Hemophilia A

DDAVP.

Primary therapy is based on disease severity and type of hemorrhage.9 Most patients with mild to moderate disease and a minor bleeding episode can be treated with 1-desamino-8-d-arginine vasopressin (desmopressin acetate [DDAVP]), a synthetic analog of the antidiuretic hormone, vasopressin. DDAVP causes release of von Wil-lebrand's factor (vWF) and factor VIII from endothelial storage sites. DDAVP increases plasma factor VIII levels by three-to five-fold within 30 minutes. The recommended dose is 0.3 mcg/kg IV (in 50 mL normal saline infused over 15-30 min) or subcutaneously or 150 to 300 mcg intranasally via concentrated nasal spray every 12 hours. Peak effect with intranasal administration occurs 60 to 90 minutes after administration, which is somewhat later than with IV administration. Desmopressin infu sion may be administered daily for up to 2 to 3 days. Facial flushing, hypertension or hypotension, GI upset, and headache are common side effects of desmopressin. Water retention and hyponatremia may occur; patients should be instructed to limit water intake while taking desmopressin. Serious side effects include seizures related to hyponatremia, most frequently seen in children younger than two years of age, and myocardial infarction in the elderly. Tachyphylaxis, an attenuated response with repeated administration, may occur after several doses.10 Use of DDAVP is contraindic-ated in patients with creatinine clearance less than 50 mL/min.

Antifibrinolytic Therapy.

Aminocaproic acid and tranexamic acid are antifibrinolytic agents that reduce plas-minogen activity leading to inhibition of clot lysis and clot stabilization. These agents are usually used as adjuncts in dental procedures or in difficult-to-control epistaxis and menorrhagia episodes.

Factor VIII Replacement.

Patients with severe hemophilia may receive primary (before the first major bleed) or secondary (after the first major bleed) prophylaxis. All hemophiliacs with a major bleed require factor VIII replacement.11 The therapy may include recombinant (produced via transfection of mammalian cells with the human factor VIII gene) or plasma-derived (concentrate from pooled plasma) factor VIII (Table 67-2). The choice of product and dose are based on the overall clinical scenario because the efficacy of various preparations does not differ. Newer-generation plasma-derived coagulation factor concentrates are considerably safer owing to advancements in viral testing and inactivation technology. While original recombinant factor VIII concentrates were stabilized with human serum albumin, potentially creating a source for viral contamination, new generation recombinant factor VIII concentrates are stabilized with sucrose, eliminating the concern for viral transmission.

The severity of hemorrhage and its location are major determinants of percentage correction to target, as well as duration of therapy (Table 67-3). The normal range of factor VIII activity level is 1 IU/mL (0.001 IU/L), which corresponds to 100% of the factor found in 1 mL of normal plasma. Minor bleeding may be treated with a goal of 25% to 30% (0.25-0.30 IU/mL [0.00025-0.0003 IU/L]) of normal activity, whereas serious or life-threatening bleeding requires at least 50% of normal activity. Factor VIII is a large molecule that remains in the intravascular space and its estimated volume of distribution is approximately 50 mL/kg. Generally, factor VIII levels increase by 2% (0.02 IU/mL [0.00002 unit/L]) for every 1 unit/kg of factor VIII con centrate infused. To calculate factor VIII replacement dose, the following equation can be used:

Table 67-2 Factor Concentrates

Bond NjiJn»

PrpType

Vlrjil I nsctlvilion w EKlujIon M.j[h ort 0[hf r <7n nie Ji.t-j

FActûr VJII CeAHnliittf

Aftjhwnale Hemofihil M MyiKiiW-P KbSa-DV) Mona it M Morocliie P

SCHIIJIL' HOSiWtC-F5 Kogerutc Kogl? nate FS ft«0<iJ3lrvni FlefaHo rldynj

Plasma

Pliim^

PU Sifid

FidLmj

HxjoroblnJm

Kctomblrkml

RroonüJlrMftl

Prior* bina^l

Reoomblnani

RhV.ijhï: liiii.iiil

REtun>birwi Bdornjin Ofclewd

SolVenl (JtrtFf^ed, (J'y haul

Solvent delprgefURioncrloru/l antibody

Pweu rira tin

Sotvcrn JtrtCT^Crtu, Ay r*ui

Salven! (IrtPitjerU, monot kina/l antibody l\ineijfiias»sfi. BfKKWflofWl indbocSy

Honc

None iotutm [Jcipftxfii

Monotkinal jntitody

Solvent daeige«, monoclonal antibody

Ww le nul Jiirityy ly

None

Albumin, hermrin, vWT

Albumin

Alhnmin, vWf

Albumin. IHWln, vWf

Albumin

Albumin

Albumin

Ailiumin DloNiii'nr.iiicynonlyXMCW' Albumin

Albumin (teuneniiuion onlyl futro&e ADumln

Albumin (lei(nenlitf«m onlyl vitro»

Table 67-3 Guidelines for Replacement Dosing With Factor VIII and Factor IX

Pnirnf Plain» F*Cto.r VIH

Pr iirt-d PI«im* FasHjr XI

Typ« if HiimDrrhd g<i

Lrvtl fli 4f Nirm Jl>

L i v.■ of Wein 1.,

DurJliön of Thiripy (cfjyi)

CMS, Intracianial, i<wüp>ui y r*jAil, retroperitoneal-sur^kal piaphyldxt iwiikj hefiumhioiii. rnutcsaHie.g,.

