hemophilia a

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Hemophilia AAndre Kurniawan

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WHAT IS HEMOPHILIA?

Inherited hemorrhagic disorder caused by deficiency of factor VIII or factor IX.

X linked recessive inheritance hence affect males exclusively.

Incidence in Hemophilia A 1 in 5000 male live births.

Incidence in Hemophilia B 1 in 30,000 male live births.

Female who carry a single mutated gene, are generally asymtomatic.

TYPES Disease Factor deficiency Inheritance

Hemophilia A VIII X linked recessive

Hemophilia B IX X linked recessive

3www.ihtc.org/patient/blood-disorders/hemophilia-a-and-b/

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CAUSES

Mutations in F8 gene

Deficiency of factor VIII

Hemophilia A

www.ihtc.org/patient/blood-disorders/hemophilia-a-and-b/

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Accurate diagnosis of hemophilia is essential to inform appropriate management. Hemophilia should be suspected in patients presenting with a history of

Easy bruising in early chilhood“Spontaneous” bleeding (bleeding for no

known reason, particularly into the joints, muscles, and soft tissues

Excessive bleeding following trauma or surgery

A family history of bleeding is obtained in about two-thirds of all patients

A definitive diagnosis depends on factor assay to demonstrate deficiency of FVIII or FIX

Guidelines For The Management of Hemophilia

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CLINICAL MANIFESTATIONS

bleeding can happen anywhere in the body.

following an injury / surgery or spontaneous.

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PATHOPHYSIOLOGY

http://accesmedicine.net/pathophysiology

8www.studyblue.com/notes/note/b-11-coagulation-cascade/

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STAGES OF HEMOSTASIS

INJURY

VESSEL WALL+PLATELET

FORMATION OF PLT PLUG

ACTIVATION OF PLASMA COAGULATION FACTORS

FORMATION OF STABLE FIBRIN CLOT

PRIMARY

SECONDARY

DISSOLUTION OF FIBRIN CLOT BY FIBRINOLYSIS

www.hemostasis.com/hemostasis/

10www.eclinpath.com/hemostasis/physiology/primary/hemostasis

COAGULATION CASCADE IN HEMOPHILIA

13Guidelines For The Management of Hemophilia

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Type of hemorrhage Hemophilia A Hemophilia B

Hemarthrosis 40 IU/kg on day1; then 20 IU/ kg on days 2, 3, 5 until joint function is normal or back to baseline. Consider additional treatment every other day for 7-10 days. Consider prophylaxis.

60-80 IU/kg on day 1; then 40 IU/kg on days 2, 4. Consider additional treatment every other day for 7-10 days. Consider prophylaxis.

Muscle or significant subcutaneous hematoma

20 IU/kg; may need every-other-day treatment until resolved.

40 IU/kg; may need treatment every 2-3 days until resolved.

Mouth, deciduous tooth or tooth extraction

20 IU/kg; antifibrinolytic therapy; remove loose deciduous tooth.

40 IU/kg; antifibrinolytic therapy; remove loose deciduous tooth.

EpistaxisApply pressure for 15-20 min; pack with petroleum gauze; give antifibrinolytic therapy; 20 IU/kg if this treatment fails.

Apply pressure for 15-20 min; pack with petroleum gauze; give antifibrinolytic therapy; 30 IU/kg if this treatment fails.

Major surgery, life threatening hemorrhage

50-75 IU/kg, then initiate continuous infusion of 2-4 IU/kg/hr to maintain FVIII >100 IU/dL for 24hr, then give 2-3 IU/kg/hr continuously for 5-7d to maintain the level at >50 IU/dL and an additional 5-7d at a level of >30 IU/dL

120 IU/kg, then 50-60 IU/kg every 12-24 hr to maintain FIX >40 IU/dL for 5-7 d and then >30 IU/dL for 7 d.

Hematuria Bed rest; 1.5 times maintenance fluids; if not controlled in 1-2 d, 20 IU/kg FVIII.

Bed rest; 1.5 times maintenance fluids; if not controlled in 1-2 d, 40 IU/kg FIX

Prophylaxis 20-40 IU/kg FVIII every other day to achieve a trough level of > 1%.

30-50 IU/kg FIX every 2-3 days to achieve a trough level of > 1%.

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Acute bleeds should be treated as quickly as possible.

In emergency situations, all patient should carry easily accesible identification indicating the diagnosis, severity of the bleeding, type of treatment product used, initial dosage for treatment.

Administration of desmopressin can raise FVIII level adequately (3 to 6 times baseline level) to control bleeding.

