The management of patients who develop factor VIII inhibitors is a complex medical and economic challenge. The clinical presentation of these patients is usually acute and requires expert and rapid decision-making, sufficient resources, and a committed health care staff to carry out the treatment plan.
These disorders are rare, but often life or limb threatening, and always demand individualized therapy. For these reasons, it is highly desirable that these seriously ill patients be managed at a Hemophilia Comprehensive Care Clinic, where the resources are readily available. When this is not possible, the treating physician should consult closely with a hemophilia clinic physician experienced in treating such patients. The ultimate goals in managing these patients are: (a) resolution of bleeding diathesis and (b) the elimination of the inhibitor. While intuitively it is preferable to separate these two major therapeutic goals, in practice both goals need simultaneous attention.

The intent of this document is not to present a comprehensive literature review, but rather to offer recommendations on practical approaches to patients with factor VIII inhibitors. These suggestions represent the work of the Inhibitor Subcommittee of the Association of Hemophilia Clinic Directors of Canada (AHCDC), but should not be considered the official policy of AHCDC

The treating physician will always have the prerogative to choose the treatment that he/she perceives to be the optimal approach to their patients. It is with this understanding that the following recommendations and comments ought to be followed.

In developing these recommendations, a few principles were considered:

a) Recombinant products are less likely to transmit infectious agents than human and/or animal products.

hemostasis in factor VIII deficient patients.

c) When choosing a specific product to be used in patients with inhibitors, the following represent the
preferable conditions:

1 For the use of recombinant human factor VIII (rHuman FVIII):

Low titre inhibitor at the time of therapy

Known anamnestic “non-responder” or low responder

Inhibitor titre can be lowered by immunoadsorbtion

c.2 For the use of porcine factor VIII (Porcine FVIII):

High anti-human titre inhibitor with little or no porcine FVIII reactivity

Laboratory monitoring of hemostatic therapy is necessary

Anti-porcine FVIII titre can be lowered by immunoadsorption

c.3 For the use of activated prothrombin complex concentrates (APCC's):

Known responsiveness to APCC's

High anti-human and anti-porcine FVIII titres

Absence of crush injury or advanced liver disease

Laboratory monitoring not a priority

c.4 For the use of Recombinant Factor VIIa (rVIIa):

High anti-human and anti-porcine FVIII titres

Laboratory monitoring not a priority

d) While the cost/benefit ratio is an important principle, safety issues were of paramount importance in designing treatment recommendations.

Aside from the specific systemic treatment(s) required for patients with factor VIII inhibitors, local management, as well as ancillary hemostatic strategies, should be employed. These include:

Rest or immobilization, local pressure, cold applications
Topical hemostatic agents (thrombin, fibrin sealants, topical gelatin sponges, topical aminocaproic acid
solution 10% et cetera)
Anti-fibrinolytic drugs (tranexamic acid or aminocaproic acid) are useful adjuncts in the management of
bleeding episodes, particularly in patients with mucosal bleeding; these agents are nonetheless
contraindicated in patients with disseminated intravascular coagulation, hematuria and in patients who have
received APCC's in the previous 12 hours
Desmopressin (DDAVP)
Platelet concentrates
Corticosteroids

Avoidance of minor trauma, trivial injury, careless phlebotomies, arterial punctures, acetylsalicylic acid containing products and non-steroidal anti-inflammatories is strongly recommended.

1.2 List of Abbreviations

FVIII	Factor VIII
Pd FVIII	Plasma derived factor VIII
B.U.	Bethesda Units
rVIIa	Recombinant factor VII a
rHumanVIII	Recombinant human factor VIII
DDAVP	Desmopressin acetate
APCC	Activated prothrombin complex concentrate
IVIG	Intravenous immunoglobulins
AHCDC	The Association of Hemophilia Clinic Directors of Canada
CI	Continuous infusion
ITI	Immune tolerance induction

1.3 Definitions

1. Low titre inhibitors

Inhibitors measured to be < 5 B.U.

2. Low responders

Patients whose inhibitor titre levels do not rise above 5 B.U. despite immunologic challenges with various
FVIII products or APCC's.

3. High responder, low titre

Patients whose inhibitor titre is low at the time of evaluation, but is known to increase above 5 B.U. in response to the administration of various FVIII products or APCC's

4. High responder, high titre

Patients whose inhibitor titre is elevated at the time of evaluation. Some of these patients may, with time, lower their titre of inhibitor and become high responder, low titre.

