Haemophilia

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

life-threatening/limb-threatening bleed

no factor inhibitor

1st line – factor concentrate

Back

1st line –

factor concentrate

Life-threatening bleeds include those occurring in the central nervous system (intracranial), gastrointestinal tract, or airway (neck/throat).[38] Large bleeding into the deep flexor muscle group within a closed space in the extremities may result in compartment syndrome, which is limb-threatening.[38]

Urgent treatment is necessary even before full assessment.[74]

The factor for relevant disorder (factor VIII for haemophilia A, factor IX for haemophilia B) should be administered urgently.

In patients with haemophilia A receiving emicizumab prophylaxis, factor VIII infusion at the dose expected to achieve haemostasis should be used for breakthrough bleeding.[38][61]

Factor levels need to be monitored to adjust dose and frequency. Monitoring is usually done by measuring a trough blood factor level before the first dose in the morning. In patients with haemophilia A receiving emicizumab prophylaxis, factor VIII level monitoring should be by chromogenic assay using bovine reagents.[38][61]

The goal is to maintain peak factor levels between 80% and 100% and trough levels no less than 40% to 50% for the first 10 to 14 days.

The factor dose needed to achieve a specific peak factor level can be determined using the following calculation: total factor dose=[weight (kg) x (desired % factor level - baseline % factor level)]/in vivo recovery.

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – supportive care + subspecialty consultations as needed

Back

Plus –

supportive care + subspecialty consultations as needed

Treatment recommended for ALL patients in selected patient group

Resuscitation and basic life supportive measures (ABC) are required.

Subspecialty consultation may be necessary, appropriate to the anatomical site of the haemorrhage.

For intracranial haemorrhage, anticonvulsant therapy may be required for management of seizures.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents such as tranexamic acid or aminocaproic acid may be used as an adjunctive therapy to factor replacement to control mucosal bleeding (oral, nasal, gastrointestinal, uterine).

Antifibrinolytic agents are contraindicated for the treatment of haematuria (as unlysed clots will behave like stones), and in the setting of thoracic surgery.[38] Antifibrinolytics should not be used for the treatment of any bleed whenever there is haematuria. Antifibrinolytics should be avoided in patients with bleeding into the thoracic cavity.

Antifibrinolytic agents should not be given concomitantly with factor VIII inhibitor bypassing fraction (an activated prothrombin complex concentrate [aPCC]) due to safety concerns regarding increased risk of thrombosis.[38]

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

low-titre factor inhibitor (<5 BU)

1st line – high-dose factor concentrate

Back

1st line –

high-dose factor concentrate

Urgent treatment is necessary, even before full assessment.[74]

High dose of the specific factor concentrate (factor VIII for haemophilia A, factor IX for haemophilia B) is usually successful at controlling bleeding in people with a low-titre inhibitor status.[63] However, if the patient is a known high responder (i.e., has had high inhibitory antibody levels in the past), it is likely that the inhibitor titre will rise considerably a few days after exposure to factor VIII or IX.

The approximate dose/kg of high-dose factor concentrate (for either factor VIII or factor IX) is calculated using a formula (2 × the titre in Bethesda units [BU] × % correction desired), but specialist advice is recommended.

In patients with haemophilia A receiving emicizumab prophylaxis, factor VIII level monitoring should be by chromogenic assay using bovine reagents.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – supportive care + subspecialty consultations as needed

Back

Plus –

supportive care + subspecialty consultations as needed

Treatment recommended for ALL patients in selected patient group

Resuscitation and basic life supportive measures (ABC) are required.

Subspecialty consultation may be necessary, appropriate to the anatomical site of the haemorrhage.

For intracranial haemorrhage, anticonvulsant therapy may be required for management of seizures.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents such as tranexamic acid or aminocaproic acid may be used as an adjunctive therapy to factor replacement to control mucosal bleeding (oral, nasal, gastrointestinal, uterine).

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

2nd line – bypassing agent

Back

2nd line –

bypassing agent

If haemostasis is not achieved with high-dose factor replacement, bypassing agents are indicated.

Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction.

The response rate for effective bleeding control is 64% to 90% for factor VIII inhibitor bypassing fraction, and 80% to 95% for recombinant factor VIIa.[70][71][72]

Thrombotic events have been reported.[73]

In haemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor bypassing fraction use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[69] If factor VIII inhibitor bypassing fraction must be used, follow local protocols for maximum dose limits. Consultation with a haemophilia specialist is advised.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – supportive care + subspecialty consultations as needed

Back

Plus –

supportive care + subspecialty consultations as needed

Treatment recommended for ALL patients in selected patient group

Resuscitation and basic life supportive measures (ABC) are required.

