Guidelines Summary
United Kingdom Haemophilia Centre Doctors’ Organisation guidelines
Guidelines for the management of acute joint bleeds and chronic synovitis in hemophilia from the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) include recommendations for patients with and without inhibitors. [67]
Hemostatic management of patients with inhibitors to factor IX includes the following:
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Patients with inhibitors should be encouraged to be on a home treatment program, and bleeds should be treated as early as possible.
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Activated prothrombin complex (aPCC) 50–100 μg kg −1 or recombinant factor VIIa (rFVIIa) 270 μg kg −1 as a single dose (or 90 μg kg −1 2–3 hourly) are equally acceptable treatments for joint or soft tissue bleeds, with repeated doses as necessary. The frequency of infusion and duration of treatment should be determined by the clinical response.
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The total daily dose of aPCC should not exceed 200 IU kg −1.
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Tranexamic acid can be considered as adjunctive therapy to aPCC and rFVIIa.
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Sequential alternating treatment of aPCC and rFVIIa can be considered for the management of limb/life-threatening bleeds.
Hemostatic management of patients without inhibitors includes the following:
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All patients with severe hemophilia A and B and other patients at risk of joint bleeding should be offered home treatment.
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The initial treatment of early and moderate bleeds should aim for a peak factor IX (FIX) level of 50 to 60 IU dL −1. This is equivalent to 40 to 60 IU kg −1 for severe hemophilia B, with extended half-life FIX being dosed at the lower end of the recommended range. Early bleeds often do not require a second infusion, and moderate bleeds often respond to a single infusion but may require up to 2 infusions.
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Children may require more frequent or higher doses, as they have a shorter factor half-life than adults.
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For joint-immobilizing bleeds, higher initial doses are recommended, which aim to raise the peak factor IX level to 60 to 80 IU dL −1. Doses should be administered every 24 hr until complete resolution of pain. For severe bleeds, more frequent administration may be required in the initial 48 hr with standard FIX.
International consensus recommendations
Consensus recommendations on the management of hemophilia B by an international group of hematology experts cover the following topics [68] :
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Factor treatment choice
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Therapeutic agent laboratory monitoring
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Pharmacokinetics considerations
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Inhibitor management
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Preparing for gene therapy
Factor treatment choice:
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Consider FIX prophylaxis in all people with severe hemophilia B, including those who have non-severe disease according to their basal FIX levels but with a severe bleeding phenotype); initiate prophylaxis as early as possible (ie, before the onset of joint bleeding) and donot interrupt it.
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Both standard half-life FIX and extended half-life recombinant FIX (EHL rFIX) are effective treatment options for prophylaxis, and can be used to offer adequate hemostatic cover for bleeds, surgery, and invasive procedures; however, when using EHLs, consider product-specific laboratory requirements for monitoring.
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Adapt the dose and frequency of FIX prophylaxis treatment to the clinical phenotype (eg, bleed rates) and lifestyle considerations, and not plasma trough levels exclusively.
Pharmacokinetics considerations
To determine whether pharmacokinetic analysis may guide individualized prophylaxis dosing, clinicians should review product-specific characteristics, as well as patient phenotype and joint status. Clinicians should consider population pharmacokinetics (ie, analysis of pharmacokinetics using a predictive algorithm derived from a large data repository for a given FIX product).
Laboratory monitoring
Recommendations for clinicians include the following:
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Chromogenic substrate assays (CSAs) provide higher levels of precision and accuracy in the assessment of FIX activity, whereas there may be variability with different one-stage assays (OSAs); however, CSAs may not be suitable for routine monitoring of recombinant FIX–albumin fusion protein (albutrepenonacog alfa).
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Insufficient evidence exists for thrombin generation assay or other global assays to guide routine clinical management.
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Current FIX gene therapy demonstrates consistently lower FIX activity when measured by CSA than by OSA; it is unclear which assay should be used to aid clinical decision making in gene therapy recipients.
Inhibitor management
Recommendations for patients with severe hemophilia B include the following:
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Determine the causative FIX genetic defect as soon as possible after the diagnosis, to identify the patients at increased risk of inhibitor development and/or severe allergic reaction.
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Perform inhibitor screening routinely, and intensify scrutiny in patients who develop allergic reactions to FIX and/or who have an inadequate response to FIX replacement therapy.
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During the first 20 exposure days, provide FIX infusion and close clinical observation for allergic reaction in the hospital setting.
