Thalassemia Syndromes

Thalassemia refers to a group of genetic disorders of globin chain production in

which there is an imbalance between the α-globin and β-globin chain production.

Beta thalassemia ; β thalassemia also classified according to severity in to :

1. β THALASSEMIA MAJOR (homozygous or cooley's anemia)
2. β THALASSEMIA MINOR( heterozygous ) or trait
3. βTHALASSEMIA INTERMEDIA

EPIDEMIOLOGY OF BETA THALASSEMIA

Although β thalassemia has more than 200 mutations, most are rare. Approximately
20 common alleles constitute 80% of the known thalassemia world wide,3% of the
world population carries genes for β thalassemia, and in Southeast Asia,5-10% of
population carries genes for α thalassemia

PATHOPHYSIOLOGY

The thalassemias are inherited disorders of Hb synthesis resulting from an

alteration in the rate of globin chain production .There are two major features
contribute to the pathogenesis of sequelae of β- thalassemia ;
First inadequate β globin chain production leading to decrease levels of normal
HbA and an imbalance in α and β globin chain production
Second impaired synthesis of one type of globin chain limits the formation of
hemoglobin tetramers that require that chain . Continued production of other type of
globin chain at a normal rate results in accumulation of excess globin chains that are
unable to participate in normal tetramer formation for lack of suitable partner. Such
uncombined globin chains are readily precipitated within that erythrocyte ,forming
insoluble inclusion bodies.
In β thalassemia inclusions of α4 chains form so rapidly during erythroide
maturation , which results in destruction of reticulocytes before release to the
circulation.
In α thalassemia beta chain tetramers(β4 or hemoglobin H) precipitates more slowly
after the red cell have left the marrow.

CLINICAL FEATURES AND COMPLICATIONS

The clinical onset of beta thalassemia major occurs gradually after birth as the
normal post- natal decline in gamma chain synthesis(HbF) reveals the defect in the
production of β-globin chain . At the age of 6 to 12 months the infant demonstrates;
pallor, irritability, and often an enlarging abdomen. Compensatory hypertrophy of the

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erythroid marrow at expense of bone may produce disfiguring cosmotic
changes.There will be head enlargement due to frontal and parietal bossing
,enlargement of maxilla cause upper frontal teeth to protrude.Marked malocclusion is
common. bridge of nose is broadened ,deepened and depressed

Bone pain and susceptibility to pathological fractures due to bone marrow

expansion . Compensatory extramedullary hematopoiesis in the liver ,spleen causes
hepatosplenomegaly and abdomenal enlargement.Spleen become more and more
enlarging with subsequent hemolysis reaching to a level causing abdomenal
discomfort, anorexia and occasionally vomiting .Iron accumulation leads to darkening
of skin because of both melanin and iron deposit in the dermis .

Patients of thalassemia are susceptible to infections for the following reasons:

1. The patient exposed to infections transmissible by blood transfusions.
2. Low transfused patients in addition to be anemic are stressed.
3. Splenectomy increases susceptibility to some infections.
4. Lymphoid hyperplasia may increase the incidence of ear, nose and throat
complications.
Encapsulated pneumococci in two –third of cases , and H.Influenzae type b and
meningococcal in the remaining.

Radiological changes :
The characteristic osseous changes in thalassimia can be shown only in
patients who receive infrequent blood transfusion .Regular transfusion to nearly
normal Hb levels suppresses the erythropoiesis and prevents bony deformities

 Radiological changes are not apparent until one year of age.

 In small bones of hand and feet, the trabecular pattern is coarse and cystic
format may be seen.
 Thickening of cortex and increase of medullary space of long bones may result
in increase bone fragility and fractures.

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  Skull x-rays will show the increase of lipoid and arrangement of trabeculae in
vertical rows, causing “hair-on-end appearance

Other important features ; Heart complications represent the leading cause of

mortality in thalassemia major.Heart hemodynamics in patients affected by
thalassemia major when there are no myocardial alterations caused by organ iron
burden ,are related to chronic anemia which include :
 Decrease in peripheral vascular resistance.
 Consequent increase in venous return.
 Increase in cardiac output.