Subspecialty consultation may be necessary, appropriate to the anatomical site of the haemorrhage.

For intracranial haemorrhage, anticonvulsant therapy may be required for management of seizures.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents such as tranexamic acid or aminocaproic acid be used as an adjunctive therapy to factor replacement to control mucosal bleeding (oral, nasal, gastrointestinal, uterine).

Antifibrinolytic agents are contraindicated for the treatment of haematuria, and in the setting of thoracic surgery.[38] Antifibrinolytics should not be used for the treatment of any bleed whenever there is haematuria. Antifibrinolytics should be avoided in patients with bleeding into the thoracic cavity.

Antifibrinolytic agents should not be given concomitantly with factor VIII inhibitor bypassing fraction due to safety concerns regarding increased risk of thrombosis.[38]

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

high-titre factor inhibitor (≥5 BU)

1st line – bypassing agent

Back

1st line –

bypassing agent

Urgent treatment is necessary, even before full assessment.[74]

Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction (an activated prothrombin complex concentrate [aPCC]).

Factor VIII inhibitor bypassing fraction contains variable amounts of activated and precursor vitamin K-dependent clotting factors (factors II, VII, IX, and X), which generate thrombin by bypassing the coagulation cascade. The factor VIII inhibitor bypassing fraction dose should not exceed 200 units/kg per day and should be given for less than 2 consecutive days.

The response rate for effective bleeding control is 64% to 90% for factor VIII inhibitor bypassing fraction, and 80% to 95% for recombinant factor VIIa.[70][71][72]

Thrombotic events have been reported.[73]

In haemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor bypassing fraction use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[69] If factor VIII inhibitor bypassing fraction must be used, follow local protocols for maximum dose limits. In these patients, inhibitor level monitoring should be by chromogenic assay using bovine reagents. Consultation with a haemophilia specialist is advised.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – supportive care + subspecialty consultations as needed

Back

Plus –

supportive care + subspecialty consultations as needed

Treatment recommended for ALL patients in selected patient group

Resuscitation and basic life supportive measures (ABC) are required.

Subspecialty consultation may be necessary, appropriate to the anatomical site of the haemorrhage.

For intracranial haemorrhage, anticonvulsant therapy may be required for management of seizures.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents such as tranexamic acid or aminocaproic acid may be used as an adjunctive therapy to factor replacement to control mucosal bleeding (oral, nasal, gastrointestinal, uterine).

Antifibrinolytic agents should not be given concomitantly with factor VIII inhibitor bypassing fraction due to safety concerns regarding increased risk of thrombosis.[38]

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

ACUTE

congenital: non-life-threatening bleed into joint or muscle

no factor inhibitor

1st line – factor concentrate

Back

1st line –

factor concentrate

The relevant factor for haemophilia A or B (factor VIII for haemophilia A, factor IX for haemophilia B) is required.

Home infusion of clotting factor VIII or IX concentrates administered by a home healthcare nurse, trained parent, or patient, may be arranged for treatment of uncomplicated bleeding episodes or for prevention (prophylaxis).[38]

In haemophilia A patients without inhibitors who are receiving emicizumab prophylaxis, factor VIII infusion at the dose expected to achieve haemostasis should be used for treatment of bleeding. In these patients, factor VIII level monitoring should be by chromogenic assay using bovine reagents.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – physiotherapy + analgesics

Back

Plus –

physiotherapy + analgesics

Treatment recommended for ALL patients in selected patient group

Additional measures include protection, rest, ice, compression, and elevation (PRICE), analgesia, and physiotherapy.

Physiotherapy should be offered to every patient when joint bleeding has ceased, and not only to those who are at risk of joint contractures (due to repeated bleeds into the same [target] joint).[77] During recovery, early mobilisation and weight bearing may be considered and should be carefully balanced with rest. Prolonged immobilisation and joint paracentesis are not routinely necessary.[77]

Analgesics such as paracetamol, opioids (e.g., codeine), or cylo-oxygenase-2 (COX-2) inhibitors may be used. These may be combined, depending on the level of analgesia required.

Codeine is contraindicated in children younger than 12 years of age, and it is not recommended in adolescents 12 to 18 years of age who are obese or have conditions such as obstructive sleep apnoea or severe lung disease as it may increase the risk of breathing problems.[102] It is generally recommended only for the treatment of acute moderate pain, which cannot be successfully managed with other analgesics, in children 12 years of age and older. It should be used at the lowest effective dose for the shortest period and treatment limited to 3 days.[103][104]

The benefits versus risks for celecoxib must be considered in each individual case. Celecoxib may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. However, it continues to be recommended in a select group of patients. It is contraindicated if there is a prior history of hypertension, thrombosis, or renal disease, or in the presence of other risk factors such as obesity, advanced age, or smoking. Patients who have no contraindications need to be informed about the potential risks and consent to treatment. The use of celecoxib in children is very uncommon.