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Recombinant activated factor VII should be the first choice for bleeding control and/or surgical cover in patientsand high-responding inhibitors, as well as in those who have developed allergic reactions; aPCC is an option, but the content of FIX and associated risk of anamnesis and/or worsening of allergic reaction(s) needs to be considered.
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Consider immune tolerance induction (ITI) to eradicate persistent inhibitors; however, the relative benefits and risks need to be taken into account; ITI should be initiated only in a hemophilia treatment center with an experienced team.
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Monitor patients closely during ITI for the development of nephrotic syndrome and/or severe allergic reactions.
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For those patients who have an allergic reaction, consider desensitization; importantly, further serious allergic reaction(s) should be anticipated in these patients, and subsequent infusions should occur in the hospital setting with appropriate resuscitation expertise and equipment.
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For FIX inhibitor eradication, first-line treatment consists of ITI protocols with a combination of FIX and immunosuppressive agents.
Preparing for gene therapy:
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Based on current AAV hemophilia B trial data, gene therapy should be considered as a future treatment option in adults with severe hemophilia B.
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As part of the informed consent process, patients should be made aware of the unpredictability of achieved FIX level and duration of expression.
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With liver-directed AAV gene therapy, patients should be aware that pre-existing liver pathology may be an exclusion criterion, and patients proceeding to gene therapy should be counselled about other potential sources of hepatotoxicity that may interfere with FIX expression (eg, medication use, alcohol)
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Clinicians should be aware that a rise in transaminase levels during the acute phase of gene therapy may indicate an immune response that can potentially threaten the expression of FIX; close monitoring of transaminase levels is needed to ensure that timely immunosuppression can be implemented.
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Clinicians should consider that the specific geographic pattern of AAV seropositivity may help direct which gene therapy is chosen.
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Coagulation Cascade
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Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.
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The hemostatic pathway: role of factor IX.
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Activation of factor IX and function of the intrinsic tenase complex. Activation of factor IX is followed by formation of the intrinsic tenase complex, which activates factor X to activated factor X, leading to a second and larger burst of thrombin production during activation of hemostasis.
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Vitamin K–dependent carboxylation of precursor factor IX to procoagulant factor IX. Carboxylation of glutamate (Glu) to gamma-carboxyglutamate (Gla) residues in the precursor protein of the vitamin K–dependent factors occurs in the endoplasmic reticulum of the hepatocyte. Reduced vitamin K is oxidized in this process. Warfarin prevents the reduction and recycling of oxidized vitamin K.
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Cell surfaced-directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor (TF)–bearing cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation. (Adapted from Hoffman and Monroe, Thromb Haemost 2001, 85(6): 958-65.)
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Knee radiographs in a patient with advanced hemophilic arthropathy demonstrate chronic severe arthritis, fusion, and loss of cartilage and joint space.
Tables
Classification |
Factor Activity, % |
Cause of Hemorrhage |
Mild |
>5-40 |
Major trauma or surgery |
Moderate |
1-5 |
Minor trauma or surgery; occasional spontaneous hemarthrosis |
Severe |
< 1 |
Lifelong spontaneous hemorrhages and hemarthroses starting in infancy |
Indication or Site of Bleeding |
Factor level Desired, % |
FIX Dose, IU/kg* |
Comment |
Severe epistaxis; mouth, lip, tongue, or dental work |
20-50 |
20-50 |
Consider aminocaproic acid (Amicar), 1-2 d |
Joint (hip or groin) |
40 |
40 |
Repeat transfusion in 24-48 h |
Soft tissue or muscle |
20-40 |
40 |
No therapy if site small and not enlarging (transfuse if enlarging) |
Muscle (calf and forearm) |
30-40 |
40 |
None |
Muscle deep (thigh, hip, iliopsoas) |
40-60 |
40-60 |
Transfuse, repeat at 24 h, then as needed |
Neck or throat |
50-80 |
50-80 |
None |
Hematuria |
40 |
40 |
Transfuse to 40% then rest and hydration |
Laceration |
40 |
40 |
Transfuse until wound healed |
GI or retroperitoneal bleeding |
60-80 |
60-80 |
None |
Head trauma (no evidence of CNS bleeding) |
50 |
50 |
None |
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) |
100 |
100 |
Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
Trauma with bleeding, surgery |
80-100 |
100 |
10-14 d |
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