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Inherited Bleeding Disorders: Haemophilias

Dr Chukwuemeka S Ugwuadu

Dept of Haematology and Blood Transfusion

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Definition

Hemophilia A (factor VIII deficiency) and

Hemophilia B (factor IX deficiency)

Rare bleeding disorders due to inherited deficiencies of coagulation factor

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Other rare ones include:
Factor VII deficiency
Factor V deficiency
Factor X deficiency
Factor II deficiency
Factor XIII deficiency
Combined factor V & VIII deficiency
Inherited disorders of fibrinogen (Hereditary Afibrinogenaemia, Hypofibrinogenaemia, Dysfibrinogenaemias
HMWK, prekallikrein deficiency
The inherited coagulation disorders are found in all racial groups and geographical locations except the F XI deficiency that is found mainly in Ashkenazi Jews

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Types

Haemophilia A (Classic) Factor VIII deficiency

Haemophilia B (Christmas Disease) Factor IX deficiency

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Haemophilia A & B

clinically similar:
occur in approximately 1 in 5,000 male births
account for 90% of congenital bleeding disorders
Hemophilia A is approximately 5 times more

common than B

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Etiology

Inherited as a sex-linked recessive trait with bleeding manifestations only in males
genes which control factor VIII and IX production are located on the x chromosome;
if the gene is defective synthesis of these proteins is defective
female carriers transmit the abnormal gene

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Genetics

They are generally inherited as autosomal recessive except the following:
F VIII and F IX => X-linked
vWF, F XI, dysfibrinogenaemia => autosomal dominant
The genetic defects are caused by:
deletion of genes
mutation in the stop codon
mutation that result in non-sense reading
mutation affecting the regulatory gene

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Genetics

The disorder is sex-linked recessive character
The gene coding for FVIII synthesis is located near the tip of the long arm of X chromosome near the gene for G6PD (Xq28)
Deletion or mutation of the gene at this locus results in reduced synthesis or defective synthesis of the F VIII
Typically, positive family history is obtained in maternal grandfather, maternal uncles, and maternal male cousins
However, 30% of patients have no family history and presumably results from spontaneous mutation
Negative family history does not rule out the possibility of haemophilia

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If a carrier female marries a normal male, the male offspring has a 50% chance of being affected while the female offspring has a 50% chance of becoming a carrier
If a haemophilic male marries a normal female, all his sons will be normal while all his daughters will be carriers
The male haemophiliacs, having only one X chromosome, transmit the gene to all their daughters but to none of their sons or male children

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Most female carriers of haemophilia A do not suffer from haemorrhagic diathesis
Haemophilia may develop in carrier females

Lyonisation predominantly of normal X chromosomes during embryogenesis
Homozygosity of haemophilic gene in the female offspring of a carrier female and an affected male
Hemizygosity of haemophilic gene due to chromosome anomalies such as Turner’s (XO) syndrome.

von Willebrand disease is a more common cause of F VIII deficiency in females

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Pathophysiology

Factors VIII and IX participate in a complex required for the activation of factor X.
After injury, the initial hemostatic event is formation of the platelet plug, together with the generation of the fibrin clot that prevents further hemorrhage.
In hemophilia A or B, clot formation is delayed and is not robust.

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Disease Severity

severity is dependent on blood levels of functioning factor VIII or IX
severity varies markedly between families but is relatively constant among family members in successive generations
remains relatively unchanged throughout life

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Classification

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Classification

% normal factor level and Causes of bleeding

Severe < 1% bleeding after trivial injury or spontaneous

Moderate 1 - 5% bleeding after minor injury; occasional spontaneous bleeds
Mild 6 - 30 % following major trauma, surgical or dental procedure

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Clinical Feature – Joint bleeds

Joints (Hemarthrosis)

Knees, ankles and elbows most common sites begin as the child begins to crawl and walk many bleeds occur between the ages of 6 and 15 years

Single joint bleed: stiffness, swelling, pain, loose pack position

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Subacute Haemathrosis

Develops after repeated bleeds into the joint

Synovium becomes inflamed

Hypertrophy, hyperplasia and increased vascularity of synovial membrane

Hemosiderosis: hemoglobin of intra articular blood is degraded and iron deposited into the joint space

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Chronic Arthropathy

Progressive destruction of a joint

Pannus (inflammed synovium), & enzymes begin to destroy articular cartilage

Microfracture and cyst formation in subchondral bone

End stage: firbrous joint contracture, and disorganization of articular surfaces

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Clinical Features – Muscle Bleeds

Bleeding into muscle or soft tissue

Less tendency to recurrent bleeds

Sites: iliopsoas, calf, upper arm and forearm, thigh, shoulder area, buttocks

Symptoms: pain, swelling, muscle spasm

Complications: nerve compression, contracture

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Other Sites of Haemorrhage

Abdomen

GI tract

Intracranial bleeds

Around vital structures in the neck

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Laboratory Findings and Diagnosis

Factor VIII or factor IX deficiency leads to prolongation of APTT.

