Faculty of Medicine & Health Sciences,

University Malaysia Sarawak

MEC 1023: INTRODUCTION TO MEDICAL GENETICS

HAEMOPHILIA
Prepared for:

Mr. Ashley Soosay

Prepared by:

NAME MATRIC NO.

SANMUGA A/L VIMALANATHAN 24957

SUGUNA A/P SERAMAN 25175

KAMINI DEVI A/P SIVARAJAH 23714

YOGANANTHAM A/L KODISERAN 25426

1
 TABLE OF CONTENTS

Page

HISTORY 3

INTRODUCTION 3

CAUSES 4

PEDIGREE 5

PUNNETT SQUARE 7

X INACTIVATION 8
RISK FACTORS 9

HAEMOSTASIS 9

SIGN AND SYMPTOMS 11

DIAGNOSIS 12

MANAGEMENT 13

COMPLICATIONS 14

REFERENCES 15

2
History

The history of hemophilia was first discovered by the Jews. They came up with the law that if a
woman had two sons that died from circumcision her third son would not be required to be
circumcised. This shows that they were aware of that women carried the hemophilia gene and
passed it down to their sons. The hemophilia became the royal disease when Queen Victoria was
a carrier and passed the carrier status down to many of her daughters. In those days the royal
families of many of the nations of Europe would marry into each others families. That is why, it
is called a royal disease because it never leaves the royal families. (“Haemophilia”,2008).

However, the first medical professional to describe a disease was Albucasis. It was all based on
those males who died of bleeding after only minor traumas in the tenth century. According to
John Conrad Otto (1803), a hemorrhagic disposition exists in certain families. He also stated that
the disorder is hereditary and is affecting mostly males.

The actual name hemophilia was first recorded at the University of Zurich in 1828. Patek and
Taylor, doctors from Harvard discovered the anti-hemophilic globulin in 1937, and a Buenos
Aires doctor, Pavlosky, discovered hemophilia A and hemophilia B.

Introduction

“Hemophilia is an inheritable disease, usually affecting only males but transmitted by women to
their male children, characterized by loss or impairment of the normal clotting ability of blood so
that a minor wound may result in fatal bleeding”. (Free, 2003)

Generally, hemophilia is a group of hereditary genetic disorder. It is a single gene disorder.

Individual will this disorder will have defect coagulation process that usually occur after injury
to blood vessels.

Coagulation process involves coagulation pathways that involve clotting factors. Individual with
haemophilia disorder have defect in the clotting factors. There are three types of haemophilia
which A, B and C. Haemophilia A is due to defect in factor VIII, haemophilia B is due to defect
in factor IX while haemophilia C is due to defect in factor XI. Haemophilia A is most common.

3
Causes

Haemophilia A and Haemophilia B are inherited in X-linked recessive pattern.

Hemophilia A occurs due to deficiency in factor VIII clotting activity whereas Haemophilia B
occurs due to deficiency in factor IX clotting activity. The deficiencies in both clotting factors
are caused by mutations in X chromosome. Haemophilia A and Haemophilia B are considered
as X-linked inheritance because the genes for the clotting factors VIII and IX are located on the
X chromosome.

A condition is considered X-linked when gene mutation that leads to the disease is
located on the X chromosome. Males have only one X chromosome so one altered copy of the
gene in each cell is sufficient to cause the condition. As females have two X chromosomes, a
mutation must be present in both copies of the gene to cause Haemophilia. Males are affected by
X-linked recessive disorders more frequently compared to females. A major characteristic of X-
linked inheritance is that fathers cannot pass X-linked traits to their sons and so when a male is
affected in X linked inherited diseases, the mutated gene is inherited from the mother. A carrier
female has 50 percent chance of passing on her X chromosome with the gene mutation for
hemophilia A or B to a boy who will be affected and 50 percent chance of passing on her X
chromosome with the normally functioning gene to a boy who will not have hemophilia. So, the
boy will either be normal or affected male and there is no possibility for a male to become a
carrier. (Wikipedia, 2005)

Generally the characteristics of X linked recessive disorder are;

1. Incidence (phenotype) is higher in male than in female

2. Mutant gene transmitted from an affected male through all his daughters (carrier)
3. Mutant gene never transmitted from male-to-male (father to son)
4. Heterozygous female (carrier) are usually phenotypically normal

As for Haemophilia C, it is inherited in an autosomal recessive pattern. This means that the gene
that causes hemophilia C can be passed on to children by either parent and can occur in both
boys and girls. Haemophilia C occurs due to deficiency in factor XI clotting activity. The gene
for factor XI is located on chromosome 4.

