Haemophilia and VWD for

MS
HAEMOPHILIA
• Three types:
1. Haemophilia A –most common
2. Haemophilia B –less common
3. Haemophilia C -rare
 Haemophilia A
Haemophilia A is an X-linked bleeding disorder
caused by deficient synthesis or synthesis of
dysfunctional factor VIII molecules or a
combination of both
A third has no family history
Occurs 4-6/100,000
It’s the commonest inherited bleeding disorder
after vWD
F8 gene is located on Xq2;8
 pathophysiology is based on insufficient
generation of thrombin by the IXa/VIIIa complex
of the intrinsic pathway
 Haemophilia A

Hamophilic male (XhY)

Carrier female Carrier female
XXh
XXh
Normal
Female
XY XY
XX Normal male Normal male
 Haemophilia A
Normal male (XY)

XXh XhY
Carrier female Haemophilic male
carrier
Female (XXh)

XX XY
Normal female Normal male
 Haemophilia A
All sons of haemophilic males with non-carrier
wives are normal

All daughters of the above couple are obligatory

carriers

Sons of carriers have 50% chance of being

affected

Daughters of carriers have 50% chance of being

carriers if father is normal.
 Haemophilia A
Can result from multiple alterations in the F8
gene:
Gene rearrangements
•Misense mutations
•Nonsense mutations
Abnormal splicing of the gene
•Deletions of all or portions of gene
Insertions of genetic elements
Over 142 mutations noted (as at 2003)
 Haemophilia A
Carrier detection can be as below:
•Family history-maternal uncles, consanguinities

•Carriers usually have 50% or less of factor VIII

levels

•vWF:FVIII is higher in carriers

•Southern blot technique to detect the intron 22

inversion

•Prenatal diagnosis thr’ DNA analysis

Haemophilia in Females
• Homozygous state
• Unfavorable Lyonisation
• Acquired F8 deficiency in pregnancy
 Clinical classification
1. Mild: factor level is 6-30% of normal (0.06-0.3
U/ml); extremely rare spontaneous bleeds,
secondary to trauma or surgery

2. Moderate: factor level is 1-5% of normal

(0.01-0.05 U/ml); occasional spontaneous
bleeds, secondary to trauma or surgery

3. Severe: factor level is ≤ 1% of normal (≤ 0.01

U/ml); spontaneous bleeds from early
infancy, requires factor replacement
 Haemarthrosis:
Accounts for approx 75% of bleeding episodes

Numerous capillaries beneath the synovium

easily damaged

Hinge joints > ball & socket joints

↓ frequency: knees, elbows, ankles, shoulders,

wrists and hips

Occurs when affected child begins to walk

 Haemarthrosis
Heralded by aura of mild discomfort-tingling sensations,
which progresses in minutes-hours to severe pains
Joint swells, warm, limited motion

May experience mild fever

Repeated bleeds destroys the articular cartilage and

leads to synovial hyperplasia

A major complication is joint deformity, associated muscle

atrophy and soft tissue contractures and chronic synovitis
 Haematomas
Characteristic of clotting factor deficiencies

May occur with or without known traumas

May stabilize and slowly resorb

May enlarge progressively and dissect in all

planes compressing vital organs

Bleeding into myocardium is not common

 Neurologic complications
Intracranial bleeds is the most dangerous
haemorrhagic event but uncommon

Spontaneous or following trivial trauma in

severely deficient patients

Suspect if unusual headaches persists

 Immediate factor replacement following

suspicion even before CT scan or MRI

Bleeding into the spinal canal is uncommon, may

produce paraplegia
Other bleeding Features
• Orophareageal
• Haematuria
• Haematomas-serosal spaces
 Lab features
APTT: prolonged

PT: normal
BT: normal
TT: is normal

Factor VIII assay: definitive diagnosis

FVIII antigen is measured by immunologic

assays. If FVIII antigen level is normal and APTT is
prolonged then the patient has dysfunctional
FVIII molecule
 Treatment
Avoid ASA, NSAIDs,

May use acetaminophen, celecoxib, rofecoxib in moderate

doses

Addictive narcotics with caution

IM injections should be avoided

Replacement therapy ASAP

Home treatment facilities

Prophylaxis is now ideal esp for the severely def

Use of tranexamic acid (local application)
 Factor VIII replacement
Several plasma products are available for use to raise VIII
levels

 FFP

Cryoprecipitate

Lyophilized VIII from pooled donors

Plasma-derived VIII produced by monoclonal antibody

techniques

VIII produced by recombinant DNA techniques e.g ADVATE

Porcine VIII is useful in pts with VIII antibodies

 VIII replacement
1 U per ml of plasma is considered 100% of normal

Required dose depends on pt’s plasma volume (approx

5% wt in kg) and the desired level

½ life of VIII is 8-12 hrs

May repeat ½ loading dose in 12hrs

Practically, 1 U per kg body wt raises circulating level by

0.02 U/ml

To achieve 1 U/ml (100%) will require 50 units per kg

body wt
 Bethesda assays for fviii inhibitors

Imidazole
Patient Normal
Buffer
Plasma plasma
(Ph 7.3)