Primary options

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

codeine phosphate: adults: 15-60 mg orally every 4-6 hours when required, maximum 240 mg/day

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

celecoxib: adults: 100-200 mg orally once or twice daily when required

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

codeine phosphate: adults: 15-60 mg orally every 4-6 hours when required, maximum 240 mg/day

and

celecoxib: adults: 100-200 mg orally once or twice daily when required

Consider – orthopaedic + pain team evaluation

Back

Consider –

orthopaedic + pain team evaluation

Additional treatment recommended for SOME patients in selected patient group

The pain team may need to be consulted.

Orthopaedic evaluation may be required if there is a risk of contracture or muscle atrophy due to recurrent bleeds at the same site.

low-titre factor inhibitor (<5 BU)

1st line – high-dose factor concentrate

Back

1st line –

high-dose factor concentrate

High-dose factor concentrate (factor VIII for haemophilia A, factor IX for haemophilia B) is usually successful at controlling bleeding.

In patients with haemophilia A receiving emicizumab prophylaxis, factor VIII level monitoring should be by chromogenic assay using bovine reagents.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – physiotherapy + analgesics

Back

Plus –

physiotherapy + analgesics

Treatment recommended for ALL patients in selected patient group

Additional measures include protection, rest, ice, compression, and elevation (PRICE), analgesia, and physiotherapy.

Analgesics such as paracetamol, opioids (e.g., codeine), or cylo-oxygenase-2 (COX-2) inhibitors may be used. These may be combined, depending on the level of analgesia required.

Primary options

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

codeine phosphate: adults: 15-60 mg orally every 4-6 hours when required, maximum 240 mg/day

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 325-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

celecoxib: adults: 100-200 mg orally once or twice daily when required

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

codeine phosphate: 15-60 mg orally every 4-6 hours when required, maximum 240 mg/day

and

celecoxib: adults: 100-200 mg orally once or twice daily when required

Consider – orthopaedic + pain team evaluation

Back

Consider –

orthopaedic + pain team evaluation

Additional treatment recommended for SOME patients in selected patient group

The pain team may need to be consulted.

Orthopaedic evaluation may be required if there is a risk of contracture or muscle atrophy due to recurrent bleeds at the same site.

2nd line – bypassing agent

Back

2nd line –

bypassing agent

Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction (an activated prothrombin complex concentrate [aPCC]).

The response rate for effective bleeding control is 64% to 90% for factor VIII inhibitor bypassing fraction, and 80% to 95% for recombinant factor VIIa.[70][71][72]

Thrombotic events have been reported.[73]

In haemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor bypassing fraction use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[69] If factor VIII inhibitor bypassing fraction must be used, follow local protocols for maximum dose limits. In these patients, inhibitor level monitoring should be by chromogenic assay using bovine reagents. Consultation with a haemophilia specialist is advised.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – physiotherapy + analgesics

Back

Plus –

physiotherapy + analgesics

Treatment recommended for ALL patients in selected patient group

Additional measures include protection, rest, ice, compression, and elevation (PRICE), analgesia, and physiotherapy.

Analgesics such as paracetamol, opioids (e.g., codeine), or cylo-oxygenase-2 (COX-2) inhibitors may be used. These may be combined, depending on the level of analgesia required.

Primary options

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

codeine phosphate: adults: 15-60 mg orally every 4-6 hours when required, maximum 240 mg/day

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

celecoxib: adults: 100-200 mg orally once or twice daily when required

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

codeine phosphate: adults: 15-60 mg orally every 4-6 hours when required, maximum 240 mg/day

and

celecoxib: adults: 100-200 mg orally once or twice daily when required

Consider – orthopaedic + pain team evaluation

Back

Consider –

orthopaedic + pain team evaluation

Additional treatment recommended for SOME patients in selected patient group

The pain team may need to be consulted.

Orthopaedic evaluation may be required if there is a risk of contracture or muscle atrophy due to recurrent bleeds at the same site.

high-titre factor inhibitor (≥5 BU)

1st line – bypassing agent

Back

1st line –

bypassing agent

Bypassing agents are first-line therapy in high-titre inhibitor patients.

Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction (an activated prothrombin complex concentrate [aPCC]).

