HEMOPHILIA

HEMOPHILIA

What is Hemophilia?

• Hemophilia is an X-linked congenital bleeding disorder with a frequency of about

one in 10,000 births.

• Hemophilia is caused by a deficiency of coagulation factor VIII (FVIII) (hemophilia A)

or factor IX (FIX) (hemophilia B) related to mutations of the clotting factor gene.

• The number of affected persons worldwide is estimated to be about 400,000.

• Hemophilia A is more common than hemophilia B, representing 80-85% of the total.

• The life expectancy of persons born with hemophilia, who have access to adequate

treatment, should approach normal with currently available treatment.

The severity of bleeding manifestations in hemophilia is generally correlated with the

clotting factor level as shown in the following table.

SEVERITY	CLOTTING FACTOR LEVEL	BLEEDING EPISODE
SEVERE	1%(˂0.01)	) Spontaneous bleeding, predominantly in joints AND MUSCLES
MODERATE	1-5%(0.01-0.05)	) Occasional spontaneous bleeding. Severe bleeding with trauma, surgery
MILD	5-40% (0.05-0.40)	) Severe bleeding with major trauma or surgery

Serious

• Joints (hemarthrosis)

• Muscle/soft tissue

• Mouth/gums/nose

• Hematuria

Life-threatening

• Central nervous system (CNS)

• Gastrointestinal (GI)

• Neck/throat

• Severe trauma

Chronic Complications of Hemophilia

• Musculoskeletal complications:

- Chronic hemophilic arthropathy;

§  Chronic synovitis;

§  Deforming arthropathy;

- Contractures;

- Pseudotumour formation (soft tissue and bone);

- Fracture;

• Inhibitors against FVIII/FIX;

• Transfusion-related infections of concern in people with hemophilia:

- Human immunodeficiency virus (HIV);

- Hepatitis B virus (HBV);

- Hepatitis C virus (HCV);

- Hepatitis A virus (HAV);

- Parvovirus B19;

- Others.

HEMOPHILIA AND SURGERY

The following issues are of prime importance when performing elective surgery on persons

with hemophilia:

• Surgical procedures should be performed in co-ordination with a team experienced in

the management of hemophilia.

• Procedures should take place in a centre with adequate laboratory support for reliable

monitoring of clotting factor level.

• Pre-operative assessment should include inhibitor screening.

• Surgery should be scheduled early in the week and early in the day for optimal

laboratory and blood bank support, if needed.

• Availability of sufficient quantities of clotting factor concentrates should be ensured

before undertaking major surgery for hemophilia.

• The dosage and duration of clotting factor concentrate coverage depends on the type

of surgery performed

Screening tests

• The following tests may be used to screen a patient suspected to have a bleeding

disorder: platelet count, BT, PT, and APTT.

• Based on these tests, the category of bleeding disorder may be identified

(See table below).

• These screening tests may not detect abnormalities in patients with mild bleeding

disorders and in those with factor XIII (FXIII) deficiency or those with low fibrinolytic

inhibitor activity (alpha 2 antiplasmin, PAI-1)

condition	PT	PTT	BT	PLATELETS COUNT
NORMAL	N	N	N	N
HEMOPHILIA A OR B	N	PROLONGED	N	N
VWD	N	N OR PROLONGED	N OR PROLONGED	N OR REDUCED
Platelet defect	N	N	PROLONGED	N OR REDUCED

Choice of products for replacement therapy

Cryoprecipitate

• Cryoprecipitate is prepared by slow thawing of fresh frozen plasma (FFP) at 4°C

for 10–24 hours.

• When cryoprecipitate appears as an insoluble precipitate and is separated by

centrifugation, it contains significant quantities of FVIII (about 5 IU/ml), von Willebrand

factor (vWF), fibrinogen, and FXIII (but not FIX or XI). The resultant supernatant is

called cryo-poor plasma and contains other coagulation factors such as factors VII,

IX, X, and XI.

Fresh Frozen Plasma and Cryo-Poor Plasma

As FFP and cryo-poor plasma contain FIX, they are still used for the treatment of

hemophilia B in countries unable to afford plasma-derived FIX concentrates.

• FFP can also be used for the treatment of bleeding in patients with some of the rarer

congenital disorders of coagulation where specific concentrates are not available

(e.g., factor V).

• FFP and cryo-poor plasma may also be used for the treatment of patients with mild

factor XI (FXI) deficiency when a specific concentrate is not available or when its use

may be contraindicated because of the potential for thrombogenicity.

Other Pharmacological Options

In addition to conventional coagulation factor concentrates, there are other agents which can be of great value in a significant proportion of cases. These include:

• Desmopressin;

• Tranexamic acid; and

• Epsilon aminocaproic acid.

Desmopressin (DDAVP)

Desmopressin (1-deamino-8-D-arginine vasopressin, also known as DDAVP) is a synthetic

analogue of antidiuretic hormone (ADH). The compound boosts the plasma levels of FVIII

and vWF after administration.

The most common mode of administration is by intravenous infusion, but it may

also be given by subcutaneous injection.