Principle of Care


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Drugs affect platelet function : ASA and NSAID should be avoided. Paracetamol/acetaminophen is a safe alternative for analgesia

Factors level should be raised to appropriate levels prior to any invasive procedures

Good oral hygiene prevents periodontal disease and dental caries, which predispose to gum bleeding


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Acute and chronic pain are common in patients with hemophilia. Adequate assesment of the cause of pain is essential to guide proper management.1.Pain caused by venous access2.Pain caused by joint or muscle bleeding3.Post-operative pain4.Pain due to chronic hemophilic arthropathy

Pain Management


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Pre-operative assesment should include inhibitor screening and inhibitor assay.

Adequate quantities of clotting factor concentrates should be available for the surgery itself and to maintain adequate coverage post-op.

The dosage and duration of clotting factor concentrate coverage depends on the type of surgery performed.

Surgery and Invasive Procedures


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Platelet count, BT, PT, and APTT may be used to screen a patient suspected of having a bleeding disorder

Bleeding time lacks sensitivity and specifity and is also prone to performance-related error. Therefore other test of platelet function such as platelet aggregometry are preferred when available.

Screening test


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Based of the result of these test, the category of bleeding disorder may be partially characterized to guide subsequent analysis

These screening test may not detect abnormalities in patients with mild bleeding disorders including some defect of platelet function, FXIII deficiency, and those rare defects of fibrinolysis, which may be associated with a bleeding tendency.

Screening test


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Clotting factor concentrates The WFH strongly recommends the use of viral inactivated plasma-derived or recombinant concentrates in preference to cryoprecipitate or fresh frozen plasma for thr treatment of hemophilia and other inherited bleeding disorders.

Product selection1. Purity of product 2. Viral inactivation/elimination

Hemostatic Agents


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Purity1. Purity of concentrates refers to the percentage of the

desired ingredient (e.g FVIII),relative to the other ingredients present.

2. Concentrate of lower purity give rise to allergic reaction3. Products with higher purity tend to be associated with low

manufaturing yields.these concentrates are, therefore, costlier.

4. Plasma-derived FVIII concentrates may contain variable amounts of von willebrand factor (VWF)

5. For treatment of FIX deficiency, a product containing only FIX is more appropriate than prothrombin complex concentrates, which also contain other clotting factors such as factor II,VII, and X, some of which may become activated during manufacture. Products containing activated clotting factors may predispose to thromboebolism


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Viral inactivation/elimination1. In process viral inactivation is the single largest

contributor to the safety of plasma-derived concentrate.

2. There is growing tendency to incorporate two specific viral-reducing steps in the manufacturing process of concentrate Heat treatment is generally effective

aganinst broad range of viruses, both with or without a lipid envelope, including HIV, HAV, HBV, and HCV

Solvent/detergent treatment is effective against HBV, HCV, and HIV but does not inactivate non-enveloped viruses such as HAV

3. Some viruses (such as human parvovirus B19) are relatively resistent to both types of process.


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4. Nano (ultra) filtration can be used to remove small viruses such as parvovirus.

FVIII concentrateFVIII concentrates are the treatment of choicehemophilia ADosage/administration5. Vials of factor concentrates are available in

dosage ranging from 250 to 3000 units each.6. In the absence of inhibitor,each unit of FVIII

per kilogram of BW infused IV will raise the plasma FVIII level approximately 2 IU/dl.

7. The half-life of FVIII is approximately 8-12 hours


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4. The patient’s factor level should be measured 15 minutes after the infusion to verify the calculated dose

5. The dose is calculated by multiplying the patient’s BW in kg by the desired rise in factor level in IU/dl, multiplied by 0.5Ex: 50 kg x 40 (IU/dl) x 0.5 = 1000 units of FVIII

6. FVIII should be infused by slow IV injection at a rate not to exceed 3 ml per minute in adults and 100 units per minute in young children


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4. Subsequent dose should ideally be based on the half-life of FVIII and on the recovery in an the individual patient

5. Continous infusion avoids peaks and troughs and is considered by some to be advantageous and more convenient.

6. Continous infusion may lead to a reduction in the total quantity of clotting factor concentrates used and can be more cost-effective in patients with severe hemophilia.


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1. The WFH supports the use of coagulation factor concentrates in preference to cryoprecipitate or fresh frozen plasma (FFP) due to concerns about their quality and safety.

2. Cryoprecipitate and FFP are not subjected to viral inactivation procedures, leading to an increased risk of transmission of viral pathogens, which is significant with repeated infusions.

3. Allergic reaction more common following infusion of cryoprecipitate than concentrate.

Other plasma products


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1. As FFP contains all the coagulation factors, it is sometimes used to treat coagulation factor deficiencies

2. Cryoprecipitate is preferable to FFP for the treatment of hemophilia A

3. Due to concerns about the safety and quality of FFP, its use is not recomended

4. It is posssible to apply some forms of virucidal treatment to packs of FFP (including solvent/detergent treatment), and the use of treated packs is recommended.

