Biology Project

Topic: Haemophilia

Name: Sadia Afreen

Class: 12-A
Gr. No.: 40177
Acknowledgement
I would like to express my special thanks of gratitude
to my teacher Mrs. Arshia Tasneem as well as our
Principal who gave me the golden opportunity to do
this wonderful project on the topic Haemophilia,
which also helped me in doing a lot of Research and I
came to know about so many new things I am really
thankful to them.
I would also like to thank my family for helping me a
lot in finalizing this project within the limited time
frame.
 Certificate
This is to certify that Miss. Sadia Afreen of
Class/Section XII-A has satisfactorily
completed the course of experiments in practical
Class XII prescribed by the CBSE course in the
laboratory of Biology in the year 2020-2021.
 INDEX
 Introduction to
 Coagulation Mechanism
 Bleeding Disorders
 Coagulation Disorders
 Haemophilia A
 Epidemiology
 Pathogenesis
 Symptoms
 Lab Diagnosis
 Treatment
 Complications
 Haemophilia B
 Epidemiology
 Lab Diagnosis
 Treatment and its Complications
 Von Willebrand Disease
 World Haemophilia Day
 HAEMOSTASIS
Blood must be maintained in a fluid state in order to function as a transport system,
but must be able to solidify to form a clot following vascular injury in order to prevent
excessive bleeding, a process known as haemostasis. Successful haemostasis is localised
to the area of tissue damage and is followed by removal of the clot and tissue repair. This
is achieved by complex interactions between the vascular endothelium, platelets,
coagulation factors, natural anticoagulants and fibrinolytic enzymes. Dysfunction of any
of these components may result in haemorrhage or thrombosis.
Haemostasis is achieved by two closely linked processes:
1. Primary haemostasis. This term is used for platelet plug formation at the site of
injury. It is an immediate phenomenon appearing within seconds of injury and is
responsible for cessation of bleeding from microvasculature. Platelets come to play a
central role in normal haemostasis as well as in thrombosis.
2. Secondary haemostasis. This involves plasma coagulation system resulting in
fibrin plug formation and takes several minutes for completion.

Coagulation mechanism is the conversion of the plasma fibrinogen into solid

mass of fibrin. The coagulation system is involved in both haemostatic process and
thrombus formation. The following pathway shows the schematic representation of
the cascade of intrinsic (blood) pathway, the extrinsic (tissue) pathway, and the
common pathway leading to formation of fibrin polymers.
Bleeding Disorders
Bleeding disorders or haemorrhagic diatheses are a group of disorders characterised by
defective haemostasis with abnormal bleeding.
Bleeding may result from abnormalities of:
(1) platelets,
(2) blood vessel walls, or
(3) coagulation.
Platelet disorders characteristically causes bleeding in the form of small haemorrhages
into the skin and mucous membranes (e.g. petechiae, purpura, ecchymoses)
Defective coagulation results in ecchymoses, haematomas, and mucosal bleeding and, in
some disorders, recurrent joint bleeding (haemarthroses).
Coagulation Disorders
The type of bleeding in coagulation disorders is different from that seen in vascular and
platelet abnormalities. Instead of spontaneous appearance of petechiae and purpuras, the
plasma coagulation defects manifest more often in the form of large ecchymoses,
haematomas and bleeding into muscles, joints, body cavities, GIT and urinary tract

Congenital Acquired

Haemophilia A Vitamin K deficiency

Haemophilia B Liver disease

Other disorders:
• DIC
Von Willebrand disease • fibrinogen deficiency
• other factor deficiencies
• massive transfusion

Coagulation factor deficiency may be congenital or acquired, and may affect one or
several of the coagulation factors. Inherited disorders are almost uniformly related to
decreased synthesis, as a result of mutation in the gene encoding a key protein in
coagulation. Von Willebrand disease is the most common inherited bleeding disorder.
Haemophilia A and B are the most common single coagulation factor deficiencies, but
inherited deficiencies of all the other coagulation factors are seen. Haemophilia Is Called
'A Royal Disease' because of occurrence of this disorder in the blood of royal families in
Great Britain and some European countries.
Classic Haemophilia (Haemophilia A)