The response rate for effective bleeding control is 64% to 90% for factor VIII inhibitor bypassing fraction, and 80% to 95% for recombinant factor VIIa.[70][71][72]

Thrombotic events have been reported.[73]

In haemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor bypassing fraction use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[69] If factor VIII inhibitor bypassing fraction must be used, follow local protocols for maximum dose limits. In these patients, inhibitor level monitoring should be by chromogenic assay using bovine reagents. Consultation with a haemophilia specialist is advised.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – physiotherapy + analgesics

Back

Plus –

physiotherapy + analgesics

Treatment recommended for ALL patients in selected patient group

Additional measures include protection, rest, ice, compression, and elevation (PRICE), analgesia, and physiotherapy.

Analgesics such as paracetamol, opioids (e.g., codeine), or cylo-oxygenase-2 (COX-2) inhibitors may be used. These may be combined, depending on the level of analgesia required.

Primary options

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

codeine phosphate: adults: 15-60 mg orally every 4-6 hours when required, maximum 240 mg/day

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

celecoxib: adults: 100-200 mg orally once or twice daily when required

paracetamol: children: 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

and

codeine phosphate: adults: 15-60 mg orally every 4-6 hours when required, maximum 240 mg/day

and

celecoxib: adults: 100-200 mg orally once or twice daily when required

Consider – orthopaedic + pain team evaluation

Back

Consider –

orthopaedic + pain team evaluation

Additional treatment recommended for SOME patients in selected patient group

The pain team may need to be consulted.

Orthopaedic evaluation may be required if there is a risk of contracture or muscle atrophy due to recurrent bleeds at the same site.

congenital: non-life-threatening bleed into urinary tract

no factor inhibitor

1st line – factor concentrate

Back

1st line –

factor concentrate

The relevant factor for haemophilia A or B (factor VIII for haemophilia A, factor IX for haemophilia B) is required.

In haemophilia A patients without inhibitor receiving emicizumab prophylaxis, factor VIII infusion at the dose expected to achieve haemostasis should be used for treatment of bleeding. In these patients, factor VIII level monitoring should be by chromogenic assay using bovine reagents.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – intravenous or oral fluids + bed rest

Back

Plus –

intravenous or oral fluids + bed rest

Treatment recommended for ALL patients in selected patient group

Fluid replacement is with intravenous or oral fluid at a rate of 1.5 times maintenance levels.

low-titre factor inhibitor (<5 BU)

1st line – high-dose factor concentrate

Back

1st line –

high-dose factor concentrate

High-dose factor concentrate (factor VIII for haemophilia A, factor IX for haemophilia B) is usually successful at controlling bleeding.

In patients with haemophilia A receiving emicizumab prophylaxis, factor VIII level monitoring should be by chromogenic assay using bovine reagents.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – intravenous or oral fluids + bed rest

Back

Plus –

intravenous or oral fluids + bed rest

Treatment recommended for ALL patients in selected patient group

Fluid replacement is with intravenous or oral fluid at a rate of 1.5 times maintenance levels.

2nd line – bypassing agent

Back

2nd line –

bypassing agent

Bypassing agents such as recombinant factor VIIa or factor VIII inhibitor bypassing fraction (an activated prothrombin complex concentrate [aPCC]) may be used if high-dose factor is inadequate.

The response rate for effective bleeding control is 64% to 90% for factor VIII inhibitor bypassing fraction, and 80% to 95% for recombinant factor VIIa.[70][71][72]

Thrombotic events have been reported.[73]

In haemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor bypassing fraction use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[69] If factor VIII inhibitor bypassing fraction must be used, follow local protocols for maximum dose limits. In these patients, inhibitor level monitoring should be by chromogenic assay using bovine reagents. Consultation with a haemophilia specialist is advised.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – intravenous or oral fluids + bed rest

Back

Plus –

intravenous or oral fluids + bed rest

Treatment recommended for ALL patients in selected patient group

Fluid replacement is with intravenous or oral fluid at a rate of 1.5 times maintenance levels.

high-titre factor inhibitor (≥5 BU)

1st line – bypassing agent

Back

1st line –

bypassing agent

Bypassing agents are first-line therapy in high-titre inhibitor patients.

Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction (an activated prothrombin complex concentrate [aPCC]).

