Haemophilia

Definition

Haemophilia is a rare bleeding disorder in which the blood doesn't clot

normally. If people have haemophilia, they may bleed for a longer time than others
after an injury. They also may bleed inside the body (internally), especially in their
knees, ankles, and elbows. (National Heart, Lung, and Blood Institute, 2013)

Haemophilia usually is inherited. Inherited means that the disorder is passed

from parents to children through genes. People born with haemophilia have little or
no clotting factor. Clotting factor is a protein needed for normal blood clotting.
There are several types of clotting factors. These proteins work with platelets to
help the blood clot. The two main types of haemophilia are A and B. The people
that suffer haemophilia A, they are missing or have low levels of clotting factor
VIII (8). If they suffer haemophilia B, they are missing or have low levels of clotting
factor IX (9). (National Heart, Lung, and Blood Institute, 2013)

Haemophilia A

Background

Haemophilia A, also called factor VIII (FVIII) deficiency or classic

haemophilia, is a genetic disorder caused by missing or defective factor VIII, a
clotting protein. It is an inherited, X-linked, recessive disorder that results from a
new mutation or an acquired immunologic process. (Drelich, 2017)

Aetiology

The gene for haemophilia is carried on the X chromosome. Haemophilia is

inherited in an X-linked recessive. Chromosomes come in pairs. Females have two
X chromosomes, while males have one X and one Y chromosome. Only the X
chromosome carries the genes related to clotting factors. A male who has a
haemophilia gene on his X chromosome will have haemophilia. When a female has
a haemophilia gene on only one of her X chromosomes, she is a "haemophilia
carrier and can pass the gene to her children. (National Heart, Lung, and Blood
Institute, 2013)
 Below are two examples of how the haemophilia gene is inherited.

(National Heart, Lung, and Blood Institute, 2013)

The father doesn't have haemophilia (the father has two normal chromosomesX
and Y). The mother is a carrier of haemophilia (the mother has one haemophilia
gene on one X chromosome and one normal X chromosome).
 (National Heart, Lung, and Blood Institute, 2013)

The father has haemophilia (the father has the haemophilia gene on the X
chromosome). The mother isn't a haemophilia carrier (the mother has two normal
X chromosomes).

The factor VIII gene in the X chromosome, with inversion and crossover,
causes a disruption in the normal factor VIII coding sequence, with an inability to
transcribe the complete, normal factor VIII protein, resulting in a loss of function.
Inadequate factor VIII results in the decreasing of thrombin by the FIXa and FVIIIa
complex, which is the intrinsic pathway of the coagulation cascade. This
mechanism, in combination with the effect of the tissue-factor pathway inhibitor,
creates a tendency for impaired clotting in response to trauma and, especially in
persons with severe haemophilia, with spontaneous bleeding. (Drelich, 2017)
 Severity

Haemophilia is classified as mild, moderate, or severe depending on the

amount of the clotting factor in a persons blood.2,3 The normal range of FVIII and
FIX is between 50% and 150%. Haemophilia severity is classified as follows:

Severity Blood clotting factor level

Normal 50%-150%

Mild haemophilia 6%-49%

Moderate haemophilia 1%-5%

Severe haemophilia <1%

(Indiana Hemophilia and Thrombosis Center, n.d.)

In mild haemophilia (6% to 49% factor activity), bleeding occurs only

after injury, trauma, or surgery. About 25% of the haemophilia
population has mild deficiency.

In moderate haemophilia (1% to 5% factor activity), bleeding occur

after minor injuries, though spontaneous bleeding episodes (i.e., without
obvious cause) may occur. About 15% of the haemophilia population has
moderate deficiency.

Persons with severe haemophilia (<1% factor activity) may experience

not only bleeding after injury, trauma, or surgery, but also spontaneous
bleeding into joints and muscles. Recurrent bleeding into joints can cause
haemophilic arthropathic, a joint disease that results in physical disability
at a young age. About 60% of the haemophilia population has severe
factor deficiency. (De Gruchy, 1989)

Signs and Symptoms

Wound bleeding is the characteristic of all haemophiliacs. It is slow and

persists for days to weeks. The onset of bleeding maybe immediate (in severe
haemophilia) or delayed for hours or even days (in mild haemophilia). After the
haemostasis occurred, recurrence of bleeding particularly common.