1.4 Products Used in Patients with Factor VIII Inhibitors in Canada*

Generic	Trade	Company		Recommended Initial Dose	Route	Subsequent Dosing
Recombinant FVIII	1) Kogenate 2) Recombinate	1) Bayer 2) Baxter	50-100 U/kg	iv	Repeat q8-12 hrs or by CI 5-10 U/kg/hr
Recombinant FVIIa	NiaStase	Novo-Nordisk	70-90 µg/kg	iv	Repeat q2 hrs until bleeding controlled, then q2-6 hrs
Porcine FVIII	Hyate C	Speywood	50-100 U/kg	iv	Repeat q8-12h or by CI 5-10 U/kg/hr
Desmopressin acetate	DDAVP Octostim	Ferring Ferring	0.3 µg/kg (max. 20 µg) or nasal spray	iv/sc or one puff each nostril	Repeat q24 hrs
Activated prothrombin complex concentrate	Feiba VH	Immuno Baxter	50-100 U/kg	iv	Repeat q6-12 hrs
Aminocaproic acid	Amicar	Wyeth-Ayerst	4-5 grams po or 100 mg/kg iv (max 5 g)	po or iv	Repeat q4-6 hrs po or by CI 15 mg/kg/hr iv (max 1 g/hr)
Tranexamic acid	Cyklokapron	Pharmacia	25 mg/kg po or 10 mg /kg iv	po or iv	Repeat po or iv q8 hrs

* For a detailed explanation of administration indications, precautions and side effects, please review the specific product monograph.

2.0 Management of Hemophiliacs with Factor VIII Inhibitors

2.1 General Comments

About 25% of hemophilia patients with severe factor VIII deficiency will develop factor VIII inhibitors.
Most inhibitors are of low titre and many of them disappear regardless of the treatment used. It is currently impossible to predict who will eventually go on to develop a high titre factor VIII inhibitor. Consequently, the discovery of a factor VIII inhibitor, even if low titre, should call for an attempt to abrogate it, thus decreasing the potential risk of development of a high titre inhibitor.

2.2 Diagnosis of Inhibitor

2.2.1 Specificity:

The diagnosis of factor VIII inhibitor, especially at low titre, can be difficult. Lupus anticoagulants sometimes mimic anti-factor VIII antibodies, especially at low dilutions. These antibodies are relatively common in young children after vaccinations, or in any age group after viral infections.

2.2.2 Titre

Determining the titre of the inhibitor, usually by the Bethesda method, to both human and porcine FVIII, is important for the management of these patients. There are many technical variables which may substantially influence this determination.

2.2.3 Clinical Significance

Some patients clearly do not respond even to high doses of factor VIII and yet the presence of the inhibitor is undetectable by Bethesda assay. Conversely, some patients clearly have easily measurable inhibitors in vitro and yet respond "normally" to treatment with "standard" doses of factor VIII.

2.3 Prevention

Although there is currently no known way of preventing the development of inhibitors in hemophiliacs, it is possible to prevent some of the bleeding problems in these patients by:

2.3.1 Early Diagnosis

Early identification of an inhibitor through frequent screening is important. Most inhibitors develop after a relatively small number of factor VIII treatment exposures. Screening programs should be designed accordingly. It is recommended that children should be screened every three to six months and adults should be screened annually. As well, screening for an inhibitor should be done before any surgical intervention.

2.3.2 Promoting prevention of bleeding by:

a) Patient education

avoidance of activities that predispose to injury

maintenance of good musculoskeletal condition and fitness, balanced physical activity, physiotherapy, etc.

proper equipment for sporting activities

shoes with shock absorbent soles

b) Active preventive dental care
c) Limitation of alcohol intake and avoidance of non-steroidal anti-inflammatory drugs
d) Early recognition and treatment of bleeding episodes
e) Consideration of radiosynovectomy at the earliest sign of the development of chronic synovitis.