Diagnosis of thalassemia

Anemia is usually sever with low Hb level to be <5.5 g/dl, unless blood transfusions
are given with hypochromic microcystic anemia, many bizarre, fragmented RBCs,
poikilocytosis and target cells.
Confirmation by Hb electrophoresis in B thalassemia major is essential before the
patient and the family are counseled which show HbF> 90% .

The WBC count is elevated, the red blood cell indices that include the MCV and
MCH, are both significantly low . The unconjugated serum bilirubin level is usually
elevated, low level of serum zinc is present. Even untransfused, eventually there is
iron accumulation with elevated serum ferritin and saturation of transferritin.

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Prenatal Diagnosis :

Molecular diagnostic test can precisely determine whether a mutation is

present anytime after approximately 8 weeks of gestation.

TREATMENT

Goals of management :

 Maintain hemoglobin at optimal level ( ensure accepted or good level of

activity ) through regular transfusion especially in homozygous β thalassemia .
(8-9 g/dl in countries where the supply of blood is limited , a minimum Hb
level of 10 g/dl (this is called hyper transfusion) , 12 g /dl (this is called super
transfusion) by regular transfusions every 3 -4 weeks
 Avoid or decrease the side effects of blood transfusion especially iron over
load and transfusion related infections .

Regular checking for : child's growth (height and weight should be checked every 3
months ) , Serum chemistries: serum calcium, phosphate, ferritin, blood sugar, liver
function tests are repeated annually or more frequently in patients with abnormal
results.

Summary of treatment :

1. Blood transfusion : Patients with β-thalassaemia major should receive

leucoreduced packed red blood cells .
Washed red cells may be beneficial for patients with thalassaemia
who have repeated severe allergic transfusion reactions
Frozen (or cryopreserved) red cells is the component derived from
whole blood in which red cells are frozen, preferably within 7 days of
collection, using a cryopreservant and stored at −60oC to −80oC or
below, based on the method used .

2. Folic acid supply : daily dose 2.5 – 5 mg orally .

3. B12
4. Vitamin C 100-250 mg taken with desferal (helps more iron to be
excreted) Vitamin C 100-250 mg taken with desferal (helps more iron
to be excreted)
5. Calcium  1000-1500 mg plus 500-1000 mg magnesium plus Vitamin D
1000-5000 iu ( all work together to maintain bone growth and heart
function)
6. Zinc 15-50 mg

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 7. Chelation therapy : Iron over laod occur from two sources namely
transfused blood and enhanced GIT iron absorption due to increased
erythropoiesis .
 Parenteral therapy (DEFEROXAMINE )
 Oral therapy (DEFERASIROX (EXJADE )
8. Vitamin E  400 iu.  Natural source preferred. d-alpha tocopherol (not
dl-alpha) .
9. SPLENECTOMY : Splenectomy is usually not needed if regular
transfusion is followed but it is indicated when there is :
 blood consumption greater than 200-250 ml/kg/year of pure red
cells, to maintain a pre-transfusion Hb around 9 g / d L .
 palpable spleen more than 6 cm bellow left costal margin with
hypersplenisim

10. bone marrow transplantation : peripheral stem cell transplantation . In

this technique, stem cells are collected from peripheral blood of the
donor by stimulating the release of stem cells from marrow to blood by
use of certain drugs and growth factors

Vaccinations :

1. Normal childhood vaccination schedule

2. Hepatitis B vaccination (from one year of age)
3. BCG
4. Annual influenza.
5. If your spleen has been removed, you also need:
Pneumovax (from two years of age and then every five years)
Haemophilus influenzae type B (Hib)
Meningococcal ACWY vaccine

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 Autoimmune Hemolytic Anemia

The incidence of AIHA is estimated to be between 0.6 and 3 cases per 100,000
persons.1,2 AIHA is mediated by antibodies, and in the majority of cases
immunglobulin (Ig) G is the mediating antibody .