Tissue bleeding. Spontaneous bleeding may occur in almost every tissue of

the body. It occurs frequently in severe haemophilia, infrequently in moderate
haemophilia, or rare in mild haemophilia. Injuries causing contusion, ligamentous
strains, or rupture of muscle fibres. Bleeding in the tissues causes the formation of
haematomas. The size of haematomas and the complications which arise can be
treated by replacement therapy.

Skin bleeding. The skin has tendency to bruise after a little injury in most of
haemophiliacs, and especially for mild and severe haemophilia, they could get
spontaneous bleeding into the skin and subcutaneous tissues.

Mouth and nose. Bleeding from the lacerations of the tongue and the upper
lip is common in children.

Synovial joints. Patients with severe haemophilia suffered recurring

haemorrhage into joint spaces. Hemarthroses may occur spontaneously, but usually
result from joint strain or a direct injury. The pain and disability of hemarthrosis
depend on the rapidity and duration of bleeding. In infants, the ankle joints are most
commonly affected, but in older children and adults the knees are most involved.
The next common in the elbows and the shoulder, wrist, hip, and finger joints are
less frequently. At first, the bleeding causes tightness in the joint with no real pain
or any visible signs of bleeding. The joint then becomes swollen, hot to touch, and
painful to bend. Then, the movement in the joint is temporarily lost. Pain can be
severe

Central nervous system. Intracranial haemorrhage, in children with severe

haemophilia, it occurs mostly after head injury. But in adults it occurs
spontaneously. It causes painful headaches, repeated vomiting, sleepiness, sudden
weakness, double vision and seizures. (De Gruchy, 1989) (National Heart Lung and
Blood Institue, 2013)
 Diagnosis

Clinical and hereditary features. The clinical features of most importance are
the sex, the age of onset, and the type of bleeding. The hereditary feature is
important in evidence of sex-linked recessive inheritance. As the hereditary aspects
are so important, a detailed family history must be taken and a family tree drawn
for accurate reference. (De Gruchy, 1989)

Laboratory findings. Haemophilia is diagnosed precisely by taking a blood

sample and measuring the level of factor activity in the blood. Haemophilia A is
diagnosed by testing the level of factor VIII activity. Haemophilia B is diagnosed
by measuring the level of factor IX activity. Beside those factors, the measuring of
Activated partial thromboplastin time (APTT) considered to make the diagnosis
more precise. And the results of clinical finding, hereditary features, and laboratory
findings are as follows for both Haemophilia A and B. (Hoffbrand and Moss, 2016)

Haemophilia A Haemophilia B

Inheritance Sex-linked Sex-linked

Main sites of Muscle, joints, post- Muscle, joints, post-

haemorrhage trauma, or postoperative trauma, or postoperative

Platelet count Normal Normal

PFA-100 Normal Normal

Prothrombin Time Normal Normal

Partial thromboplastin
Prolonged Prolonged
time

Factor VIII Low Normal

Factor IX Normal Low

(Hoffbrand and Moss, 2016)

 Treatment

Replacement therapy. Bleeding episodes are treated with factor VIII

replacement therapy, and spontaneous bleeding is usually controlled if the patients

factor VIII level is raised to 3050% of normal. For major surgery, serious post

traumatic bleeding or when haemorrhage is occurring at a dangerous site, the factor

VIII level should be elevated to 100% and then maintained above 50% when acute

bleeding has stopped, until healing has occurred. 1Diamine8Darginine

vasopressin (DDAVP; desmopressin) provides an alternative means of increasing

the plasma factor VIII level in milder haemophiliacs. Following the intravenous

administration of this drug, there is a two to fourfold rise maximum at 3060

minutes in the patients own factor VIII by release from endothelial cells. DDAVP
may also be taken subcutaneously or nasally.

Prophylactic treatment. Prophylaxis is the regular infusion of clotting factor

concentrates to prevent bleeding. The idea of prophylaxis came from the
observation that people with moderate or mild haemophilia (who have clotting
factor levels of 1% or more) rarely experience spontaneous bleeding. They also
have less joint damage than people who have severe haemophilia (World Federation
of Hemophilia, 2014).

