFESTATIONS

22
CLINICAL MANIFESTATIONS
Musculoskeletal bleeding
• Deep bleeding into joints and muscles
• Begin when child reaches toddler age.
• In toddlers ankle the most common
site.
• Later knees and elbow become common sites.

Hemophilia : Diagnosis
• Screening tests
• Normal PT , Raised APTT.
• Definitive diagnosis specific factor VIII or IX by assays

25
Carrier state and Genetic testing
Three approaches:
1. Patient and family history
2. Coagulation-based assays: unreliable
3. DNA testing: GOLD standard
Prenatal diagnosis

Hemophilia: Management
Lifestyle modifications: Goal - Prevention of bleeding.
- Avoid drugs that affect platelet function -NSAIDs
- paracetamol - safe for analgesia.
- Regular exercise to promote strong muscles, protect joints, and
improve fitness.
- Avoid contact sports ; swimming and cycling encouraged.
- Recognize early signs of bleeding - a tingling sensation or “aura”.
- trained to seek treatment at this stage.
- Carry identification indicating the diagnosis, severity, and contact
information .

Hemophilia: Management
Available pharmacological agents
• Factor concentrates
• Cryoprecipitate
• Fresh Frozen Plasma
• Adjuvant Pharmacological Options
• Desmopressin (DDAVP)
• Tranexamic acid
• Epsilon aminocaproic acid (EACA)

Factor VIII Factor IX
•Half-life – approx. 8–12 hours. • About 18-24 hours.
•Each FVIII unit/ per kg i.v. will raise
plasma FVIII level approximately 2%.
• Each FIX unit per kg i.v. will raise
plasma FIX level approx. 0.7 to 1.0%.
•Dose of factor VIII= desired % rise x body
wt (kg) x 0.5
• Dose of factor IX= desired % rise x body
wt (kg) x 1.4
Factor concentrates

Cryoprecipitate
- Prepared by slow thawing of FFP at 4°C for 10–24 hours.
- Contains – FVIII, vWF, fibrinogen, & FXIII (not FIX or XI).
- supernatant - cryo-poor plasma and contains other coagulation factors VII,
IX, X, and XI.
- FVIII /bag of cryoprecipitate is 60-100 units (avg-80 units) in a 30-40 ml vol.
-does not contain factor IX, so no use in Haemophilia B
Concerns :
- factor content of individual packs variable.

Desmopressin
• Only effective in mild hemophilia A - single i.v. infusion
of 0.3 mg/kg expected to boost FVIII level 3-6 fold
• Ineffective in severe hemophilia A
• No value in hemophilia B - does not affect FIX levels
• Nasal spray available - useful for home treatment of
minor bleeding problems.

Tranexamic acid / EACA
• Antifibrinolytic agent, competitively inhibits activation of
plasminogen to plasmin.
• Valuable in controlling bleeding from mucosal surfaces (e.g.,
oral bleeding, epistaxis, menorrhagia)
- dental surgery
- eruption of teeth
• Tranexa dose for children - 25 mg/kg up to three times daily
- 500 mg tablet can be crushed, dissolved in water for
topical use on bleeding mucosal lesions.

Prophylactic Therapy
• Administration of clotting factors at regular intervals to prevent
bleeding
- Patients with clotting factor level > 1% seldom have
spontaneous bleeding
• 25-40 IU/kg of clotting factor concentrates
- 3 times/week for hemophilia A
- twice a week for hemophilia B
• Expensive but preservation of joint function & improved QOL
• Administered by subcutaneous access port of central line

Normal Von Willebrand Factor
• The vWF gene is located on chromosome 12.
• The basic mature vWF molecule is a monomer composed of 2050 amino acids.
• vWF monomers associate with each other through disulphide bonds to form
multimers of varying sizes.
• The large multimers of vWF are more effective in haemostasis as they have greater
binding sites for mediating adhesion of platelets to subendothelium.
• Most of the vWF is synthesised by endothelial cells from where they are secreted
constitutively or are stored in Weibel-Palade bodies for later secretion.

• In megakaryocytes vWF is stored in a granules and is secreted when platelets
are activated.
• Soon after their secretion into the blood, vWF multimers are cleaved by the
metalloprotease ADAMTS13 (A Disintegrin And Metalloprotease with
Thrombospondin type 1 motif 13).
• ADAMTS13 cleaves a site within the A2 domain of vWF.
• In thrombotic thrombocytopenic purpura, degradation of large vWF multimers
does not occur due to deficiency of ADAMTS13.
• In plasma, vWF and F VIII circulate as a non-covalently bound complex.

Major Function of vWF
Haemostasis–
(i) vWF
mediates adhesion of platelets to subendothelium by binding to platelet glycoprotein
receptor Gp Ib (and also to Gp IIb/IIIa when platelets are activated) and
subendothelium;
and
(ii) vWF forms a noncovalent complex with F VIII in circulation and serves to
prevent the degradation and rapid removal of F VIII from circulation.

Von Willebrand disease
• is a markedly heterogeneous congenital bleeding disorder characterised by
deficiency or functional defect of vWF.
• most common congenital bleeding disorder with overall prevalence in the general
population being 1%.

• For mild mucous membrane bleeding, antifibrinolytic agents tranexamic acid can
be used.
• For significant bleeding, two treatment options in vWD are desmopressin and
plasma-derived F VIII concentrate rich in high molecular weight multimers or
cryoprecipitate.
• Desmopressin or 1-deamino-(8-D-arginine)- vasopressin (DDAVP), a synthetic
vasopressin analogue, is the treatment of choice in type 1 vWD. (iv/nasal spray)
• Desmopressin raises vWF and F VIII:C levels by stimulating their release from
storage sites. It is not much effective in vWD types 2A and 3.

• Desmopressin is contraindicated in type 2B as it aggravates thrombocytopaenia.
• Plasma-derived F VIII concentrate rich in vWF or cryoprecipitate is the treatment
of choice in those cases not responsive to desmopressin such as type 2 variant and
type 3 vWD.
• In platelet-type vWD, platelet concentrates may be tried as both desmopressin and
cryoprecipitate can induce thrombocytopaenia.

References
• Essentials of Hematology- Kawathalkar 2nd edition
• World Federation of Hemophilia guidelines 2021
• https://www.slideshare.net/vardhanbobby/von-willebrand-disease-232841948
• https://www.slideshare.net/derosaMSKCC/vwd

vin willebrand factor, disease and Hemophilia

In this document