1. Worm type : AIHA in which IgG antibodies are the offending antibodies is
referred to as warm AIHA. “Warm” refers to the fact that the antibody binds
best at body temperature (37°C). The incidence of warm AIHA is
approximately 1 case per 100,000 patients per year; this form of hemolysis
affects women more frequently than men .
Clinical Manifestations : may occur in either of 2 general clinical patterns:
 An acute transient type lasting 3-6 mo and occurring predominantly in
children ages 2-12 yr, accounts for 70-80% of patients. It is frequently
preceded by an infection, usually respiratory. The spleen is usually
enlarged and is the primary site of destruction of immunoglobulin (Ig)
G–coated RBCs. Underlying systemic disorders are unusual. A
consistent response to glucocorticoid therapy, a low mortality rate, and
full recovery are characteristic of the acute form.
 chronic course, which is more frequent in infants and in children >12
yr old , may continue for many months or years
 treatment : First line Prednisone 1 mg/kg/day and Folic acid 1 mg/day
Second line Rituximab 375 mg/m2 weekly for 4 weeks or
Splenectomy
2. Cold type :
 In cold AIHA, the hemolysis is mediated by IgM antibodies directed
against red cells , which bind maximally at temperatures below 37°C.
 It is important to diagnose cold AIHA because the standard therapy
for warm AIHA (steroids) is ineffective in cold AIHA.
 Because C3-coated red cells are taken up primarily in the liver,
removing the spleen is also an ineffective therapy
 Treatment : Rituximab 375 mg/m2 weekly for 4 weeks , Folic acid 1
mg/day Keep patients and infused products warm.

3. DRUG-INDUCED HEMOLYTIC ANEMIA :

The rate of severe drug-related AIHA is estimated at 1:1,000,000, but less
severe cases may be missed. Most patients will have a positive DAT without
signs of hemolysis ( anemia and jaundice ) , but in rare cases patients will have
relentless hemolysis resulting in death. The hapten mechanism is most often
associated with the use of high-dose penicillin .

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 Drugs Implicated in Autoimmune Hemolytic Anemia

Most Common
Cefotetan
Ceftriaxone
Piperacillin
Fludarabin
Other Implicated Drugs
Acetaminophen
Amphotericin B
Beta-lactams (any)
Carboplatin
Cephalosporins (any)
Chlorpromazine
Chlorpropamide
Cimetidine
Erythromycin

Coombs test :
The Coombs test checks the blood to see if it contains certain antibodies .
Antibodies are proteins that your immune system makes when it detects that
something may be harmful to your health but If the immune system’s detection is
wrong, it can sometimes make antibodies toward your own cells. This can cause many
kinds of health problems.

 Direct Coombs test . is more common and checks for antibodies that are
attached to the surface of patient red blood cells
 Indirect Coombs test. checks for unattached antibodies that are floating in the
bloodstream

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Quantitative and Qualitative Platelet Disorders

Introduction

 Platelet :
Platelets, or thrombocytes, are small discoid cells (0.5 to 3.0 μm) that are
synthesized in the bone marrow and stimulated by the hormone
thrombopoietin . The parent cells of platelets are called megakaryocytes .
Thrombopoietin is responsible for stimulating maturation and platelet release.
This hormone is generated primarily by the kidney and partly by the spleen
and liver. Platelets have no nucleus but do have granules: alpha granules, and
dense granules .normal life span from 5 to 10 days .

Causes of Thrombocytopenia.

1. Decreased production of platelets

 Bone marrow deficit
o Aplastic anemia: congenital and acquired
o Marrow infiltration: leukemia, disseminated cancer,
multiple myeloma , infection as in typhoid fever or
brucellosis .
 Toxic effect: selective impairment of platelet production
o Drug-induced: thiazides, cytotoxic drugs, radiotherapy, etc.
o Infections: human immunodeficiency virus (HIV) which
suppresses the production of megakaryocytes
o Toxins in chronic use (alcohol, cocaine)
 Ineffective megakaryopoiesis
o Megaloblastic anemia (Vitamin B12/Folic acid deficiency
anemia)
2. Increased peripheral destruction and utilization
 Immunologic destruction: antibodies targeted against platelets
o Primary: idiopathic thrombocytopenic purpura,
o Secondary: systemic lupus erythematosus; posttransfusion;
Infections: infectious mononucleosis, HIV,
cytomegalovirus; Drug-
associated: quinidine, heparin
 Non-immunologic destruction: excessive platelet consumption in
thrombi
QUANTITATIVE o DISORDERS
ThromboticOFthrombocytopenic
PLATELETS purpura
o Hemolytic uremic syndrome
o Disseminated intravascular coagulation
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 Idiopathic (Autoimmune) Thrombocytopenic Purpura

The most common cause of acute onset of thrombocytopenia in an otherwise

well child is (autoimmune) idiopathic thrombocytopenic purpura (ITP).