 Classic haemophilia or haemophilia A is the second most common hereditary

coagulation disorder next to von Willebrand’s disease occurring due to deficiency
or reduced activity of factor VIII (anti-haemophilic factor).
 The disorder is inherited as a sex-(X-) linked recessive trait and, therefore,
manifests clinically in males, while females are usually the carriers.
 The disease has been known since ancient times but Schönlein in 1839 gave this
bleeder’s disease its present name haemophilia.
 The frequency of haemophilia varies in different races, the highest incidence being
in populations of Britain, Northern Europe and Australia.
 As the gene is on the X chromosome, haemophilia A is a sex-linked disorder.
Thus, all daughters of haemophiliacs are obligate carriers and they, in turn, have a
1 in 4 chance of each pregnancy resulting in the birth of an affected male baby, a
normal male baby, a carrier female or a normal female.
o The chances of a proven carrier mother passing on the abnormality to her
children is 50:50 for each son and 50:50 for each daughter.
o A haemophilic father will have normal sons as they inherit his Y
chromosome only that does not carry the genetic abnormality.
 PATHOGENESIS: Haemophilia A is caused by quantitative reduction of factor
VIII in 90% of cases, while 10% cases have normal or increased level of factor
VIII with reduced activity. Factor VIII is synthesised in hepatic parenchymal cells
and regulates the activation of factor X in intrinsic coagulation pathway.
 Factor VIII circulates in blood complexed to another larger protein, von
Willebrand’s factor (vWF), which comprises 99% of the factor VIII-vWF
complex. Normal haemostasis requires 25% factor VIII activity.

 CLINICAL FEATURES: Patients of haemophilia suffer from bleeding for hours

or days after the injury. The clinical severity of the disease correlates well with
plasma level of factor VIII activity. Most symptomatic haemophilic patients have
factor VIII levels below 5%.
o Haemophilic bleeding can involve any organ but occurs most commonly as
recurrent painful haemarthroses (bleeding into joint) and muscle
haematomas (localized bleeding outside of blood vessels), and sometimes
as haematuria (blood in urine).
o Patients with severe haemophilia (< 1% of normal factor VIII levels)
present with spontaneous bleeding into skin, muscle and joints.
o Spontaneous Retroperitoneal and oropharyngeal bleeding and intracranial
haemorrhage are rare features, but when they occur, they are the most
feared complications.
o Babies with severe haemophilia have an increased risk of intracranial
haemorrhage, and it is appropriate to avoid head trauma and to perform
imaging of the newborn within the first 24 hours of life.
 o Individuals with moderate and mild haemophilia (factor VIII levels 1–40%)
present with the same pattern of bleeding, but usually after trauma or
surgery, when bleeding is greater than would be expected from the severity
of the insult.
o The major morbidity of recurrent bleeding in severe haemophilia is
musculoskeletal. Bleeding is typically into large joints, especially knees,
elbows, ankles and hips. Muscle haematomas are also characteristic, most
commonly in the calf and psoas muscles. If early treatment is not given to
arrest bleeding, a hot, swollen and very painful joint or muscle haematoma
develops.

 LABORATORY FINDINGS. The following tests are abnormal:

o 1. Whole blood coagulation time is prolonged in severe cases only.
o 2. Prothrombin time is usually normal.
o 3. Activated partial thromboplastin time (APTT or PTTK) is typically
prolonged.
o 4. Specific assay for factor VIII shows lowered activity.
 o The diagnosis of female carriers is made by the findings of about half the
activity of factor VIII, while the manifest disease is associated with factor
VIII activity below 25%.
o Antenatal diagnosis by chorionic villous sampling is possible in families
with a known mutation.

 TREATMENT:
o Symptomatic patients with bleeding episodes are treated with factor VIII
replacement therapy, consisting of intravenous infusion factor VIII
concentrates or plasma cryoprecipitates. A Factor VIII replacement is also
given before surgical procedure.
o factor VIII concentrates are freeze-dried and stable at 4°C and can therefore
be stored in domestic refrigerators, allowing patients to treat themselves at
home at the earliest indication of bleeding.
o Give factor VIII (e.g., Recombinate) to obtain a 15% (for mild bleeding) to
50% (for severe bleeding) factor VIII level. The duration should range from
a single dose of factor VIII to therapy bid for up to 2 weeks. Dose is
calculated as follows: Factor VIII dose = (Target level - baseline level) ×
weight (kg) × 0.5 unit/kg
o Factor VIII concentrate prepared from blood donor plasma is now screened
for HBV, HCV and HIV, and undergoes two separate virus inactivation
processes during manufacture; these preparations have a good safety record
o In addition to raising factor VIII concentrations, resting of the bleeding site
by either bed rest or a splint reduces continuing haemorrhage. Once
bleeding has settled, the patient should be mobilised and physiotherapy
used to restore strength to the surrounding muscles.
o All non-immune potential recipients of pooled blood products should be
offered hepatitis A and B immunization
o The vasopressin receptor agonist DDAVP raises the vWF and factor VIII
levels by 3–4-fold, which is useful in arresting bleeding in patients with
mild or moderate haemophilia A.
o In addition to treatment ‘on demand’ for bleeding, factor VIII can be
administered 2 or 3 times per week as ‘prophylaxis’ to prevent bleeding in
severe haemophilia. This is most appropriate in children, but its widespread
use is limited by the high cost of factor VIII preparations.
 o Complications of coagulation factor therapy Before 1986, coagulation
factor concentrates from human plasma were not virally inactivated with
heat or chemicals, and many patients became infected with HIV and
hepatitis viruses HBV and HCV. Since 1989, viral inactivation of these
blood products has eradicated the risk of viral infection. Another serious
complication of factor VIII infusion is the development of anti-factor VIII
antibodies, which arise in about 20% of severe haemophiliacs. Such
antibodies rapidly neutralise therapeutic infusions, making treatment
relatively ineffective. Infusions of activated clotting factors, e.g. VIIa or
factor VIII inhibitor bypass activity (FEIBA), may stop bleeding.