The response rate for effective bleeding control is 64% to 90% for factor VIII inhibitor bypassing fraction, and 80% to 95% for recombinant factor VIIa.[70][71][72]

Thrombotic events have been reported.[73]

In haemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor bypassing fraction use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[69] If factor VIII inhibitor bypassing fraction must be used, follow local protocols for maximum dose limits. In these patients, inhibitor level monitoring should be by chromogenic assay using bovine reagents. Consultation with a haemophilia specialist is advised.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – intravenous or oral fluids + bed rest

Back

Plus –

intravenous or oral fluids + bed rest

Treatment recommended for ALL patients in selected patient group

Fluid replacement is with intravenous or oral fluid at a rate of 1.5 times maintenance levels.

congenital: non-life-threatening nasal or oral bleeding

no factor inhibitor: mild haemophilia A

1st line – desmopressin + supportive care

Back

1st line –

desmopressin + supportive care

Desmopressin can be used in individuals (with a demonstrated positive response to desmopressin) with mild haemophilia A (factor levels >5%) with nasal or oral bleeding.[69]

A desmopressin test dose should be given in the doctor's office or clinic, which should produce a 2- to 4-fold rise in the levels of factor VIII or a peak level sufficient for management of the type/severity of bleeding or surgical procedure.

In the outpatient setting, desmopressin may be administered intranasally (150 micrograms in patients <50 kg, 300 micrograms in patients >50 kg; lower concentration intranasal preparations for enuresis will not be effective) or subcutaneously prior to dental procedures or for the management of oral/nasal mucosal bleeding. If bleeding is controlled, venipuncture is avoided.

Peak desmopressin levels tend to be higher and achieved faster following intravenous administration, which is typically used in the inpatient setting.

During desmopressin use, patients should be advised to limit water intake in order to reduce the risk of excessive fluid retention and the risk of developing hyponatraemia and seizures. A practical guide is to limit fluid intake to ≤1.5 L for 24 hours after desmopressin administration. Serum sodium concentration should be monitored when repeated doses of desmopressin are given. Avoid more than 3 consecutive daily doses of desmopressin to reduce the risk of tachyphylaxis. Desmopressin should not be used in children <2 years of age.

Supportive care includes general observation and red blood cell transfusion if needed.

Primary options

desmopressin: outpatient weight <50 kg: 150 micrograms intranasally once daily, maximum 3 days treatment; outpatient weight >50 kg: 300 micrograms intranasally once daily, maximum 3 days treatment; outpatient: 0.3 micrograms/kg subcutaneously initially, a second dose may be given 8-24 hours after the first according to response; inpatient: 0.3 micrograms/kg intravenously initially, a second dose may be given 8-24 hours after the first according to response

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents such as tranexamic acid or aminocaproic acid may be used as an adjunctive therapy to factor replacement to control mucosal bleeding (oral, nasal, gastrointestinal, uterine). Antifibrinolytic agents are contraindicated for the treatment of haematuria, and in the setting of thoracic surgery.[38] Antifibrinolytics should not be used for the treatment of any bleed whenever there is haematuria. Antifibrinolytics should also be avoided in patients with bleeding into the thoracic cavity.

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

2nd line – on-demand factor VIII concentrate + supportive care

Back

2nd line –

on-demand factor VIII concentrate + supportive care

If initial treatment is unsuccessful or the bleeding is severe, factor VIII concentrate is given on-demand every 12 to 24 hours until symptoms have resolved. Treatment can be administered on an outpatient basis.

Supportive care includes general observation and transfusions as needed.

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents should not be given concomitantly with factor VIII inhibitor bypassing fraction due to safety concerns regarding increased risk of thrombosis.[38]

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

no factor inhibitor: haemophilia B or moderate-severe haemophilia A

1st line – on-demand factor concentrate + supportive care

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1st line –

on-demand factor concentrate + supportive care

The appropriate factor concentrate (factor VIII for haemophilia A or factor IX for haemophilia B) is given on-demand every 12 to 24 hours until symptoms have resolved. Treatment can be administered on an outpatient basis.

Desmopressin is not effective for the treatment of patients with haemophilia B, as factor IX levels are not influenced by desmopressin.

Supportive care includes general observation and transfusions as needed.

In haemophilia A patients without inhibitors receiving emicizumab prophylaxis, factor VIII infusion at the dose expected to achieve haemostasis should be used for treatment of bleeding. In these patients, factor VIII level monitoring should be by chromogenic assay using bovine reagents.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

low-titre factor inhibitor (<5 BU)

1st line – high-dose factor concentrate + supportive care

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1st line –

high-dose factor concentrate + supportive care

High dose of the specific factor concentrate (factor VIII for haemophilia A, factor IX for haemophilia B) is usually successful at controlling bleeding.

Supportive care entails hydration and transfusions as needed.

In haemophilia A patients receiving emicizumab prophylaxis, factor VIII level monitoring should be by chromogenic assay using bovine reagents.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents should not be given concomitantly with factor VIII inhibitor bypassing fraction (an activated prothrombin complex concentrate [aPCC]).[38]

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

2nd line – bypassing agent + supportive care

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2nd line –

bypassing agent + supportive care

If high-dose factor concentrate does not control bleeding after initial dose, switching treatment to a bypassing agent is recommended.