<jjpeilV ial hematoma

30-30

Facta*VlLq-B-lihcuM lû-lidat« Facta« IX:q 12 hover U)-l« days hacTBi viitq h o^c* î-îijyi Fartai IX: q 1J-2« tiow?f 1-? days

Dose of factor VIII (units) = weight (kg) x (desired percentage increase) x 0.5

Thus, to increase factor VIII levels by 50% (e.g., from 0 to 50%) in a 70 kg (154 lb)

patient, an IV dose of 1,750 units is required. The half-life of factor VIII ranges from 8

to 15 hours. Half the initial dose is given every half-life (every 8-12 hours) to maintain

the desired factor VIII level. Although intermittent bolus infusions of factor VIII

concentrates have been used successfully, continuous-infusion protocols are being instituted successfully in patients requiring prolonged treatment of acute hemorrhage to avoid dangerously low trough levels and decrease the overall cost of therapy.

Hemophilia B Factor IX Replacement

Hemophilia B therapy may include recombinant (produced via transfection of mammalian cells with the human factor IX gene) or plasma-derived (concentrate from pooled plasma) factor IX (see Table 67-2). Guidelines for choosing the factor-concentrate formulation for hemophilia B are similar to the guidelines for hemophilia A. However, older-generation factor IX concentrates containing other vitamin K-de-pendent proteins (e.g., factors II, VII, and IX), called prothrombin complex concentrates (PCCs), have been associated with thrombogenic side effects. Consequently, these products are not first-line treatment for hemophilia B. Because it is a small protein, the factor IX molecule passes into both the intravascular and the extravascular spaces. Therefore, the volume of distribution of recombinant factor IX is twice that of factor VIII. Consequently, 1 unit of factor IX administered per kilogram of body weight yields a 1% rise in the plasma factor IX level (0.01 IU/mL [0.00001 units/L]). To calculate the factor IX replacement dose, the following equation can be used:

Dose of factor IX (units)

= weight (kg) x (desired percentage increase) x F Where F = 1 for human plasma-derived products and 1.2 for recombinant factor IX.

Thus, to increase factor IX levels by 50% (e.g., from 0 to 50%) in a 70 kg (154 lb) patient, the required dose of factor IX is 4,200 units IV (using the recombinant factor IX product). The half-life of factor IX ranges from 18 to 22 hours; therefore, doses are given every 12 to 24 hours.

Treatment of Patients With Factor VIII or IX Inhibitors

Factor VIII and IX inhibitors are antibodies that develop in 20% and 5% of hemophilia A and hemophilia B patients, respectively, in response to replacement therapy. These antibodies bind to and neutralize the activity of infused factor concentrates. Although the inhibitors do not increase hemorrhage frequency, their existence challenges the treatment of bleeding episodes. Titers of inhibitors are measured and reported in Beth-esda units (BU), and this measurement is used to guide therapy (Fig. 67-2). Management options for acute bleeding in patients with factor inhibitors include the ad ministration of factor VIII concentrates, PCCs, recombinant factor VIIa (rFVIIa), and porcine factor VIII. Immune tolerance induction can be attempted to prevent future bleeding episodes.

Factor VIII concentrates can be used in patients with low inhibitor levels to control acute bleeding episodes. The dose of factor VIII is determined based on clinical response (see Fig. 67-2).

PCCs contain the vitamin K-dependent factors II, VII, IX, and X. These agents bypass factor VIII at which the antibody is directed (see Fig. 67-2). However, PCCs carry the risk of serious thrombotic complications.

Factor VIIa (rFVIIa) is a bypassing agent designed to generate thrombin only at tissue injury sites, where it binds tissue factor. Due to its local action, rFVIIa is associated with fewer systemic thrombotic events than PCC. rFVIIa is used effectively in surgeries and spontaneous bleeds.13

Plasma-derived porcine factor VIII participates in the coagulation cascade in place of human factor VIII. However, due to contamination with parvovirus, it is no longer available. Recombinant porcine factor VIII is currently under review and could serve as a third-line agent (only after factor VIIa and a PCC have failed) owing to the relatively high incidence of cross-reactivity with factor VIII inhibitors.

Treatment Algorithm Hemophilia
FIGURE 67-2. Treatment algorithm for the management of patients with hemophilia A and factor VIII antibodies. Porcine factor VIII is currently not available in the United States. (BU, Bethesda unit; PCC, prothrombin complex concentrate; aPCC, activated prothrombin complex concentrate.)

Induction of immune tolerance is often performed with the goal of eliminating the inhibitor. Immune tolerance induction is accomplished by the administration of repetitive doses of factor VIII or IX with or without immunosuppressive therapy. It is effective in 70% of patients with hemophilia A and 30% of patients with hemophilia B.

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