Haemophilia B

The inheritance and clinical features of factor IX deficiency (Christmas

disease, haemophilia B) are identical to those of haemophilia A. Indeed, the two
disorders can only be distinguished by specific coagulation factor assays. The

incidence is onefifth that of haemophilia A. Factor IX is coded by a gene close

to the gene for factor. Its synthesis is vitamin Kdependent. Carrier detection and

antenatal diagnosis are performed as for haemophilia A. The principles of

replacement therapy are similar to those of haemophilia A. Bleeding episodes are

treated with highpurity factor IX concentrates. Because of its longer biological

halflife, infusions do not have to be given as frequently as do factor VIII

concentrates in haemophilia A. Recombinant factor IX is preferred, but higher

doses are needed than with plasma. (Hoffbrand and Moss, 2016)

Haemostasis

Background

Haemostasis is the physiologic mechanism that stops bleeding after injury to

the vasculature (DeSancho and Rand, 2003). The normal haemostatic response to
vascular damage depends on a closely linked interaction between the blood vessel
wall, circulating platelets and blood coagulation factors. (Hoffbrand and Moss,
2016)

(Hoffbrand and Moss, 2016)

Figure The involvement of blood vessels, platelets and blood coagulation in

haemostasis

Haemostasis Responses

Immediate vasoconstriction of the injured vessel and reflex constriction of

small arteries and arterioles is responsible for slowing of blood flow to the area of
injury. The reduced blood flow activates platelets and coagulation factors.
Circulating platelets adhere and aggregate at sites of blood vessel injury. The
adhesion is depending on the presence of the von Willebrand factor (vWF). It
carries factor VIII. VWF is synthesized both in endothelial cells and

megakaryocytes, and stored in WeibelPalade bodies and platelet granules. The

stored VWF can raise the plasma levels when released under the influence of stress,
exercise, adrenaline and infusion of desmopressin. (Hoffbrand and Moss, 2016)

The platelets aggregation characterized by crosslinking of platelets

through active GPIIb/IIIa receptors with fibrinogen bridges. Stimulation of a

platelet leads to an increase in GPIIb/IIIa molecules, enabling platelet cross

linking via VWF and fibrinogen bridges. Primary activation by agonists induces
intracellular signalling, leading to the release of granule contents. Thromboxane
A2 (TXA2) is released and lowers platelet cyclic adenosine monophosphate
(cAMP) levels and initiates the release reaction (Hoffbrand and Moss, 2016).

Activation of platelets results in exposure of anionic phospholipids. The

phospholipid is available for two reactions in the coagulation cascade. The first
(tenase) involves factors IXa, VIIIa and X in the formation of factor Xa. The second
(prothrombinase) results in the formation of thrombin from the interaction of factors
Xa, Va and prothrombin (II). (DeSancho and Rand, 2003)

Factor number Name

I Fibrinogen
II Prothrombin
III Tissue factor
V Labile factor
VII Proconvertin
VIII Antihaemophilic factor
IX Christmas factor
X Stuart-power factor
XI Plasma thromboplastin antecedent
XII Hageman (contact) factor
XIII Fibrin stabilizing factor
 Prekallikrein (Fletcher factor)
High Molecular Weight Kininogen (Fitzgerald Factor)
(Hoffbrand and Moss, 2016)

Table The coagulation factors

Coagulation Cascade

(Hoffbrand and Moss, 2016)

Figure The pathway of coagulation cascade initiated by Tissue Factor (TF)

Initiation. Coagulation is initiated after vascular injury by the interaction of

the membrane bound tissue factor (TF), exposed and activated by vascular injury,

with plasma factor VII. The factor VIIatissue factor (extrinsic factor Xase)
complex activates both factor IX and factor X. The factor Xa, in the absence of its
cofactor, forms small amounts of thrombin from prothrombin. This is insufficient
to initiate significant fibrin polymerization. Amplification is needed. (Hoffbrand
and Moss, 2016)

Amplification. In this amplification phase the intrinsic Xase, formed by IXa

and VIIIa on phospholipid surface in the presence of Ca2+, activates sufficient Xa,
which then, in combination with Va, PL and Ca2+, forms the prothrombinase
complex and results in the explosive generation of thrombin which acts on
fibrinogen to form the fibrin clot. Thrombin hydrolyses fibrinogen, releasing
fibrinopeptides A and B to form fibrin monomers. Fibrin monomers link
spontaneously by hydrogen bonds to form a loose insoluble fibrin polymer. Factor
XIII is also activated by thrombin and stabilizes the fibrin polymers with the

formation of covalent bond crosslinks. (DeSancho and Rand, 2003) (Hoffbrand

and Moss, 2016)

Anticoagulation

It is important that the effect of thrombin is limited to the site of injury.