2.4 Management of Bleeding Patients - Algorithms

Algorithm A

BLEEDING IN A NEWLY DIAGNOSED INHIBITOR PATIENT
WITH A LOW TITRE, < 5 BU HUMAN

Minor Bleeding:
Use recombinant human FVIII, or plasma derived human FVIII, if former is not available, in a dose of 100 units/kg bolus, followed by 50-100 U/kg at 8-12 hour intervals, for as long as judged necessary to control bleeding. Attaining therapeutic plasma levels of > 0.5 IU/mL is recommended. An antifibrinolytic agent may be administered concomitantly, if not contraindicated. Inability to maintain therapeutic levels of FVIII, associated with persistent bleeding and despite controlling for surgical causes, calls for switching the treatment to a high responder algorithm (see Algorithm D).
Major Bleeding:
Use recombinant human FVIII, or plasma derived factor VIII if the former is not available, in a dose of 100 U/kg bolus, followed by either continuous infusion of 10 units/kg/hour or by intermittent administration of 50-100 U/kg every 8-12 hours, to achieve plasma factor VIII levels of > 0.5 IU/mL. Therapeutic levels of plasma factor VIII should be maintained until bleeding resolves. An antifibrinolytic agent may be administered concomitantly, if there are no contraindications. In case of failure to attain hemostatic factor VIII levels, treat patient as a high responder (see Algorithm D).

If bleeding is controlled by either (a) or (b), and achieving immune tolerance is an intended goal, we recommend a maintenance dose of human FVIII of 50 units/kg, given three times per week for four weeks.
If after four weeks the inhibitor is:

Undetectable: continue with the administration of rHuman FVIII in a dose of 25 units/kg twice
weekly for three months (immune tolerization), and then stop. If the inhibitor is abrogated, then the patient
should be treated in the future as a hemophiliac without inhibitor.
Detectable, with titre of antihuman FVIII of:
- < 5 BU - discontinue further immune tolerization, and treat only if bleeding; these inhibitors will likely
  remain low titre or may spontaneously resolve, but their management is predictable and most often
  controllable. (see Algorithm B)
- > 5 BU - treat as high responder (see Algorithm C & D).

Algorithm A

Algorithm B

KNOWN LOW RESPONDER (INHIBITOR TITRE NEVER RECORDED AS EXCEEDING 5 BU)

Recombinant human FVIII, or plasma derived FVIII when the former is not available, should be used. The dose should be monitored according to the response, and is typically about twice the usual dose.
Antifibrinolytic agents may be helpful, particularly when there is mucosal bleeding.

Algorithm B

Algorithm C

BLEEDING IN A KNOWN HIGH RESPONDER (>5 BU) WITH A LOW TITRE
(< 5 BU)

a) Minor Bleeding:

Recombinant FVIIa in a dose of 70-90 µg/kg, every 2 hours, or an APCC in a dose of 50-100 U/kg every 12 hours should be given. Either may be repeated three to four times, as necessary. While concomitant use of antifibrinolytics can be administered with rVIIa, these should not be given less than 12 hours after APCC administration.

In the event of failure to respond to either rFVIIa or APCC, porcine FVIII should be given in a bolus dose of 75-100 U/kg followed by either continuous infusion of 5-10 U/kg/hr or by intermittent administration of 50-100 U/kg every 8-12 hours.

b) Major Bleeding or Surgery:

Porcine FVIII in a bolus dose of 100 U/kg should be administered, followed by either continuous infusion of 5-10 U/kg/hr or by intermittent administration of 50-100 U/kg every 8-12 hours, to maintain factor VIII activity of > 0.75 U/mL. Subsequent boluses of porcine FVIII may be required to attain therapeutic FVIII levels. Porcine FVIII is an appropriate agent in patients who have not previously been exposed to this agent or in those whose anti-porcine inhibitor level is known to be less than 5 B.U. Sometimes a good clinical response may be observed even in the absence of recovery of measurable plasma levels of factor VIII activity. Porcine FVIII infusion should be maintained until the bleeding episode is contained or there is clear evidence of failure.

Recombinant human FVIII, or plasma derived FVIII, if the former is not available, may be used initially, in a dose of 100 U/kg bolus followed by continuous infusion at 5-10 U/kg/hr or by intermittent administration
of 50-100 U/kg every 8-12 hours to attain plasma factor VIII levels of > 0.75 U/mL. Repeated boluses may be required to attain therapeutic FVIII levels. An anamnestic response with subsequent elevation of anti-human inhibitor is predictable.

Antifibrinolytic agents can be used with porcine and recombinant human FVIII.

In the event of failure with either porcine FVIII or recombinant human FVIII, the patient should be treated as a high responder with a high titre of factor VIII inhibitors, who failed the administration of porcine FVIII (see Algorithm D).