EPIDEMIOLOGY

In a small number of children, estimated at 1 in 20,000, 1-4 wk after exposure

to a common viral infection . The peak age is 1-4 yr, although the age ranges
from early in infancy to the elderly . In childhood, males and females are
equally affected . ITP seems to occur more often in late winter and spring
after the peak season of viral respiratory illness .

PATHOGENESIS
The exact antigenic target for most such antibodies in most cases of
childhood acute ITP remains undetermined . After binding of the antibody to
the platelet surface, circulating antibody-coated platelets are recognized by the
Fc receptor on splenic macrophages, ingested, and destroyed. Most common
viruses have been described in association with ITP, including Epstein-Barr
virus and HIV , Epstein-Barr virus-related ITP is usually of short duration and
follows the course of infectious mononucleosis. HIV-associated ITP is usually
chronic . In some patients ITP appears to arise in children infected with
Helicobacter pylori

CLINICAL MANIFESTATIONS
The classic presentation of ITP is a previously healthy 1-4 yr old child who
has sudden onset of generalized petechiae and purpura. There is a history of a
preceding viral infection 1-4 wk before the onset of thrombocytopeni .
Splenomegaly, lymphadenopathy, bone pain, pallor , cytopenias, or congenital
anomalies suggests other diagnoses (leukemia, syndromes) . Fewer than 1% of
patients develop an intracranial hemorrhage. Approximately 20% of children
who present with acute ITP go on to have chronic .
A classification system has been proposed from the United Kingdom to
characterize the severity of bleeding in ITP on the basis of symptoms and
signs, but not platelet count:

1. No symptoms
2. Mild symptoms: bruising and petechiae, occasional minor epistaxis, very little
interference with daily living

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3. Moderate: more severe skin and mucosal lesions, more troublesome epistaxis and
menorrhagia
4. Severe: bleeding episodes—menorrhagia, epistaxis, melena— requiring
transfusion or hospitalization, symptoms interfering seriously with the quality of life .

LABORATORY FINDINGS
 Severe thrombocytopenia (platelet count < 20 × 109 /L) is common,
and platelet size is normal or increased, reflective of increased platelet
turnover .
 In acute ITP, the hemoglobin value ( except in profuse bleeding ) ,
white blood cell (WBC) count, and differential count should be
normal.
 Bone marrow examination shows normal granulocytic and erythrocytic
series, with characteristically normal or increased numbers of
megakaryocytes .
Indications for bone marrow aspiration/biopsy include :
1. an abnormal WBC count or differentia
2. unexplained anemia as well as findings on history and physical
examination suggestive of a bone marrow failure syndrome or
malignancy (Splenomegaly, lymphadenopathy, bone pain, pallor ,
cytopenias, or congenital anomalies ) .
3. when you need to start steroid therapy .

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TREATMENT

1. No therapy other than education and counseling of the family and patient for
patients with minimal, mild, and moderate symptoms, as defined earlier

2. Per the American Society of Hematology Guidelines: “A single dose of IVIG

[intravenous immunoglobulin] (0.8-1.0 g/kg) or a short course of corticosteroids
should be used as first-line treatment.” IVIG at a dose of 0.8-1.0 g/kg/day for 1-2
days induces a rapid rise in platelet count (usually >20 × 109 /L) in 95% of
patients within 48 hr .IVIG appears to induce a response by downregulating Fc-
mediated phagocytosis of antibody-coated platelets

3. Prednisone. Corticosteroid therapy has been used for many years to treat acute
and chronic ITP in adults and children. Doses of prednisone of 1-4 mg/kg/24 hr
appear to induce a more rapid rise in platelet count than in untreated patients with
ITP.
4. Intravenous anti-D therapy. For Rh-positive patients, IV anti-D at a dose of 50-75
µg/kg causes a rise in platelet count to >20 × 109 /L in 80-90% of patients within
48-72 hr.