4
Generally the characteritcs of autosomal dominat disorder are;

1. Both male and female are affected equally.

2. Only affects individuals in one generation in a single sibship (brother & sister), not
affecting the previous and subsequent generation.
3. The parents of the affected individuals could be consanguineous

Acquired hemophilia is a spontaneous autoimmune disorder caused by autoantibodies

development against plasma coagulation factors, most frequently against FVIII. This leads to
FVIII deficiency.

Pedigree

The following Pedigree explains the X linked recessive pattern

5
The following Pedigree explains the autosomal recessive pattern

6
Punnett Square

The following Punnett Square explains how X-linked recessive inheritance works.

X-linked recessive disorder

A = normal allele
Affected male X Normal female
a = recessive mutant allele
(aXY) (AXAX)

a
X Y

A
A XaX A
XY
X

Carrier female Normal male

A A
X XaX A
XY

Carrier female Normal male

Probability of normal child/offspring : 50%

Probability for male to be normal : 100%

Probability of for female to be a carrier : 100% (phenotypically normal)

7
The following Punnett Square explains how autosomal recessive inheritance works.

Autosomal recessive disorder

Heterozygote (Aa) X Heterozygote (Aa)

A = normal allele
(carrier) (carrier) a = recessive mutant allele

A a

AA Aa
A
normal carrier

a Aa aa
carrier affected

Probability of normal child/offspring : 25%

Probability for carier : 50%

Probability of affected child/offspring : 25%

X Inactivation

A heterozygous female of an X-linked recessive disorder shows the affected phenotype as the
result of “skewed” X-inactivation.

Female has two X chromosomes but this does not mean that there is double dosage of the
genes on X chromosome compared to male. This is due to X inactivation, whereby one of the
two X chromosomes present in female is inactivated.

Skewed X inactivation occurs when there is unbalanced X inactivation. There are two
possibilities on how this can occur. The first possibility is when the paternal X is preferentially
inactivated, resulting in most of the cells carry an active maternal X. The second possibility is

8
when the maternal X is preferentially inactivated, resulting in most of the cells carry an active
paternal X. In all or most of the cells of a zygote, the inactivated X chromosome is the one
carrying the normal allele. In a manifesting heterozygote, the mutant allele is located on the
active X chromosome in all or most of the cells, resulting in a heterozygous female expressing
the affected phenotype of an X-linked recessive disorder. (Carrel, L. & Willard, H., 2005)

Risk factors

Risk factors for hemophilia in general include a family history of bleeding and being male.
Acquired haemophilia may occur concurrently with rheumatoid arthritis, ulcerative colitis,
asthma, psoriasis, cancer and rarely triggered by pregnancy or as a reaction to some medicines

Haemostasis

When there is injury to blood vessels, vasoconstriction occurs. After 1 to 2 minutes, platelets
adhere to the endothelial wall. This is mediated by von Willebrand Factor (vWF). After
adhesion, platelet activation will occur. This is initiated by binding of agonist such as collagen,
thrombin and ADP to platelets and followed by intracellular phosphorylation cascade. This will
result in release of content of granules such as ADP and Ca ion. Activated platelets synthesize
thromboxane A2. After that, platelets aggregation occurs. This is stimulated ADP and
thromboxane A2. Platelet aggregation will form primary haemostatic plug.