Blood coagulation would lead to dangerous occlusion of blood vessels (thrombosis)
if left to continue coagulating. So that, there are protective mechanisms with
coagulation factor inhibitors, blood flow and fibrinolysis. (Hoffbrand and Moss,
2016)

Coagulation factor inhibitors. The first inhibitor to act is TFPI, which is

synthesized in endothelial cells and is present in plasma and platelets and
accumulates at the site of injury caused by local platelet activation. TFPI inhibits
Xa and VIIa and tissue factor to limit the main in vivo pathway. Then, the other
inhibitors are Protein C and Protein S. These are inhibitors of coagulation cofactors
V and VIII. The resulting complex activates the vitamin K-dependent serine
protease, protein C, which can destroy activated factors V and VIII, thus preventing
further thrombin generation. The action of protein C is enhanced by another vitamin

Kdependent protein, S, which binds protein C to the platelet surface. In addition,

activated protein C enhances fibrinolysis. (DeSancho and Rand, 2003)

 Blood flow. At the periphery of a damaged area of tissue, blood flow rapidly
achieves dilution and dispersal of activated factors before fibrin formation has
occurred. (De Gruchy, 1989)

Fibrinolysis. Finally, fibrin is digested by the fibrinolytic system, the major

components of which are plasminogen and tissue-type plasminogen activator (tPA).
Plasminogen, a proenzyme in blood and tissue fluid, is converted to the serine
protease plasmin by activators either from the vessel wall. TPA is a serine protease

that binds to fibrin. This enhances its capacity to convert thrombusbound

plasminogen into plasmin. Plasmin generation at the site of injury limits the extent
of the evolving thrombus. Both proteins are incorporated into polymerizing fibrin,
where they interact to generate plasmin, which, in turn, acts on fibrin to dissolve
the preformed clot. (DeSancho and Rand, 2003) (Hoffbrand and Moss, 2016)

(Hoffbrand and Moss, 2016)

Figure The fibrinolytic system

Tests of Haemostatic Function

Defective haemostasis with abnormal bleeding may result from: (1) Vascular
injury; (2) Thrombocytopenia or disorder of platelet function; and (3) Defective
blood coagulation. Laboratory diagnostic helps to assess the platelet level in plasma
and the function, vessel wall, and coagulation components of haemostasis.
(Hoffbrand and Moss, 2016)
 Blood count and peripheral blood smear. As thrombocytopenia is a common
cause of abnormal bleeding, patients with suspected bleeding disorders should have
a complete blood count including platelet count and peripheral blood smear. A
peripheral blood smear can help to know pseudo thrombocytopenia and to look for
abnormally shaped platelets. (Ballas and Kraut, 2008)
Platelet function activity. the test of choice for evaluation of platelet function
was bleeding time; however, the use of bleeding time to predict surgical bleeding
has been questioned as it is insensitive and has poor reproducibility (Ballas and
Kraut, 2008). The Platelet Function Analyzer (PFA)-100 has been shown to be
superior to bleeding time in detecting von Willebrand's disease. The PFA-100
simulates the formation of the platelet plug in vivo by passing the patient's blood
through an aperture coated with collagen/epinephrine and collagen/adenosine
diphosphate. In patients with von Willebrand's disease and other platelet function
disorders, the amount of time required for the platelets to aggregate is prolonged
(Hoffbrand and Moss, 2016) (Harrison et al., 2002). The reported sensitivity of the
PFA-100 for diagnosing von Willebrand's disease and other platelet function
disorders is 88 to 90 percent with a specificity of 86 to 94 percent. Although the
PFA-100 is more sensitive than bleeding time, a negative result should not preclude
further testing for von Willebrand's disease or other platelet function disorders.
(Hayward et al., 2006)
Screening tests of blood coagulation. Screening tests provide an assessment
of the extrinsic and intrinsic systems of blood coagulation and the central
conversion of fibrinogen to fibrin. The prothrombin time (PT) measures factors
VII, X, V, prothrombin and fibrinogen. Tissue thromboplastin (a brain extract) or
[synthetic] tissue factor with lipids and calcium is added to citrated plasma. The

normal time for clotting is 1014 s. The activated partial thromboplastin time

(APTT) measures factors VIII, IX, XI and XII in addition to factors X, V,

prothrombin and fibrinogen. The phospholipid, a surface activator (e.g. kaolin) and

calcium are added to citrated plasma. The normal time for clotting is

approximately 3040 s. The thrombin (clotting) time (TT) is sensitive to a

deficiency of fibrinogen or inhibition of thrombin. Diluted bovine thrombin is

added to citrated plasma at a concentration giving a clotting time of 1416 s with

normal subjects. (Hoffbrand and Moss, 2016)

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