The response rate for effective bleeding control is 64% to 90% for factor VIII inhibitor bypassing fraction, and 80% to 95% for recombinant factor VIIa.[70][71][72]

Thrombotic events have been reported.[73]

Supportive care includes observation and transfusions as needed.[73]

In haemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor bypassing fraction use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[69] If factor VIII inhibitor bypassing fraction must be used, follow local protocols for maximum dose limits. In these patients, inhibitor level monitoring should be by chromogenic assay using bovine reagents. Consultation with a haemophilia specialist is advised.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents should not be given concomitantly with factor VIII inhibitor bypassing fraction due to safety concerns regarding increased risk of thrombosis.[38]

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

high-titre inhibitor (≥5 BU)

1st line – bypassing agent + supportive care

Back

1st line –

bypassing agent + supportive care

Bypassing agents are first-line therapy in high-titre inhibitor patients.

Bypassing agents include recombinant factor VIIa or factor VIII inhibitor bypassing fraction (an activated prothrombin complex concentrate [aPCC]).

The response rate for effective bleeding control is 64% to 90% for factor VIII inhibitor bypassing fraction, and 80% to 95% for recombinant factor VIIa.[70][71][72]

Thrombotic events have been reported.[73]

Supportive care includes observation and transfusions as needed.

In haemophilia A patients with inhibitors who are receiving emicizumab prophylaxis, factor VIII inhibitor bypassing fraction use may be associated with thrombotic microangiopathy and thrombosis and should be avoided for up to 6 months after emicizumab use.[69] If factor VIII inhibitor bypassing fraction must be used, follow local protocols for maximum dose limits. In these patients, inhibitor level monitoring should be by chromogenic assay using bovine reagents. Consultation with a haemophilia specialist is advised.[38][61]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Consider – antifibrinolytic agent

Back

Consider –

antifibrinolytic agent

Additional treatment recommended for SOME patients in selected patient group

Antifibrinolytic agents should not be given concomitantly with factor VIII inhibitor bypassing fraction due to safety concerns regarding increased risk of thrombosis.[38]

Antifibrinolytic agents are usually well tolerated. The most common adverse effect is gastrointestinal discomfort.

Primary options

aminocaproic acid: 100-200 mg/kg orally/intravenously as a loading dose, followed by 100 mg/kg every 6 hours for 5-14 days, maximum 30 g/day

tranexamic acid: 10 mg/kg intravenously every 6-8 hours while unable to take oral medication, followed by 25 mg/kg orally every 6-8 hours for 3-8 days

acquired

1st line – bypassing agent or recombinant porcine factor VIII

Back

1st line –

bypassing agent or recombinant porcine factor VIII

Treatment of acquired haemophilia involves the use of bypassing agents (such as factor VIII inhibitor bypassing fraction [an activated prothrombin complex concentrate (aPCC)], recombinant activated factor VIIa) or recombinant porcine factor VIII to control acute bleeding episodes.[78][79][80]

Recombinant activated factor VIIa is indicated for use in patients with acquired haemophilia A due to inhibitors.[69]

Recombinant porcine factor VIII is less likely to be affected by antibodies against human factor VIII that are present in people with acquired haemophilia A.

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Plus – immunosuppression

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Plus –

immunosuppression

Treatment recommended for ALL patients in selected patient group

Immunosuppression with prednisolone plus cyclophosphamide is usually effective at reducing inhibitor production and bringing about a sustained rise in the factor VIII level.

Rituximab, usually in combination with prednisolone, may be an alternative immunosuppressive agent.[81][82]

Primary options

prednisolone: 1 mg/kg orally once daily

-- AND --

cyclophosphamide: 50-100 mg/day orally

rituximab: 375 mg/square metre of body surface area intravenously once weekly for 4 weeks

ONGOING

inhibitors to factor VIII or IX

1st line – immune tolerance induction (ITI)

Back

1st line –

immune tolerance induction (ITI)

The ultimate goal in patients with factor inhibitors is to eliminate the inhibitor with the use of ITI.[96]

Patients receive high doses of factor VIII or IX concentrate for months to years, usually given once a day, although some patients may be treated 3 times/week.