In severe hemophilia, APTT is usually 2–3 times the upper limit of normal.

All other screening tests of within normal Limit

The specific assay for factors VIII and IX will confirm the diagnosis of hemophilia.

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Laboratory diagnosis

Coagulation screening tests show:
prolongation of PTTK
normal PT
Thromboplastin generation test (TGT) - abnormal
normal bleeding time
normal TT
normal platelet count
Specific factor assays show a decreased F VIII activity <35u/dl
Normal F VIII:C level in plasma is 50 to 150%. It is affected by various factors such as venous stasis before collection of blood, prolonged storage of blood, severe exercise, pregnancy, inflammation, fever, liver diseases, hyperthyroidism, and haemolysis.
All other factors are normal

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Management

Replacement of missing clotting factor

Plasma products

Cryoprecipitate

Concentrates of Factor VIII Factor IX

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Treatment

MULTIDISCIPLINARY
Bleeding episodes are treated with F VIII replacement therapy
This can be achieved by using blood and blood products (FVIII concentrate, cryoprecipitate, plasma(FFP) and whole blood transfusion
Administration of one unit per kg body weight of F VIII raises plasma level by 2 units/ dl
The approximate minimum desired F VIII levels required to control bleeding are- (i) Mild bleeding: 30% (0.3 units/ml), (ii) Serious or major bleeding: 50% (0.5 units/ml) and (iii) Major Surgery: 80–100% (0.8 units/ml)
Units of F VIII to be administered = required rise in % units × weight in kg/2
Required rise in units/ml = (Required level of F VIII in patient’s plasma in units/ml – Actual F VIII level before infusion)

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To maintain the desired levels repeated doses are necessary as half-life of F VIII is about 8 to 12 hours
Prophylactic therapy is also advocated
In this form of treatment, F VIII is regularly and periodically administered (every 2–3 days) to maintain the concentration of F VIII greater than 1%
Prevents serious, and spontaneous haemorrhages, i.e. a severe disease is converted to a moderate disease
This form of therapy has been shown to significantly reduce the joint disease
However, prophylactic therapy is not commonly employed due to the high cost and limited supply of F VIII concentrates.

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Cryoprecipitate

(F VIII:C, von Willebrand factor, fibrinogen, and fibronectin and also contains some amount of F XIII)

Desmopressin[Desamino-D-arginyl vasopressin (DDAVP)]

Used in mild to moderate haemophilia
increases levels of F VIII and von Willebrand factor in plasma by stimulating their release from endothelial cells and platelets

Antifibrinolytic agents eg epsilon-aminocaproic acid and traxenamic acid
Local supportive measures used in treating haemarthroses and haematomas include resting the affected part and the prevention of further trauma
Liver transplantation can bring about a cure
Gene therapy
Physiotherapy
Orthopaedic care

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Management (contd)

Early, appropriate therapy is the hallmark of excellent hemophilia care.

Mild to moderate bleeding, levels of factor VIII or factor IX must be raised to hemostatic levels in the 35–50% range.

For life-threatening or major hemorrhages, the dose should aim to achieve levels of 100% activity

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Role of Desmopressin in Haemophilia A

With mild factor VIII hemophilia, the patient's endogenously produced factor VIII can be released by the administration of desmopressin acetate.

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Other Medical Treatment

Analgesics (no aspirin)
Good dental care
Education – life-long management
Psychological counseling
Acute and long-term management of musculoskeletal problems

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Musculoskeletal Management

Acute Bleeds:
Immediate replacement factor
Immobilize joint
No weight bearing
Immediate medical attention if complications arise

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Musculoskeletal Management (contd)

After 24 hours:
Continue minimal or no weight bearing for lower extremity bleed
Active range of motion; gentle stretching
Corrective positioning (splinting ??)
Isometric strengthening; progress to isotonic

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