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Other causes of quantitative platelet disorders :

 Drug-Induced Thrombocytopenia
 Nonimmune Platelet Destruction : Hemolytic-Uremic Syndrome , Thrombotic
Thrombocytopenic Purpura , Kasabach-Merritt Syndrome

QUALITATIVE DISORDERS OF PLATELETS (Platelet Function Disorders )

 Acquired Disorders of Platelet Function

A number of systemic illnesses are associated with platelet dysfunction, most
commonly, liver disease, kidney disease (uremia), and disorders that trigger
increased amounts of fibrin degradation products.
 Congenital Abnormalities of Platelet Function :
Severe platelet function defects usually present with petechiae and purpura
shortly after birth, especially after vaginal delivery. Defects in the platelet
GPIb complex (the VWF receptor) or the αIIb-β3 complex (the fibrinogen
receptor) cause severe congenital platelet dysfunction. These include :
1. Bernard-Soulier syndrome :
A severe congenital platelet function disorder, is caused by absence or severe
deficiency of the VWF receptor (GPIb complex) on the platelet membrane .
This syndrome is characterized by thrombocytopenia, with giant platelets and
markedly prolonged bleeding time (>20 min) or PFA-100 closure time .
Platelet aggregation tests show absent ristocetin-induced platelet aggregation,
but normal aggregation to all other agonists . Ristocetin induces the binding of
VWF to platelets and agglutinates platelets.

2. Glanzmann thrombasthenia :
Is a congenital disorder associated with severe platelet dysfunction that yields
prolonged bleeding time and a normal platelet count. Platelets have normal
size and morphologic features on the peripheral blood smear, and closure
times for PFA-100 or bleeding time are markedly abnormal. Aggregation
studies show abnormal or absent aggregation with all agonists used except
ristocetin, because ristocetin agglutinates platelets and does not require a
metabolically active platelet . This disorder is caused by deficiency of the
platelet fibrinogen receptor αIIb-β3, the major integrin complex on the platelet
surface .

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TREATMENT OF PATIENTS WITH PLATELET DYSFUNCTION

Successful treatment depends on the severity of both the diagnosis and the
hemorrhagic event . In all but severe platelet function defects,
 desmopressin 0.3 µg/kg IV may be used for mild to moderate bleeding . In
addition to its effect on stimulating levels of VWF and factor VIII,
desmopressin corrects bleeding time and augments hemostasis in many
individuals with mild to moderate platelet function defects .
 platelet transfusions of 1 unit/5-10 kg corrects the defect in hemostasis and
may be lifesaving In both conditions, hematopoietic stem cell transplantation
has been curative

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Bleeding disorders

Hemostasis is the active process that clots blood in areas of blood vessel injury yet
simultaneously limits the clot size only to the areas of injury. Over time, the clot is
lysed by the fibrinolytic system, and normal blood flow is restored. If clotting is
impaired, hemorrhage occurs. If clotting is excessive, thrombotic complications
ensue.

The main components of the hemostatic process are the vessel wall, platelets,
coagulation proteins, anticoagulant proteins, and fibrinolytic system.Most components
of hemostasis are multifunctional; fibrinogen serves as the ligand between platelets
during platelet aggregation and also serves as the substrate for thrombin that forms the
fibrin clot. Platelets provide the reaction surface on which clotting reactions occur,
form the plug at the site of vessel injury, and contract to constrict and limit clot size.

Process of Hemostasis :
1. Primary hemostasis leads to the generation of the hemostatic plug and
requires the activity of vascular and platelet factors .
1.1. Blood vessels contribute to hemostasis via several processes:
 vasoconstriction: an immediate and transient response (less than 1
minute duration), which
reduces the blood loss from the damaged zone through:
o Reflex (neurogenic) mechanisms
o Humoral mechanisms: endothelin released by endothelial cells and
thromboxane A2 (TxA2) released by platelets
 vascular endothelium:
o synthesizes the von Willebrand factor (fvW), with an essential role in
platelet adhesion (fvW is also the carrier for the clotting factor VIII)
o synthesizes prostacyclines (PGI2) with antiagregant and vasodilator
effects
o releases the tissue factor (TF), a process induced by cytokines (TNF,
IL-1); TF activates
further the extrinsic pathway of coagulation
 subendothelial structures (collagen, fibronectine), which are
exposed, due to the damage of the vascular endothelium:
o initiates the adhesion, aggregation, and secretion (release of
granule content) Ÿ platelet plug formation
o activates factor XII (Hageman) which initates the intrinsic
pathway of coagulation.
1.2 Thrombocytes:

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  potentiate the vascular spasm via the release of vasoconstrictor factors
(TxA2, serotonin,histamine)
 contribute to the primary haemostasis via the platelet plug formation
 participate in the secondary haemostasis via the release of platelet
membrane phospholipids, which act as elective sites for calcium ions
binding.