Algorithm D

BLEEDING IN A PATIENT KNOWN TO BE A HIGH RESONDER (> 5 BU)
WITH A HIGH TITRE INHIBITOR (> 5 BU)

a) Minor Bleeding

Recombinant FVIIa in a dose of 70-90 µg/kg every two hours, or an APCC in a dose of 50-100 U/kg every 12 hours, should be given. Either may be repeated three to four times as necessary. While concomitant use of antifibrinolytics is not contraindicated with rVIIa, this should not be given less than 12 hours post APCC administration.

In the event of failure to respond to either rFVIIa or APCC, porcine FVIII should be given in a bolus dose of 75-100 U/kg followed by either continuous infusion of 5-10 U/kg/hr or by intermittent administration of 50-100 U/kg every 12 hours, as needed.

b) Major Bleeding or Surgery

If the anti-porcine FVIII inhibitor levels are known to be < 5 BU, then porcine FVIII in a dose of 100 U/kg bolus followed by either continuous infusion at 5-10 U/kg/hr or intermittent administration of 50-100 U/kg at 8-12 hours can be used. Repeated boluses of porcine FVIII may be required to overcome the inhibitor. Antifibrinolytic agents can be used if there are no contraindications.

In the event that anti-porcine inhibitor titres are high or unknown, then recombinant FVIIa or an APCC may be used. Recombinant factor VIIa should be used in a dose of 70-90 µg/kg iv bolus which may be repeated every two hours for 4-6 doses as required. Antifibrinolytic agents can be used if there are no contraindications. The recommended bolus dose of the APCC is 50-100 U/kg and may be repeated at the same dose every 12 hours for 4 doses.

In the case of failure to control the bleeding with rVIIa, APCC's or with porcine FVIII,plasmapheresis or extracorporeal immunoadsorption and porcine FVIII infusions and platelet concentrates may be used to correct bleeding diathesis.

Algorithm D

2.5 Induction of Immune Tolerance

An important goal in the management of patients with factor VIII inhibitors is to eliminate the inhibitor, or less desirably, to convert a high titre inhibitor into a low titre one. The abrogation of the inhibitor makes the management of bleeding patients considerably more manageable.

Morbidity and mortality associated are significantly decreased in patients whose inhibitors are abolished.

One method to eliminate inhibitors is through the process of immune tolerance induction (ITI). Because of the considerable expense and complexity related to most ITI protocols, coordinating the available resources
and counseling of patients are important parts of this process. Patients with multiple recurrent bleeds, high inhibitor titres and no significant comorbid associations should be considered for ITI.

The highest priority for ITI are young children; in these individuals the potential harm from inhibitors is greatest and yet the success rate of ITI is the highest (and the total doses required for ITI are the least).

While many regimens of ITI have been described and used, no single protocol has yet been adopted as a standard for managing inhibitor patients. They vary with respect to inclusion criteria, schedule of factor VIII administration, specific products used, and duration of treatment.

To better understand the value of ITI in these subsets of patients, we recommend that hemophiliac patients with inhibitors be enrolled in prospective, randomized, well-designed, national and international studies
whenever possible. This is particularly needed due to the small number of patients having this condition.
Results of these studies will allow us to make evidence-based decisions on ITI protocols, and will shed light on the cost/benefit ratio of ITI in hemophiliac patients with inhibitors.

3.0 Management of Non-Hemophiliacs with Factor VIII Inhibitors

3.1 General Comments

3.1.1 Accurate diagnosis is essential. Factor VIII inhibitors in non-
hemophiliacs are usually diagnosed in actively bleeding patients, in whom the aPTT is found to be prolonged. They may rarely be found fortuitously in non-bleeding patients, for example when the aPTT is performed as a screening test prior to an invasive procedure. In all cases, but especially in the patient who is not bleeding, it is important to keep in mind that lupus anticoagulants are much more common than factor VIII inhibitors. Lupus anticoagulants also prolong the aPTT, and may artefactually lower the factor
VIII activity level if the sample is not sufficiently diluted.

3.1.2 The aPTT and mixing studies are screening tests. The diagnosis can only be confirmed by assay for factor VIII activity and anti-factor VIII inhibitor titre by Bethesda assay. The measurement of anti-porcine factor VIII inhibitor titre is strongly recommended.

3.1.3 Porcine factor VIII is usually more successful than human factor VIII, as the inhibitor usually has little or no cross-reactivity with the porcine molecule.

3.1.4 Appropriate investigation and treatment should be initiated for diseases known to be associated with a risk of factor VIII inhibitors, namely autoimmune disorders, malignancies, and dermatologic disorders.
Any drugs which may possibly be implicated should be discontinued.