50/50 mix

Incubate
2hr @ 37*C

FVIII assay

Buffered
FVIII
Patient Normal
Deficient
plasma Plasma plasma
Ph 7.4

50/50 mix
Incubate
2 hr @ 37*C

FVIII assay
Treatment of patients with inhibitors of FVIII
induce immune tolerance

porcine FVIII (has low cross-reactivity with human factor VIII

antibody)

FVIII inhibitor-bypassing agents (FEIBA-

factoc 8 inhihibitor byepassing activity),
including FIX complex, activated prothrombin
complex concentrate (aPCC) & activated FVII
plasmapheresis, IVIG, or immunosuppressive therapy with
cyclophosphamide & prednisone

rituximab + prednisone ± mycophenolate mofetil

VON WILLEBRAND
DISEASE
OUTLINE
• INTRODUCTION
• OVERVIEW OF VWF
• EPIDEMIOLOGY
• CLASSIFICATION
• CLINICAL FEATURES
• DIAGNOSIS
• TREATMENT
• PROGNOSIS
• DIFFERENTIALS
INTRODUCTION
• vWD is a bleeding disorder due to qualitative
(functional activity) & or quantitatively deficiency in
vWF and is characterized by prolonged bleeding
• Most common inherited bleeding disorder, but a small
percentage is acquired
• Formally designated as Angiohemophilia, Vascular
hemophilia, Pseudohemophilia, Constitutional throm-
bopathy, & Idiopathic prolonged bleeding time.
History
• First recognised in 1926 among the inhabitant of Aaland
Island
• 1931: Erik von Willebrand described novel bleeding
disorder:
Hereditary Pseudohemophilia
Prolonged BT & normal platelet count
Mucosal bleeding
Both sexes equally affected
• 1950: Prolonged BT was associated with decreased
FVIII
• 1970: Discovery of vWF
• 1980: vWF gene cloned
EPIDEMIOLOGY OF vWD
• Inheritance is autosomal dominant (Type 3 is autosomal recessive)
• About 1% of the population has vWD
• Very wide range of clinical manifestations
• Clinically significant vWD: 125 person per million population
• Severe disease is found in approx 0.5-5 person per million population
• Male & female are equally affected
OVERVIEW OF VWF
• A protein weighing 300-kDa composed of 2813
amino acid which then form multimer up to 106Da
• VWF is the largest glycoprotein circulating in plasma
• Two monomers bind through a disulfide bonds to
form a dimer and several such dimers are seen
• Multiple dimers combine to form vWF multimer
• Produced in endothelial cells and stored in Weibel
Palade bodies & to a lesser degree by megakayocytes
and stored in platelets α-granules
• Only small amount (endothelial source) circulate in
plasma
Functions of vWF
• Mediates adhesion of platelets to site of vascular
injury (links exposed collagen to platelets)
• Mediate platelet to platelet interaction:
• binds GPIb & GPIIb-IIIa on activated platelets
• Stabilizes the hemostatic plug against shear forces
 Protective carrier of FVIII
Release of vWF:

• Constitutive pathway: assembled vWF multimers

released at steady rate from endothelial cells
• Regulatory pathway: stored prior to the release in
the Weibel-Palade bodies from endothelial cells
• Platelet vWF does not contributes significantly to
serum levels, it is released on platelet activation
• Massive release following induction by epinephrine, histamine, &
vasopressin (regulated pathway)
• Chronic elevation is due to increased synthesis, occurs as part of the
“acute phase” response to injuries, inflammation, infection,
neoplasm, pregnancy & hyperthyroidism
Genetics•
A gene on chromosome 12 codes for the synthesis of
the vWF macromolecule.