2. Secondary hemostasis (coagulation) involves a series of enzymatic reactions

occurring through the activation of 2 pathways: intrinsic pathway and extrinsic
pathway. Coagulation requires the activity of plasma coagulation factors which
interact to produce thrombin, which converts soluble fibrinogen to the fibrin

 In the intrinsic pathway (contact phase), factor XII (Hageman), in the

presence of high molecular weight kininogen (HMW-kininogen) and
prekallikrein, will activate factor XI (to XIa) that in turn will trigger
the generation of factor IXa from factor IX. Factor IXa then combines
with factor VIIIa and procoagulant phospholipid (present on the
surface of activated platelets and tissue cells) to form a complex that
activates factor X.

 In the extrinsic pathway (tissue factor dependent phase), factor VIIa

and tissue factor directly activate factor X .

 Both intrinsic or extrinsic pathway elicit the activation of the common

pathway, resulting in formation of the fibrin clot

2. Control of haemostasis
Several inhibitory mechanisms prevent activated coagulation reactions from
amplifying uncontrollably, causing extensive local thrombosis or disseminated
intravascular coagulation. :

 Inactivation of the soluble activated clotting factors

a. Antithrombin III (AT III) inhibits thrombin (f. IIa),
factor Xa, factor XIIa, factor XIa, and factor IXa. This
inhibitory effect is enhanced up to 2000 times by
heparin (endogenous, released by mastocytes, and
exogenous, drug products).
b. Protein C and free protein S (cofactor of protein C),
which are vitamin K–dependent proteins, form a
complex that inactivates factors VIIIa and Va by
proteolysis.

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 Fibrinolysis (lysis of the fibrin clot) :

16
Approach to bleeding disorders

Bleeding in a child can present as petechiae, purpura,

epistaxis/mucosal bleeding, hematomas, gastrointestinal and
genitourinary bleeding, excessive bleeding with procedures and
surgery, as well as intracranial hemorrhage. Other children present
with an incidental abnormal coagulation screen, often during
presurgical screening, in the absence of clinical bleeding .

Consider a platelet or vascular disorder if the bleeding is mucosal in

nature or a clotting factor deficiency if it consists of deep-seated
hematomas or hemarthroses .

Nosebleeds and menorrhagia are the most common manifestations

of von Willebrand disease (VWD).
A family history of bleeding in only males suggests hemophilia A or
B
A palpable, purpuric rash with the typical lower extremity
predominance suggest the vasculitis of Henoch-Schönlein purpura

Coagulation disorders

Disorders of coagulation can be acquired or hereditary .

A. INHERITED coagulation disorders = hereditary defects of clotting factors:

a. Von Willebrand disease

b. Hemophilia A – factor VIII deficiency
c. Hemophilia B – factor IX deficiency
B. ACQUIRED coagulation disorders

1. Decreased synthesis of clotting factors:

a. Liver diseases
b. Vitamin K deficiency

2. Increased consumption of clotting factors:

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 Disseminated intravascular coagulation (DIC)

Inherited coagulation disorders

1. von Willebrand disease (vWD) .

Definition: vWD is a hereditary deficiency of von Willebrand factor

(vWF), is a common disorder (1% of the population) , Von Willebrand disease
usually is inherited as an autosomal dominant trait,which causes platelet
dysfunction. vWF is synthesized and secreted by vascular endothelium to
promote the platelet adhesion of platelets to the vessel wall. vWF is also
required to maintain normal plasma factor VIII activity. Thus, deficiency in
vWF will be responsible for:

 Reduced platelet adhesion = abnormal primary hemostasis.

 Reduced levels of factor VIIIa = abnormal secondary hemostasis

Deficit:

 quantitative = (partial = type 1 or absolute = type 3)

 qualitative = (type 2 = dysproteinemia)
 Approximately 80% of patients with von Willebrand disease have
classic (type 1)

Manifestations: mixed hemorrhagic syndrome (mild to moderate):

 bruising, purpura, petechiae (rapid, superficial hemorrhages)

 excessive menstrual flow, GI bleeding (late, profound hemorrhages)
 Screening coagulation tests reveal a normal platelet count, normal
INR, prolonged BT and aPTT.