3.1.5 The inhibitor titre as measured by Bethesda assay has a poor correlation with clinical bleeding behaviour in non-hemophiliac inhibitor patients. Assay results are therefore less valuable in guiding therapy in these patients than they are in hemophilia patients with inhibitors.

3.1.6 Many of these patients have never received human blood products and
may not require them in the future. Therefore if a factor VIII inhibitor bypassing agent is used, rVIIa is generally preferable to APCC's.

3.2 Algorithms: Management of Bleeding Patients

Algorithm E

PATIENTS WHOSE BLEEDING IS NOT IMMINENTLY LIFE OR LIMB THREATENING

The measurement of plasma factor VIII level, and the inhibitory titres against human and porcine FVIII is recommended.

Immunosuppression should be undertaken in most cases. The following regimen is
advised:

Begin prednisone 1 mg/kg/day (or equivalent) for three weeks or until elimination of the inhibitor
Immunoglobulins (IVIG) may also be given in a dose of 0.4 g/kg/day for 5 consecutive days. The
response to this agent is variable.
For the control of bleeding, non-pharmacologic or ancillary therapies may be sufficient in some cases.

Where hemostatic therapy is necessary, these choices are available:
- Desmopressin (DDAVP) may induce a hemostatic response. It is given in a dose of 0.3 µg/kg IV or SC (in the 4 µg/mL or 15 µg/mL formulations), to a maximum dose of 20 µg, or intranasally (as the high concentration formulation, 150 µg/puff, one puff into each nostril) as per the manufacturer's directions.
  This may be repeated at 24 hours, but the response to subsequent doses may decline.
- If desmopressin (DDAVP) fails (persistent or worsening of bleeding), give porcine FVIII 50-100 IU/kg, unless the anti-porcine FVIII titre is known to be high. If the immediate factor VIII increment is not satisfactory, determine whether the clinical situation will permit an observation period of three to four hours; a hemostatic response to porcine FVIII is sometimes seen even with only a small increment in factor VIII level. Some patients may require a repeated bolus of porcine FVIII of 50-100 U/kg to achieve therapeutic levels (>0.25 IU/ml). If the factor VIII and/or clinical response is satisfactory, repeat treatment either as intermittent administration at 12-24 hour intervals, or by continuous infusion at 5-10 U/kg/hr, as needed, at dosage levels determined by factor VIII levels and the clinical response.
- If porcine FVIII fails (persistent or worsening bleeding), give either rVIIa at 70-90 µg/kg every two hours, or an APCC at 50 -100 units/kg every 12 hours as needed, for three to four doses. In mild bleeding, one or two doses of either product may suffice. If further doses of rVIIa are needed, the interval may subsequently be lengthened according to the clinical response. Preliminary experience indicates that concomitant administration of antifibrinolytic agents and rVIIa is safe, but they are not indicated with the
  use of APCC's.

Concurrent use of immunosuppressive medications, eg. cyclophosphamide or azathioprine in a dose of 1.5 mg/kg/day (maximum 100 mg/day) should be considered for 8 to 12 weeks to eradicate the inhibitor.
Immunosuppressive drugs are contraindicated during pregnancy and lactation and should be carefully selected in young children and/or young adults. In postpartum patients, the inhibitors almost always resolve spontaneously, although the time course is unpredictable

Algorithm F

FOR PATIENTS WHOSE BLEEDING IS IMMINENTLY LIFE OR LIMB THREATENING

Begin prednisone and IVIG if appropriate, according to the considerations described above.
For first line hemostatic therapy, the physician should consider either porcine FVIII or rVIIa. The choice will depend on a judgment concerning the relative merits of a specific, measurable agent versus a recombinant product together with immediate availability. Relevant considerations will include age, previous blood product exposure and known inhibitor titre. If the titre is high, or if it is unknown and the
patient has recently received porcine FVIII, then rVIIa should be used.
If porcine FVIII is used, the initial dose should be 75-100 IU/kg. If there is a good factor VIII response (> 0.5 IU/mL), follow-up treatments may be given by intermittent injections (at 8-12 hour intervals) or by continuous infusion at 5-10 IU/kg/hr. If the response is inadequate, repeat bolus of porcine FVIII at 100-
200 IU/kg and measure recovery of plasma factor VIII. If the treatment with porcine FVIII fails, proceed to use rVIIa or an APCC.
For recombinant VIIa, the recommended dose is 70-90 µg/kg given every two hours for 4-6 doses as needed. APCC's should be administered in a dose of 50-100 IU/kg, every 6-12 hours for 4-6 doses, as needed. Antifibrinolytics can be used with either porcine FVIII or rVIIa but not with the APCC's due to the risk of thrombosis.
Failure of the above therapies calls for the use of plasmapheresis or extracorporeal immunoadsorption followed by porcine or recombinant human FVIII, according to availability and the titre of inhibitor against human or porcine FVIII.
Red cell transfusions may be needed if bleeding is profuse.
Concurrent use of immunosuppressive medications, eg. cyclophosphamide or azothiaprine in a dose of 1.5 mg/kg/day (maximum 100 mg/day) should be considered for 8 to 12 weeks to eradicate the inhibitor.
Immunosuppressive drugs are contraindicated during pregnancy and lactation and should be carefully selected in young children and/or young adults.