• Analysis of the amino acid sequence shows

extensive repetition which defines four distinct
domains that are repeated from two to four times
each.
• There are three A-domains, three B-domains, two C-
domains and four D-domains
Classification is based on:
*Either a quantitative deficiency of vWF or functional deficiency of vWF
(qualitative)
Classification
• Quantitative Defect of vWF
• Type 1
• Type 3 (Complete deficiency)
• Qualitative Defect of vWF
• Type 2
• Acquired Defect
Type 1 Variant
• Partial quantitative deficiency of vWF
• vWF levels are usually in the 30 to 50 U/dl range
• Autosomal dominant
• 70% to 80% of vWD
• Mild to moderate dx, but bleeding may increase with
physical trauma or surgery or during menstruation.
• Factor VIII levels are generally equal to, or higher
than, vWF levels
Type 3 Variant
• Total or near total deficiency of vWF
• The most severe form of vWD
• Autosomal recessive disorder
• Makes up about 5% of vWD,
• Rare, with an estimated frequency of 1 in 1 million persons
• This bleeding disorder is generally diagnosed during infancy.
Hematoma formation is common, epistaxis may be life-threatening,
and hemarthrosis may occur owing to the low factor VIII levels that
are seen in this condition
• Plasma from patients with type 3 vWD contains essentially no
detectable vWF, and vWF is not present in either platelets or
endothelial cells.
• The factor VIII level is generally in the 1 to 10 U/dl range, similar to
that seen in moderate to mild hemophilia A
Type 2 Variant
• Qualitative deficiency of vWF
• Mild to moderate dx
• Autosomal dominant
• less common but may represent up to 10 to 15% of cases of vWD
• suspected when the severity of the patient's symptoms seems in
excess of the observed vWF and factor VIII levels
• vWF antigen, FVIII, & multimers analysis are found to be within
normal range
CLINICAL MANIFESTATION
• Most px have little or no symptoms
• For most with symptoms: mild manageable bleeding disorder with
clinically severe hemorrhage only with trauma or surgery
• Type 2 & 3: Bleeding episodes may be severe & potentially life
threatening
• Disease may be more pronounced in female because of menorrhagia
• Bleeding often exacerbated by the ingestion of aspirin
• Severity of symptoms tend to decrease with age due to increasing
amount of vWF
CLINICAL MANIFESTATION
• Epistasis 60%
• Easy bruising/haematomas
• Menorrhagia
• Gingival bleeding
• GI bleeding
• Dental extractions
• Trauma/wounds
• Post-partum
• Post-operative
DIAGNOSIS
• Platelets count is normal
• vWD Screening: PT is normal, APTT usually normal except in type 3
• BT: prolonged
• It lacks sensitivity & specificity
• Subject to wide variation
• Not currently recommended
• PFA100 (plt fxn activity) has now replaced BT
• Direct VWF assay is now possible
APTT
• Mildly prolonged in approx 50% of patients
• Normal PT does not rule out vWD
• Prolongation is secondary to low levels of FVIII

PT:
• Usually within reference range
• Prolongation of both the PT & APTT signal a problem with acquisition
of a proper specimen or a disorder other than or in addition to vWD
Diagnostic Difficuties
• vWF level vary greatly with: physiologic stress, oestrogen,
vasopressin, growth factors, adrenal stimulation
• vWF level may be normal intermittently in patient with vWD
• Measurement should be repeated to confirm abnormal
result
• Repeating test at interval of more than 2weeks is
advisable to confirm or definitively exclude the diagnosis
optimally at a time remote from hemorrhagic events,
pregnancy, infections, strenuous exercise
• vWF level vary with blood type. Individuals with blood
group O have vWF levels that are on average 30% lower
than that of people with blood groups A, B, or AB
• Lab diagnosis rest on:
• Amount of vWF present
• Functional capacity of vWF.
• Investigation to sub classify the pathology is based on
1. FVIII binding
2. Platelet dependent function
3. Collagen-binding function
Diagnosis cont.
• Ristocetin
• Good for evaluating vWF function
• Results are difficult to standardize
• Method:
• Induce vWF binding to GP1b on platelets
• Ristocetin cofactor activity: it measures the aggegationn of metabolically inactive
platelets
• RIPA(Ristocetin-induced platelet aggregation): measures metabolically active platelets
• Aggregometer is used to measure the rate of aggregation
TREATMENT
• The goal of therapy is to correct the dual defect of haemostasis:
1. Abnormal endothelium-platelet adhesion and
platelet-platelet cohesion caused by the deficiency
-abnormality of VWF, and the abnormal intrinsic
coagulation pathway due to reduced circulating level of FVIII
Choice of Treatment Types-2
1. Desmopressin{DDAVP (1-deamino-8-D-arginine vasopressin)}
2. Transfusion therapy with plasma derived FVIII/VWF products
• A test-infusion with
• desmopressin should be given to all patients with clinically relevant
VWD and FVIII/VWF>10 U/dL, especially if elective surgery is planned.
vWD: DDAVP
• Treatment of choice for vWD Type 1
• It is a synthetic analogue of the antidiuretic hormone vasopressin
• Maximal rise of vWF & FVIII is observed in 30-60miniutes
• Typical maximum rise is 2-4 folds for vWF, and 3-6 fold for FVIII
• Hemostatic levels of both factors are usually maintained for at least
6hours
• Effective for some forms of type 2 vWD
• May cause thrombocytopenia in type 2B
• Ineffective for type 3 vWD
• Transfusion therapy with blood products containing FVIII/VWF is at
the moment the treatment of choice in the patients who are
unresponsive to desmopressin.
• Cryoprecipitate: contains FVIII, vWF, FXIII, Fibronectin & Fibrinogen
PROGNOSIS
• Prognosis is very good
• Most patient have a normal lifespan
• The prognosis can depend however, on accurate diagnosis &
approprate treatment
DIFFERENTIALS
• Haemophilia A, B
• Thrombocytopenia
CONCLUSION
• vWD, though not very common is a bleeding disorder caused by
quantitative & or qualitative defect of vWF. It is either inherited or
acquired, causes mild to moderate mucocutaneous bleed. Diagnosis
requires extensive lab test, and treatment entails the use of DDAVP
& or transfusion of FVIII/vWF concentrate. Prognosis is good