• A single intravenous infusion at a dose of 0.3 micrograms/kg body weight can be

expected to boost the level of FVIII three- to sixfold.

• The peak response is seen approximately 90 minutes after completion of the infusion.

Tranexamic acid

Tranexamic acid is an antifibrinolytic agent that competitively inhibits the activation of

plasminogen to plasmin. It promotes clot stability and is useful as adjunctive therapy in

hemophilia and some other bleeding disorders. Tranexamic acid is also of use in FXI

deficiency, where its use to cover dental, gynecologic, or urologic surgery in FXI-deficient

patients may obviate the need for replacement therapy with concentrates or plasma.

Tranexamic acid is usually given in tablet form at a typical dose of 3 or 4 grams (in

divided doses) daily for an adult and is generally very well tolerated.

Aminocaproic acid

Epsilon aminocaproic acid (EACA) is a drug similar to tranexamic acid but it is less widely

used nowadays as it has a shorter plasma half-life, is less potent, and is more toxic.

Administration:

• EACA is typically administered to adults at the following dosage: 5 gm immediately

followed by 1 gm every hour for 8 hours or till bleeding stops. It is available as tablets

and injection. A 250 mg/ml syrup formulation is available and the commonly used

pediatric dosage is 50-100 mg/kg (maximum 5 gms) PO or IV every 6-8 hours.

Treatment of Hemophilia A (FVIII Deficiency)

FVIII concentrates

Commercially prepared, lyophilized FVIII is available under a variety of brand names. All

plasma-derived products have undergone viral attenuation. Consult the product insert guide

for specific instructions.

Dosage

• Vials of factor concentrates are available in dosages ranging from approximately 250

to 2000 units each.

Each FVIII unit per kilogram of body weight infused intravenously will raise the plasma

FVIII level approximately 2%. The half-life is approximately 8–12 hours. Verify the

calculated dose by measuring the patient’s factor level.

• Calculate the dosage by multiplying the patient’s weight in kilograms by the factor

level desired multiplied by 0.5. This will indicate the number of factor units required.

Example: (50 kg x 40 (% level desired) x 0.5 = 1,000 units of FVIII).

Refer to Table 1 on page 45 for suggested factor level and duration of replacement

required based on type of hemorrhage.

Cryoprecipitate/fresh frozen plasma

• Only use cryoprecipitate if factor concentrates are not available. Cryoprecipitate is

best prepared from repeatedly tested and virus-negative donors.

Treatment of Hemophilia B (FIX Deficiency) FIX concentrates

• Commercially prepared, lyophilized FIX concentrates are available under a variety of

brand names. All plasma-derived products have undergone viral attenuation. FIX

concentrates fall into two classes:

- Pure coagulation FIX products, and

- Prothrombin complex concentrates (PCCs).

Dosage

• Vials of FIX concentrates are available in doses ranging from approximately 300 to

1200 units each.

• Each FIX unit per kilogram of body weight infused intravenously will raise the plasma

FIX level approximately 1%. The half-life is about 18-24 hours. Verify calculated doses

by measuring the patient’s factor level.

• Recombinant FIX (rFIX; BeneFIX®, Wyeth) has a lower recovery, and each FIX unit

per kg body weight infused will raise the FIX activity by approximately 0.8% in

adults and 0.7% in children < 15 years of age. The reason for lower recovery of rFIX

is not entirely clear.

• To calculate dosage, multiply the patient’s weight in kilograms by the factor level

desired. This will indicate the number of factor units required.

Example: 50 kg x 40 (% level desired) = 2000 units of plasma-derived FIX. For rFIX,

the dosage will be 2000 ÷ 0.8 (or 2000 x 1.25) = 2500 units for adults, and

2000 ÷ 0.7 (or 2000 x 1.43) = 2860 units for children.

Fresh frozen plasma (FFP)

• For patients with hemophilia B, fresh frozen plasma should only be used if FIX concentrates are unavailable.

HEMOPHILIA AND ANESTHESIA

IN PREPARING FOR SURGERY

 patients with haemophilia A for surgery, factor VIII levels are routinely raised to approach 100% of normal activity.

 It should be maintained for the first 3 postoperative days from the day 4 onwards it should be maintained at 80%, from 7th day onwards it is allowed to decline to 40% of  normal activity.

 Intramuscular pre medication should be avoided.

 Vascular access itself does not cause excessive bleeding and should be appropriate for the proposed procedure.

 If the decision is made to proceed with neuraxial anaesthesia, a subarachnoid block using a small gauge spinal needle may be preferable to epidural anaesthesia.

 extra care should be taken in manipulation or intubation of the airway as it can cause submucosal haemorrhages, which can prove life threatening.

 Nasal intubation should be avoided, as it can prove traumatic and bleeding from the site can lead to aspiration.

 Care should be taken during positioning of the extremities and pressure points should be padded to prevent intramuscular haematomas or haemarthrosis.

 Post operatively analgesics such as aspirin and other NSAIDs should not be given as it can predispose to gastrointestinal haemorrhage.

 Patien tcontrolled analgesia is a safe and effective alternative to intramuscular injections.