Fresh Frozen Plasma (FFP)


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Dosage/administration1. One ml of FFP contains 1 unit of factor activity2. It is difficult to achieve FVIII levels higher than 30

IU/dl with FFP alone3. FIX levels above 25 IU/dl are difficult to achieve. 4. An acceptable starting dose is 15-20 ml/kg


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1. Cryoprecipitate is prepared by slow thawing of FFP at 4°C for 10-24 hours

2. Cryoprecipitate contains significant quantities of FVIII (about 3-5 IU/ml),VWF,fibrinogen and FXIII but not FIX or FXI.

3. Due to concerns about safety and quality of cryoprecipitate, its use in the treatment of congenital bleeding disorders is not recommended and can only be justified in situations where clotting factor concentrate are not available

Cryoprecipitate


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Dosage/administrationA bag of cryoprecipitate made from unit of FFP (200-250 ml) may contain 70-80 units of FVIII in a volume of 30-40 ml

Other pharmacological optionsIn addition to conventional coagulation factor concentrates, other agents can be of great value in a significant proportion of cases. These include :1.Desmopressin 2.Tranexamic acid3.Epsilon aminoproic acid


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Desmopressin1. Desmopressin is a synthetic analogue of

vasopressin that boosts plasma levels of FVIII and VWF

2. DDAVP may be the treatment of choice for patients with mild or moderate hemophilia A when FVIII can be raised to an appropriate theraupetic level because it avoids the expense and potential hazards of using a clotting factor concentrate

3. Desmopressin does not affect FIX levels and is no value in hemophilia B

4. DDAVP is particularly useful in the treatment or prevention of bleeding in carriers of hemophilia.


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4. Although DDAVP is not licensed for use in pregnancy, there is evidence that it can be safely used during delivery and in the post-partum period in an otherwise normal pregnancy. Its use should be avoided in preeclampsia because of the already high levels of VWF.

5. Obvious advantages of DDAVP over plasma products are the much lower cost and the absence of any risk of transmission of viral infections.

6. DDAVP may also be useful to control bleeding and reduce the prolongation of bleeding time associated with disorders of hemostasis, including congenital platelet disorders.


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1. Desmopressin is given subcutaneously in most patients, it can also be administered by intravenous infusion or by nasal spray.

2. Appropriate preparations include : 4 μg/ml for iv use 15 μg/ml for iv and sc use 150 μg/ml per meterd dose as nasal spray

3. A single dose of 0.3 μg/ml BW, either by iv or sc route, can be expected to boost the level FVIII three to six fold

Dosage/administration


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4. For iv use, DDAVP is usually diluted in a least 50-100 ml of physiological saline and given by slow iv infusion over 20-30 minutes

5. The peak response is seen approximately 60 minutes after administration either intravenously or subcutaneously

6. Closely spaced repetitive use of DDAVP over several days may result in decreased response (tachyphylaxis). Factor concentrates may be needed when higher factor levels when higher factor levels are required for a prolonged period

7. Rapid infusion may result in tachycardia,flushing, tremor and abdominal discomfort


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1. Tranexamic acid is an antifibrinolytic agent that competitively inhibits the activation of plasminogen to plasmin.

2. It promote clot stability and is useful as adjunctive therapy in hemophilia and some other bleeding disorders.

3. Regular treatment with tranexamic acid alone is of no value in the prevention of hemarthroses in hemophilia

4. It is valuable in controlling bleeding from skin and mucosal surfaces (e.g. Oral bleeding, epistaxis, menorrhagia)

Tranexamic acid


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1. Tranexamic acid is given is an tablet 3-4 times daily. It can also be given by iv infusion 2-3 times daily, and also available as a mouthwash

2. GI upset (nausea, vomitting, or diarrhea) may rarely occur as a side effect, resolve if the dosage is reduced. Rapid injection may result dizziness and hyotension.

3. A syrup formulation is for pediatric use.

Dosage/administration


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4. Tranexamic acid is commonly prescribed for seven days following dental extractions to prevent post-op bleeding.

5. Tranexamic acid may be given alone/together with standard of coagulation factor concentrates.


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Epsilon aminocaproic acid (EACA)EACA is similar to tranexamic acid but is less widely used as it has a shorter plasma half-life, is less potent, more toxic

Dosage/administration1. EACA is typically administered to adult orally or

intravenously every 4-6 hours up to a max of 24 g/day in an adult

2. A 250 mg/ml syrup is also available3. GI upset is common complication, reducing the dose

often helps4. Myopathy is a rare adverse reaction specifically

reported, typically occuring after administration of high doses for several weeks

5. The myopathy is often painful and associated levels of creatine kinase and even myoglobinuria


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Terima Kasih

hemophilia a

Healthcare