Fibrin formation is an important step in haemostasis. Fibrin polymerizes to form cross linked
fibrils that stabilize haemostatic plugs. The chemical reaction that involved in this coagulation
process can be divided into two that are intrinsic and extrinsic pathway. Intrinsic pathway is
initiated by exposure of blood to a number of nonendothelial surfaces such as glass or collagen
of damaged blood vessels. In intrinsic pathway, prekallikrein is converted to kallikrein. This
causes sequential conversion of factor XII, XI and IX to active form. Active form of factor VIII
stimulates active form of factor IX to convert factor X to active form. Extrinsic pathway is
initiated by thromboplastin which is released when there is tissue damage. It activates factor VII.
Tissue factor which is released when there is tissue damage, stimulates active form of factor VII
to convert factor X to active form.

9
In common pathway, activated factor V stimulates activated factor X to covert prothrombin (II)
to thrombin (IIa). Thrombin converts fibrinogen (I) to fibrin (Ia). Lastly, activated factor XIII
stimulates fibrin to polymerize and form cross linked fibrils. (MacFarlane, R.G.,1964)

The following diagram shows the coagulation cascade

10
Sign and symptoms

The clinical features depend on the level of factor that is deficit. Patient with hemophilia will
have severe bleeding following injury or surgery. In severe cases, spontaneous bleeding will
occur. Patient with hemophilia have deficiency in clotting factor. Thus the normal coagulation
cascade is disrupted and fibrin is not formed. Since there is no fibrin, cross linked fibrin is not
formed and haemostatic plug become unstable and rupture. Thus bleeding occurs.

In hemophilia A, there is no factor VIII. Thus, there is no activation of factor X. In hemophilia

B, there is no factor IX. Thus, there is no activation of factor X also. In hemophilia C, there is no
factor XI. Thus there is no activation of factor IX and X. In all types of hemophilia, the defect is
in intrinsic pathway.

Bleeding can cause many problems to our body system. Generally blood loss can cause
weakness. In the cardiovascular and respiratory systems, blood loss can cause hypotension,
tachycardia and dyspnea. Blood loss reduces blood volume which reduces total peripheral
resistance. Thus blood pressure is reduced. When blood volume is reduced, stroke volume is also
reduced. To compensate this, heart rate increases. Thus, tachycardia occurs. Bleeding into lung
may cause obstruction. This causes dyspnea.

In the musculoskeletal system, conditions tingling, cracking, warmth, pain, stiffness, tenderness,
pain with movement, decreased range of motion and refusal to use joint can occur. All these are
caused by bleeding into muscles and joints. Bleeding into joints increases friction between the
articulating bones.

In the gastrointestinal system (GI), upper GI bleding can cause symptoms like hematemesis and
melena while lower GI bleeding can cause symptoms like abdominal pain, bleeding per rectum
and fresh blood in stool.

In the genitourinary system, mainly hematuria will occur. Blood pass through the glomerulus
into the renal tubules and is excreted in the urine.

11
In the central nervous system, sign and symptoms of increased intracranial pressure can occur.
Bleeding in the brain can increase the intracranial pressure. Sign and symptoms of increased
intracranial pressure are headache, nausea and vomiting.

Other symptoms like bruising, epistaxis and hemoptysis.

Diagnosis

A good diagnosis comes from a proper history taking. For patient with bleeding problem, history
such as family history, previous medical problem, drug intake, smoking and alcohol
consumption should be taken.

Next step is physical examination. In physical examination, the patient should be examined from
head to toes. In patient with bleeding disorder, most of symptoms of bleeding will be present.

Then laboratory investigation should be carried out. In patient with bleeding disorder, the
following tests should be carried out;

a) Full blood count and blood film

Full blood count measures the amount of total red blood cell, hemoglobin, hematocrit, total
white blood cell and total number of platelet. This is important to rule of thrombocytopenia
and blood disorder such as leukemia
b) Coagulation test
i) Prothrombin time (PT)
PT measures factor I, II, V, VII and X. Prolonged PT suggests problem in extrinsic
patway
ii) Activated partial prothromboplastin time (aPTT)
aPTT measures factor I, II, V, VIII, IX, X, XI, and XII. Prolonged aPTT suggests
problem in intrinsic pathway
iii) Thrombin time (TT)
TT is used to measure the fibrinogen. Prolonged TT suggests fibrinogen deficiency

12
c) Bleeding time (BT)
BT measures platelet function. Prolonged PT suggests von Willebrand disease
d) Specific assay
Specific assay is carried out to determine the factor that is deficit

Imaging studies such as X-ray is carried out to observe bleeding into joints and CT scan to
observe bleeding into brain.

