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Chapter 136 Inhibitors in Hemophilias 2029

Treatment Options for Bleeding in a Patient With Factor VIII Deficiency and an Inhibitor
Low Titer, Low Responder Life- or Limb-Threatening Bleeding
Mild Bleeding • FVIII in high doses to maintain levels of 100%
• Local and conservative measures, such as rest, ice, compression, • Frequent monitoring for an anamnestic response, usually within 5
and elevation to 7 days
• If the patient is known to respond to DDAVP (i.e., mild hemophilia • After the anamnestic response develops:
A), 0.3 µg/kg IV or 300 µg intranasal (150 µg per nostril; 150 µg • Recombinant FVIIa (270 µg/kg, may be considered with caution
for patients <50 kg) for minor bleeding or treatment before minor versus 90 µg/kg every 2 to 3 hours)
surgery • Activated prothrombin complex concentrates (50 to 100 units/
• Oral antifibrinolytic therapy (ε-aminocaproic acid or tranexamic kg, with a maximum daily dose of 200 units/kg)
acid) for mucosal bleeding High Titer, High Responder
• FVIII dosing to raise the level to 50% Mild Bleeding
• Recombinant FVIIa (90 to 120 µg/kg, followed by 90 µg/kg every 2
to 3 hours) • Local and conservative measures, such as rest, ice, compression,
• Activated prothrombin complex concentrates (50 to 100 units/kg, and elevation
with maximum daily dose of 200 units/kg) • Oral antifibrinolytic therapy (ε-aminocaproic acid or tranexamic
• Concurrent treatment with antifibrinolytics should be administered acid) for mucosal bleeding
with caution • Recombinant FVIIa (270 µg/kg, should be considered with caution
versus 90 µg/kg every 2 to 3 hours)
Life- or Limb-Threatening Bleeding • Activated prothrombin complex concentrates (100 units/kg, with a
• FVIII dosing to maintain FVIII activity levels at 100% maximum daily dose of 200 units/kg)
• Recombinant FVIIa (270 µg/kg for one dose may be considered • Concurrent treatment with antifibrinolytics should be administered
with caution versus 90 µg/kg every 2 to 3 hours) with caution
• Activated prothrombin complex concentrates (100 units/kg, with Life- or Limb-Threatening Bleeding
maximum daily dose of 200 units/kg)
• Concurrent treatment with antifibrinolytics should be administered • Recombinant FVIIa (270 µg/kg, should be considered with caution
with caution versus 90 µg/kg IV every 2 to 3 hours)
• Activated prothrombin complex concentrates (100 units/kg, with a
Low Titer, High Responder maximum daily dose of 200 units/kg)
Mild Bleeding • If available, immunoadsorption can be attempted to rapidly lower
• Local and conservative measures, such as rest, ice, compression, the inhibitor titer so as to allow use of FVIII
and elevation Main Features of the Agents Effective for Inhibitor Treatment/Prophylaxis
• If the patient is known to respond to DDAVP (i.e., mild hemophilia • Content APCC: activated vitamin k-dependent clotting factors;
A), 0.3 µg/kg IV or 300 µg intranasal (150 µg for patients <50 kg) rFVIIa: recombinant FVIIa alone
for minor bleeding or treatment before minor surgery • Mechanism of action APCC: activate plasma FX and FII; rFVIIa:
• Oral antifibrinolytic therapy (ε-aminocaproic acid or tranexamic activates FX on platelets
acid) for mucosal bleeding • Half-Life APCC: putatively 8-12 hours; rFVIIa: 2-3 hours
• Recombinant factor VIIa (270 µg/kg, bolus may be considered with • Efficacy APCC: about 80%; rFVIIa: about 80%
caution versus 90 µg/kg every 2 to 3 hours)
• Activated prothrombin complex concentrates (100 units/kg, with a
maximum daily dose of 200 units/kg, may induce anamnesis)

of exogenous FVIII therapy ineffective, so that even when exogenous with severe liver disease. PCCs were hypothesized to be useful to treat
FVIII replacement is anticipated to be effective in the short term, FVIII inhibitor-related bleeding because of their thrombogenic
treatment should start with factor VIIa (FVIIa) or an APCC if pro- properties. Prepared from large pools of normal donor plasma, the
longed periods of replacement therapy are necessary. PCCs contain the vitamin K–dependent clotting factors prothrom-
In the case of a severe bleed or a life-threatening emergency, the bin, FVII, FIX, and FX, as well as anticoagulant proteins C and S.
inhibitor titer should be determined as rapidly as possible, but treat- Heparin or antithrombin is added to some preparations to limit
ment should not be delayed until the results are available. For patients activation of the coagulation factors during the manufacturing
with a known persistent high-titer antibody, prompt replacement process and with administration. All PCCs undergo a viral inactiva-
treatment should consist of a bypass agent, either an APCC or tion process. In comparison with placebo, PCCs were shown to be
recombinant FVIIa (rFVIIa). partially effective in controlling approximately 50% of bleeding
episodes in patients with FVIII alloantibody inhibitors, compared
105
with 25% for product containing albumin alone. A major caveat
Surgery is that administration of PCCs to treat hemorrhage in hemophiliacs
with inhibitors is not the treatment of choice and is justified only in
Surgery in patients with hemophilia, especially those who have an the absence of more effective therapies. 105
inhibitor, requires the involvement of an entire facility experienced
in the preoperative and postoperative care of such patients. Replace-
ment therapy recommendations for surgical procedures are similar to Activated Prothrombin Complex Concentrates
those for hemorrhage. For known low responders, adequate hemo- and Factor VIIa
stasis can be achieved with higher doses of FVIII. For the high-
responding patient, APCC or rFVIIa are the most effective in the APCCs are PCCs that are supercharged by virtue of their partial
postoperative setting. 8–10 activation during the manufacturing process with activated FVII
credited for the maximum clotting potential. In a randomized,
double-blind trial, an APCC showed significantly better control of
Prothrombin Complex Concentrates bleeding events in severe hemophiliacs with inhibitors than did PCCs
(p = .0085); however, APCC was judged effective in only 64% of the
106
Prothrombin complex concentrates (PCCs) were designed for treat- episodes versus 52% effectiveness for PCC. Uncontrolled clinical
ment of bleeding events associated with hemophilia B, congenital studies have shown that APCCs are effective in treating 81% to 93%
deficiencies of the other vitamin K–dependent clotting disorders, or of joint bleeds. 107,108 One should bear in mind, however, that APCCs