Hemophilia A and B: An Overview
ADJUVANT THERAPY
Desmopressin
Desmopressin is a synthetic vasopressin analogue that increases plasma factor VIII and von Willebrand factor (VWF) levels; it is used to prevent and treat bleeding episodes associated with dental and surgical procedures in patients with mild and moderate hemophilia A and von Willebrand disease.22 Desmopressin causes the release of VWF and factor VIII from storage in the Weibel–Palade bodies of the endothelial cells that line the blood vessels. Individual response to desmopressin varies, with factor VIII level increasing between 2 and 15 times baseline level in patients with mild or moderate hemophilia A.23 It is therefore recommended that patients undergo a therapeutic trial of desmopressin with laboratory measurement of response to factor VIII before it is used for treatment of bleeding episodes or as prophylactic therapy before dental and other surgical procedures. A similar response is generally seen in an individual patient with subsequent doses, and thus the factor VIII level attained after a trial dose can be used to predict the response to future therapy.24
The recommended intravenous dosage of desmopressin is 0.3 µg/kg, administered in 25 to 50 mL of normal saline, over a period of 20 to 30 minutes.25 A concentrated form of desmopressin is available for intranasal administration to treat bleeding disorders. The appropriate dose of concentrated intranasal desmopressin is 150 µg (1 puff) for persons weighing less than 50 kg, and 300 µg (1 puff in each nostril) for persons weighing more than 50 kg.26
,Antifibrinolytic Therapy
Antifibrinolytics (both epsilon-aminocaproic acid [EACA] and tranexamic acid) reversibly block the lysine binding sites of plasminogen, preventing its activation to plasmin and thus inhibiting the lysis of polymerized fibrin. EACA is also believed to stabilize the active form of thrombin activatable fibrinolysis inhibitor (TAFIa). It is believed that inactivation of TAFIa is due to conformational rearrangements in the TAFIa molecule; EACA has been shown to slow down spontaneous inactivation of TAFIa, thus curtailing fibrinolysis.27 Although hemostasis is generally achieved with either factor VIII replacement or desmopressin, the risk of recurrent bleeding from oral mucosal surfaces is dramatically reduced with the use of antifibrinolytic agents. These agents are typically contraindicated in patients with hematuria because they can cause a clot to form in the urinary bladder or ureters, leading to obstruction.
EACA is available in intravenous, oral tablet, and elixir formulations; the oral dose is 100 to 200 mg/kg initially (maximum dose, 10 g), followed by 50 to 100 mg/kg per dose every 6 hours (maximum dose, 5 g). Tranexamic acid is available in 650-mg capsules; the dose is 25 mg/kg every 6 to 8 hours.28,29 To treat spontaneous oral hemorrhage or to prevent bleeding from dental procedures in patients with hemophilia, either drug is usually begun in conjunction with desmopressin or factor replacement therapy immediately prior to the procedure and continued for up to 7 days or until mucosal healing is complete. Nonsteroidal anti-inflammatory drugs and aspirin affect platelet function and hence are contraindicated in affected individuals.30
PROPHYLAXIS
Patients with mild to moderate hemophilia typically bleed only after trauma, although the trauma needed to induce bleeding may be more minor than that which would cause bleeding in a normal individual. They usually do not suffer from significant morbidities, whereas patients with severe hemophilia often have spontaneous severe muscle and joint bleeds and can develop early crippling hemophilic arthropathy. Hence, routine prophylaxis has now become the standard of care in the United States and other developed countries in the management of patients with severe hemophilia. Prophylactic replacement therapy with cryoprecipitate in boys with severe hemophilia was first used nearly 50 years ago in Sweden31 and the Netherlands,32 and was shown to reduce the number and the severity of bleeds.32 Moreover, it was observed that early prophylaxis was more effective in preventing arthropathy compared to starting later in life, and that radiologic joint damage could not be reversed by prophylaxis. Subsequently, primary prophylaxis, defined as the start of regular, continuous treatment before the age of 2 years or after the occurrence of first joint bleed,33 was recommended and eventually became the standard treatment; it is currently recommended by the World Health Organization/World Federation of Hemophilia (WFH).34
The timing to begin prophylaxis is somewhat controversial, but many authors suggest starting prophylaxis before the first hemarthrosis occurs. Several studies have reported a wide variation in the age at first joint bleed, ranging from 0.2 to 5.8 years, with medians of 1.6 to 1.7 years.35,36 It has been suggested that arthropathy is best prevented if prophylaxis is started before the second or third joint bleed, but the benefits of starting before the occurrence of first bleed have not been established.37,38 The Swedish experience provides strong support for early prophylaxis.39 In an analysis of 121 patients with severe hemophilia, age at initiation of prophylaxis was an independent predictor of the development of arthropathy, but dose and interval of prophylaxis at the start of prophylactic treatment were not.39