Management

Bleeding episodes of hemophilia are treated with factor VIII and factor IX for hemophilia A and
B respectively. The amount of factor concentrates needed depend upon the severity of bleeding,
the site of the bleeding, and the size of the patient.

We can also use clotting factors concentrates that is called as recombinant factor which does not
use human blood and immunoaffinity-purified factor preparation, which are heat and solvent-
detergent. Both this treatment can prevent the risk of getting viral infection.

DDDAVP(desmopressin) is an alternative treatment for milder hemophilia . Following the

intravenous administration of this drug, there is a 2-4 fold rise maximum at 30-60 min in the
patient’s own factor VIII by release from endothelial cells. DDAVP may also be taken
subcutaneously or nasally. DDAVP also has an antidiuretic action.

Prophylactic (PRO-fih-lac-tik) therapy is a replacement therapy on a regular basis to prevent

bleeding. Other than that, demand therapy is used when the patients need replacement therapy to
stop bleeding when it occurs. Patients with severe hemophilia is also given leucocytes depleted
plasma and also cryoprecipitate as a last option as both can increase the risk of getting infection.

There are many management of hemophilia such as prehospital care and emergency department
care in which it is responsible to correct the coagulation pathway immediately. Consultations
also should be done when patients present with hemorrhagic complications. Further impatient
care which consist hemostatic and supportive care with appropriate consultation is also needed.
Furthermore, home treatment is needed for patients who frequently facing bleeding

13
complications where they themselves take medications as instructed. There is also complications
that occurs after the treatment. (Dimitrios, P.,2010)

Complications

There are many complications of hemophilia. One of it is hemorrhage. As the factor deficiency
occurs in hemophilia, patients tend to bleed as coagulation pathway is affected. Generally, it
causes weakness and orthostasis.

One of the major complications of hemophilia is joint damage or “hemophilic arthropathy” that
can occur when there is bleeding into joints. This is the most common clinical complication of
hemophilia. Bleeding into knees, elbows, ankles, shoulders, and hips can lead to chronic swelling
and later joint deformity. Joint damage in hemophilic occurs because there are large number of
blood vessels in the synovium so, when there is bleeding in the joint, the synovium absorbs the
blood in an attempt to remove it. When the synovium gets thicker, the more blood vessels it
accumulates and causes bleeding to occur. Furthermore, when there is bleeding, there is an
obstruction which causes renal colic, hematuria and gastrointestinal haemorrhage.

Hemophilic pseudotumors are large encapsulated haematomas with progressive cystic swelling
from repeated hemorrhage. . Patients have tendency to get virally infected for example, Human
immunodeficiency virus (HIV),Hepatitis B virus (HBV),Hepatitis C virus (HCV),Hepatitis A
virus (HAV).Parvovirus B19. (Dimitrios, P.,2010)

14
References
Carrel, L. & Willard, H. (2005). X chromosome. Wikipedia, online, retrieved 17th April 2011,
from http://en.wikipedia.org/wiki/Xchromosome
Dimitrios, P., (2010). Haemophilia. eMedicine, online, retrieved 18th April 2011, from
http://emedicine.medscape.com/article/210104-workup
Haemophilia Information Online (2008). History of Haemophilia, online, retrieved 17th April
2011, from http://www.hemophilia-information.com/history-of-hemophilia.html
MacFarlane, R.G., (1964). "An enzyme cascade in the blood clotting mechanism, and its
function as a biochemical amplifier". Nature 202: 498–9
Otto, J.C. (1803). Haemophilia. Wikipedia, online, retrieved 17th April 2011, from
http://en.wikipedia.org/wiki/Haemophilia
Wikipedia (2011). X chromosome, online, retrieved 18th April 2011, from
http://en.wikipedia.org/wiki/Xchromosome

15