Algorithm F

Algorithm G

PATIENTS WHO HAVE FAILED TO RESPOND TO THE INITIAL ATTEMPT
AT IMMUNOSUPPRESSION (BUT HAVE NO ACTIVE BLEEDING)

If the factor VIII activity is below the hemostatic level (approximately <0.15 IU/ml) and/or surgery or an invasive procedure is contemplated, administer further immunosuppressive therapy as follows:
1. prednisone + IVIG as described above and either cyclophosphamide or azathioprine (e.g. 1.5 mg/kg/day to a maximum of 100 mg/day). Immunosuppressive drugs are contraindicated during pregnancy and
  lactation, and should be carefully selected in young children and/or young adults.
2. IVIG 0.4 g/kg/day for five days or cyclosporine A, 4 mg/kg/day in two divided doses (adjusted to maintain plasma levels between 125-225 mg/ml).
Maintenance doses of IVIG may be given if there was a favourable response to the initial course of therapy. The optimal treatment schedule should be determined empirically.
If the above measures fail after approximately six weeks of treatment, further immunosuppressive therapy may be attempted. Additional drugs which may be useful are methotrexate, 6-mercaptopurine and vincristine. Combination regimens, for example cyclophosphamide, vincristine and prednisone, have been used with some success.
If the factor VIII level is in the hemostatic range and there is no surgery or invasive procedure contemplated, the physician may choose to monitor the inhibitor level without therapy.

Algorithm G

4.0 PHYSICIAN CONTACT LIST

Name	Address	Email	Phone	Fax
Annie Kaplan	30 Bond Street (70 Bond LL), Toronto, On, M5B 1W8	Annie Kaplan<ahcdc@smh.toronto.on.ca	416-864-5042	416-864-5251
Georges Rivard	3175 Chemin Cote Ste-Catherine Montreal, PQ H3T 1C5	rivardge@medclin.umontreal.ca	514-345-4639	514-345-4884
Morel Rubinger	ON205 -100 Olivia St. Winnipeg, MB R3E 0V9	morel@mctrf.mb.ca	204-787-2128	204-787-1345
Jerry Teitel	St. Michael's Hospital 30 Bond Street Toronto, ON M5B 1W8	teitelj@smh.toronto.on.ca	416-864-5128	416-864-5870
Irwin Walker	McMaster University Medical Centre 1200 Main Street West Hamilton, ON L8N 3Z5	walkeri@fhs.mcmaster.ca	905-521-2100 x6384	905-521-4971

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SUGGESTIONS FOR THE MANAGEMENT OF HEMOPHILIACS AND NON-HEMOPHILIACS WITH FACTOR VIII INHIBITORS

TABLE OF CONTENTS

Generic

Trade

Company

Recommended Initial Dose

Route

Subsequent Dosing

2.2.1 Specificity:

2.2.2 Titre

2.2.3 Clinical Significance

2.3.1 Early Diagnosis

2.3.2 Promoting prevention of bleeding by:

Algorithm C

BLEEDING IN A KNOWN HIGH RESPONDER (>5 BU) WITH A LOW TITRE (< 5 BU)

Algorithm D

Algorithm E

Algorithm F

Algorithm G

4.0 PHYSICIAN CONTACT LIST

SUGGESTIONS

FOR THE MANAGEMENT OF

HEMOPHILIACS AND NON-HEMOPHILIACS

WITH FACTOR VIII INHIBITORS

Recommended
Initial Dose

Subsequent
Dosing

BLEEDING IN A KNOWN HIGH RESPONDER (>5 BU) WITH A LOW TITRE
(< 5 BU)