The international multicentre trial (International Immune Tolerance Study) demonstrated that high-dose (200 U/kg/day) and low-dose (50 U/kg 3 times per week) factor VIII regimens achieved a comparable success rate of about 70% in patients with haemophilia A factor inhibitors.[97] However, the low-dose approach was slower to achieve the tolerisation end point, and was associated with more bleeding events during ITI.[97][98]

The success rate is lower with haemophilia B factor inhibitors.[38] Furthermore, haemophilia B patients with factor inhibitors and a history of anaphylaxis to factor IX should be monitored carefully for the development of nephrotic syndrome during ITI with factor IX concentrates.[38]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

while inhibitor is present and/or during ITI

Plus – prophylaxis

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Plus –

prophylaxis

Treatment recommended for ALL patients in selected patient group

While the factor inhibitor remains present, the patient continues to be at risk of bleeding.

Prophylaxis with a bypassing agent may be used to decrease bleeding rates in patients with factor inhibitors.[68] This may be done during ITI (although bleeding rates tend to decrease once ITI is initiated), if unable to initiate ITI, or if ITI fails to clear the inhibitor.

Prophylaxis with bypassing agents reduces overall and joint bleeding rates in patients with factor inhibitors compared with on-demand treatment, but does not significantly improve health-related quality of life.[100]

Typical infusion schedules vary depending on the bypassing agent used. Consult specialist for guidance on dose.

Emicizumab, a humanised monoclonal antibody, is approved for prophylaxis in haemophilia A patients with and without inhibitors.[92][93]

Consult with a specialist for guidance on dose, treatment of acute bleeds, and prophylaxis for surgery, and for appropriate monitoring tests for quantitation of coagulation factor VIII activity and factor VIII inhibitors while using emicizumab.

after successful ITI

Plus – prophylaxis

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Plus –

prophylaxis

Treatment recommended for ALL patients in selected patient group

Prophylaxis is recommended after successful ITI.[38][83] It is defined as the regular administration of a haemostatic agent/agents with the goal of preventing bleeding in people with haemophilia while allowing them to lead active lives and achieve quality of life comparable to non-haemophilia individuals.[38]

For haemophilia A, the typical infusion schedule is 2 to 3 times weekly with standard recombinant or plasma-derived factor VIII, or once every 5 to 7 days for extended half-life (long-acting) factor VIII. Standard recombinant or plasma-derived factor IX is usually administered twice weekly for haemophilia B; however, extended half-life factor IX molecules are generally administered once every 7 to 14 days to maintain trough levels of 3% to 5% or higher.[38]

Individualised prophylaxis protocols using target trough levels and pharmacokinetic-guided profiling (taking into account considerations such as joint status, physical activity and lifestyle, availability of clotting factors, patient ability to undertake self-guided care, and acceptability of various regimens) are intended to optimise patient outcome.[88][89] Extended half-life clotting factor concentrates may be given more frequently than once every 7 to 14 days, with the aim of increasing the trough levels to allow for a more active lifestyle without much increase in overall factor consumption.

Prophylaxis is also recommended following the initial treatment of intracranial bleeding.[83] In this scenario, different treatment regimens have been suggested, ranging from infusions every other day to weekly infusions.

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor concentrate formulation and dose.

Emicizumab, a humanised monoclonal antibody, is approved for prophylaxis in haemophilia A patients with and without inhibitors.[92][93]

In patients after ITI success, it is not clear if prophylaxis using clotting factor concentrate is required to maintain tolerance, so that the merit of using emicizumab versus clotting factor infusion for post ITI prophylaxis is at this time not clear and needs further study. Consult with a specialist for guidance on dose, treatment of acute bleeds, and prophylaxis for surgery, and for appropriate monitoring tests for quantitation of coagulation factor VIII activity and factor VIII inhibitors while using emicizumab.

with recurrent bleeds into single joint

Plus – orthopaedic evaluation for radioactive synovectomy

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Plus –

orthopaedic evaluation for radioactive synovectomy

Treatment recommended for ALL patients in selected patient group

The majority of patients will require a single injection, although some patients may require more than one injection to the same joint at different times. The procedure can be performed in adults and children.

Synoviorthesis offers some advantages over surgical synovectomy: less invasive; outpatient procedure; associated with fewer infections; reduced risk of postoperative bleeding.[105]

If radioactive synovectomy fails, then surgical synovectomy may be considered. If there is severe joint damage, a joint replacement or fusion may be indicated.

no VIII/IX inhibitors: severe haemophilia

1st line – prophylaxis

Back

1st line –

prophylaxis

Prophylaxis is indicated in most patients with severe haemophilia A or B.[68] It is defined as the regular, continuous administration of a haemostatic agent/agents, with the goal of preventing bleeding in people with haemophilia while allowing them to lead active lives and achieve quality of life comparable to non-haemophilia individuals.[38]

Primary prophylaxis refers to therapy initiated in young patients (aged <3 years) with haemophilia, prior to clinically detectable joint damage (preventive therapy) and before the second major joint bleed.[83] Secondary prophylaxis refers to therapy initiated after 2 or more bleeds into large joints, and before the onset of joint disease.[1][83] Tertiary prophylaxis refers to therapy initiated after development of joint disease.[83]

Formulations of factor concentrates vary; consult specialist for guidance on selecting the most appropriate factor formulation and dose.