Treatment. The treatment depends on the severity of bleeding.

 Desmopressin : is the treatment of choice for most bleeding episodes

in patients with type 1 disease and some patients with type 2 disease
 virally attenuated, vWF-containing concentrate (Humate P),When
high levels of vWF are needed but cannot be achieved satisfactorily
with desmopressin
 Cryoprecipitate should not be used because it is not virally attenuated
 Hepatitis B vaccine should be given before the patient is exposed to
plasma-derived products
 As in all bleeding disorders, aspirin should be avoided.

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Hemophilias

Definition: hereditary bleeding disorders caused by deficiencies of either clotting

factor VIII or IX (factor VIII deficiency is ten times more common than factor IX
deficiency). Both types of hemophilias are X-linked recessive disorders, which
primarily affects males, all daughters of affected men being obligate carriers.
However, one-third of new cases represent spontaneous mutations (no family history).

HEMOPHILIA A - factor VIII deficiency, represents 80% of cases.

HEMOPHILIA B - factor IX deficiency (Christmas disease), unfrequent, is clinically

indistinguishable from hemophilia A and presents the same screening test
abnormalities. Specific factor assays are required to distinguish the two. ƒ Treatment:
recombinant factor IX.

Classification: severity of the disease is given by the percent of normal factor VIII
activity in the circulation:

 Mild hemophilia: factor levels 5 to 40% of normal (bleeding occurs after

serious trauma or surgery)
 Moderate hemophilia: factor levels 1-5% of normal (bleeding occurs after
minimal trauma)
 Severe hemophilia: factor levels < 1% of normal (spontaneous bleeding
throughout life, usually beginning soon after birth, eg, scalp hematoma after
delivery or excessive bleeding after circumcision).

Clinical manifestations:

 Bruises and hematoma

 Bleeding into joints with pain and swelling (hemarthrosis): most common
manifestation responsible for the chronic hemophilic arthropathy:
 Repeated joint bleeds lead to synovial inflammation and increased
vascularity and thickening of the synovium. This progressively
increases the risk of a re-bleed.
 Vicious cycle (the synovium degenerates away and then cartilage and
bone are attacked)
 Most severe hemophiliacs need knee joint replacement by adulthood.

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  Gastrointestinal and urinary tract hemorrhage o blood in stool and urine
 ! Never purpura and petechiae (since primary hemostasis is not affected
Positive diagnosis :

 prolonged APTT

 normal BT, PT, and platelet count

 Factor VIII assay determine the severity of the hemophilia

Treatment.

1. Early, appropriate replacement therapy is the hallmark of excellent hemophilia

care .
2. For life-threatening bleeding, levels of 80% to 100% of normal factor 8 or
factor 9 are necessary .
3. For mild to moderate bleeding episodes (hemarthroses), a 40% level for factor
8 or a 30% to 40% level for factor 9 is appropriate .
4. The dose can be calculated using the knowledge that 1 U/kg body weight of factor 8
increases the plasma level 2%, whereas 1.5 U/kg of recombinant factor 9
increases the plasma level 1%:

Dose for factor 8=desired level (%)× weight (kg)× 0.5

or
Dose for recombinant factor 9=desired level (%) × weight (kg) × 1.5
5. Desmopressin acetate :
Is a synthetic vasopressin analog with minimal vasopressor effect .
Desmopressin triples or quadruples the initial factor 8 level of a patient with
mild or moderate (not severe) hemophilia A, but has no effect on factor 9
levels . 0.3 mcg/kg IV over 15-30 minutes; for preop, 30 minutes before
procedure

Note
 Patients treated with older factor 8 or 9 concentrates derived from
large pools of plasma donors were at high risk for hepatitis B, C, and
D and HIV. Recombinant factor 8 and factor 9 concentrates are safe
from virally transmitted illnesses
 Inhibitors are IgG antibodies directed against transfused factor 8 or
factor 9 in congenitally deficient patients. Inhibitors arise in 15% of
severe factor 8 hemophiliacs but are less common in factor 9
hemophiliacs .

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