 COMPLICATIONS:
o Recurrent bleeding into joints leads to synovial hypertrophy, destruction of
the cartilage and secondary osteoarthrosis.
o Complications of muscle haematomas depend on their location. A large
psoas bleed may extend to compress the femoral nerve;
o Calf haematomas may increase pressure within the inflexible fascial sheath,
causing a compartment syndrome with ischaemia, necrosis, fibrosis, and
subsequent contraction and shortening of the Achilles tendon

Christmas Disease (Haemophilia B)

 Inherited deficiency of factor IX (Christmas factor or plasma thromboplastin
component) which is also present on the X chromosome produces haemophilia B.
 Haemophilia B is rarer than haemophilia A; its estimated incidence is 1 in 100,000
male births.
 Queen Victoria was a carrier of haemophilia B and passed the disease onto three
of her children.
 The inheritance pattern and clinical features of factor IX deficiency are
indistinguishable from those of classic haemophilia
 Accurate laboratory diagnosis is critical since haemophilia B requires treatment
with different plasma fraction. The usual screening tests for coagulation are
similar to those in classic haemophilia but bioassay of factor IX reveals lowered
activity.
  TREATMENT. Therapy in symptomatic haemophilia B consists of infusion of
either fresh frozen plasma or a plasma enriched with factor IX.
o Recombinant factor IX (e.g., Benefix), FFP or factor IX concentrates (e.g.,
Proplex, Konyne). Because of the longer half-life, once-daily treatment is
sufficient. Dose is calculated as follows:
Factor IX dose = (Target level - baseline level) × weight (kg) × 1 unit/kg
 Although factor IX concentrates shared the problems of virus transmission seen
with factor VIII, they do not commonly induce inhibitor antibodies (< 1%
patients); when this does occur, however, it may be heralded by the development
of a severe allergic type reaction.
 Complication of the treatment: hepatitis, chronic liver disease and AIDS, the
replacement therapy in factor IX deficiency may activate the coagulation system
and cause thrombosis and embolism.

von Willebrand’s Disease

 most common inherited coagulation disorder
 incidence: 1:1,000 individuals of either sex.
 autosomal dominant; The gene for vWF is located at chromosome 12.
 primary defect is reduced synthesis or chemically abnormal factor VIII–related
antigen [von Willebrand’s factor (vWF)] produced by platelets and endothelium,
resulting in abnormal platelet function.
World Haemophilia Day

World Haemophilia Day was created by the World Federation of Haemophilia in 1989,
and the date it’s celebrated on, April 17th, was chosen in honor of the founder of the
organization’s birthday, Frank Schnabel.
The day’s purpose is to raise awareness about the disease as well as other bleeding
disorders and also to raise money for the treatment of those who cannot afford it.
Haemophilia affects approximately 400,000 people worldwide, many of whom are not
fully aware of their condition or are not getting the treatment they need. Because a
relatively small percentage of the world’s population suffers from haemophilia, many
people are not aware just how serious this condition is and how much more difficult and
dangerous it makes the lives of those who have it. And this is where World Haemophilia
Day comes in.

Numerous events are organized every year on World Haemophilia day, filled with
educational presentations and other events that promote an awareness of the disease and
those who suffer from it.
 BIBLIOGRAPHY:

th
 Harsh Mohan - Textbook of Pathology, 6 Edition
th
 Robbins – Pathologic Basis of Disease, 7 Edition
th
 Harrison’s Manual of Medicine, 19 Edition
nd
 Davidson’s Principles and Practice of Medicine, 22 Edition
 https://www.daysoftheyear.com/days/world-hemophilia-day/
 Google Images