Emicizumab, a humanised monoclonal antibody, is approved for prophylaxis in haemophilia A patients with and without inhibitors.[92][93]

with recurrent bleeds into single joint

Plus – orthopaedic evaluation for radioactive synovectomy

Back

Plus –

orthopaedic evaluation for radioactive synovectomy

Treatment recommended for ALL patients in selected patient group

Radioactive synovectomy (synoviorthesis) may be recommended when there are recurrent bleeds into a target joint. Orthopaedic evaluation is needed prior to the procedure. In the US, the most commonly used radioisotope is phosphorus-32. Yttrium-90 has also been used successfully.[75] The majority of patients will require a single injection, although some patients may require more than one injection to the same joint at different times. The procedure can be performed in adults and children.

Synoviorthesis offers some advantages over surgical synovectomy: less invasive; outpatient procedure; associated with fewer infections; reduced risk of post-operative bleeding.[76]

If radioactive synovectomy fails, then surgical synovectomy may be considered. If there is severe joint damage, a joint replacement or fusion may be indicated.

no VIII/IX inhibitors: mild-moderate haemophilia with recurrent bleeds into single joint

1st line – orthopaedic evaluation for radioactive synovectomy

Back

1st line –

orthopaedic evaluation for radioactive synovectomy

Radioactive synovectomy (synoviorthesis) may be recommended when there are recurrent bleeds into a target joint. Orthopaedic evaluation is needed prior to the procedure. In the US, the most commonly used radioisotope is phosphorus-32. Yttrium-90 has also been used successfully.[75]The majority of patients will require a single injection, although some patients may require more than one injection to the same joint at different times. The procedure can be performed in adults and children.

Synoviorthesis offers some advantages over surgical synovectomy: less invasive; outpatient procedure; associated with fewer infections; reduced risk of post-operative bleeding.[76]

If radioactive synovectomy fails, then surgical synovectomy may be considered. If there is severe joint damage, a joint replacement or fusion may be indicated.

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Haemophilia

Treatment algorithm

life-threatening/limb-threatening bleed

factor concentrate

supportive care + subspecialty consultations as needed

antifibrinolytic agent

Primary options

high-dose factor concentrate

supportive care + subspecialty consultations as needed

antifibrinolytic agent

Primary options

bypassing agent

supportive care + subspecialty consultations as needed

antifibrinolytic agent

Primary options

bypassing agent

supportive care + subspecialty consultations as needed

antifibrinolytic agent

Primary options

congenital: non-life-threatening bleed into joint or muscle

factor concentrate

physiotherapy + analgesics

Primary options

orthopaedic + pain team evaluation

high-dose factor concentrate

physiotherapy + analgesics

Primary options

orthopaedic + pain team evaluation

bypassing agent

physiotherapy + analgesics

Primary options

orthopaedic + pain team evaluation

bypassing agent

physiotherapy + analgesics

Primary options

orthopaedic + pain team evaluation

congenital: non-life-threatening bleed into urinary tract

factor concentrate

intravenous or oral fluids + bed rest

high-dose factor concentrate

intravenous or oral fluids + bed rest

bypassing agent

intravenous or oral fluids + bed rest

bypassing agent

intravenous or oral fluids + bed rest

congenital: non-life-threatening nasal or oral bleeding

desmopressin + supportive care

Primary options

antifibrinolytic agent

Primary options

on-demand factor VIII concentrate + supportive care

antifibrinolytic agent

Primary options

on-demand factor concentrate + supportive care

antifibrinolytic agent

Primary options

high-dose factor concentrate + supportive care

antifibrinolytic agent

Primary options

bypassing agent + supportive care

antifibrinolytic agent

Primary options

bypassing agent + supportive care

antifibrinolytic agent

Primary options

acquired

bypassing agent or recombinant porcine factor VIII

immunosuppression

Primary options

inhibitors to factor VIII or IX

immune tolerance induction (ITI)

prophylaxis

prophylaxis

orthopaedic evaluation for radioactive synovectomy

no VIII/IX inhibitors: severe haemophilia

prophylaxis

orthopaedic evaluation for radioactive synovectomy

no VIII/IX inhibitors: mild-moderate haemophilia with recurrent bleeds into single joint

orthopaedic evaluation for radioactive synovectomy