Pediatric Clinics of North America - CIPERJ

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366 RODRIGUEZ & HOOTS Antifibrinolytic agents, epsilon-aminocaproic acid and tranexamic acid, both lysine derivatives, also are useful adjuvant therapy for patients who have mild to severe hemophilia. They exert their effect by inhibiting the proteolytic activity of plasmin and, therefore, inhibiting fibrinolysis. The use of antifibrinolytic agents is indicated in the presence of mucosal bleeding, primarily oral, nasal, and menstrual blood loss. Its use is contraindicated in presence of hematuria because of increased risk for intrarenal or ureteral thrombosis, in the presence of disseminated intravascular coagulation, or thromboembolic disease. Both drugs are available for use in the United States in an intravenous form (epsilon-aminocaproic acid at 100 mg/kg/dose every 6 hours; tranexamic acid at 10 mg/kg/dose every 6–8 hours). Currently, only epsilon-aminocaproic acid is available for use in the United States in an oral form. Topical agents, such as fibrin sealant, which is prepared by mixing two plasma-derived protein fractions (fibrinogen-rich concentrate and thrombin concentrate), are used for local bleeding control in hemophilia. There are concerns, however, regarding the use of bovine thrombin in this setting. First, there seems to be a high rate (approximately 20% or higher) of antibody formation [19] against thrombin and factor V, which may inactivate an individual’s own endogenous factor V or thrombin production, thereby creating a new bleeding diathesis. Another legitimate concern is the potential risk for transmitting blood-borne pathogens, such as variant Creutzfeldt- Jakob virus [20]. When available commercially, the use of recombinant human thrombin will likely minimize these risks. A phase 3, prospective, randomized, double-blind, comparative study evaluating the safety and efficacy of topical recombinant human thrombin and bovine thrombin in surgical hemostasis has been published [21]. The primary objective of this study was to evaluate the efficacy of both products whereas the secondary objective was to evaluate safety and antigenicity. This multicenter study enrolled more than 400 patients, who were randomized in a 1:1 ratio. The study showed that both topical agents had a comparable efficacy of 95% with similar adverse events rates. A statistically significant lower incidence of antibodies, however, was identified against recombinant human thrombin (1.5%) compared with antibovine thrombin (21.5%). Based on the results of this study, recombinant human thrombin seems the preferred option to achieve topical hemostasis. Recombinant factor VIIa is a Food and Drug Administration–approved product used to promote hemostasis in patients who have hemophilia A or B with inhibitors. Its mechanism of action includes binding of activated factor VII to tissue factor, which activates factor X and leads to thrombin generation. Recombinant factor VIIa also binds the surface of activated platelets independent of tissue factor, activating factor X and leading to thrombin generation. The standard dose in hemophilia with inhibitors is 90 to 120 mg/kg every 2 to 3 hours until hemostasis is achieved. Subsequent dosing and interval is based on clinical judgment. At the present time, there
ADVANCES IN HEMOPHILIA 367 is no validated laboratory test to monitor recombinant factor VIIa therapy. Clinical experience shows an excellent or effective response in more than 90% of patients who have hemophilia and low risk for thrombosis [22,23]. Experimental aspects of synovitis and alternative methods for intervention In hemophilia, the joints are the most common site of serious bleeding [10]. Synovitis occurs after repeated episodes of bleeding into the joints and is characterized by a highly vascular synovial membrane with prominent proliferation of synovial fibroblasts and infiltration by inflammatory cells [24]. Ultimately, destruction of the cartilage and bone leads to crippling arthritis if adequate treatment is not administered in a timely manner. The exact mechanisms leading to the characteristic changes seen in synovitis are not understood fully. It is hypothesized, however, that synovial cell proliferation, immune system activation, and angiogenesis (the formation of new blood vessels from preexisting ones) occur secondary to the presence of blood components, especially iron, in the joint space. These events selfamplify each other, ultimately leading to cartilage and bone destruction (Fig. 2). Different therapeutic options for synovial control in hemophilia are available. For example, the synovium can be removed surgically by means of an open or arthroscopic synovectomy. Another alternative, synoviorthesis, allows for the destruction of the synovial tissue by intra-articular injection of a chemical or radioactive agent. The main indications for synoviorthesis are chronic synovitis and recurrent hemarthroses. The procedure is performed by an orthopedic surgeon or invasive radiologist/nuclear medicine specialist who has expertise in hemophilia. The majority of patients require a single injection, although a few patients may require more than one injection to the same joint at different time periods. Synoviorthesis offers several advantages over surgical synovectomy. It is less invasive and costly, requires minimal factor coverage, is associated with fewer Blood Iron c-myc mdm2 Synovial cell proliferation Synovial cell apoptosis Synovial hyperplasia Monocytes/ macrophages VEGF IL-1α IL-6 TNFα Endothelial cells T-cells Fibroblasts Macrophages SMCs Osteoclasts Inflammatory mediators Cartilage/ bone destruction Vessel formation Fig. 2. Proposed mechanism in the pathogenesis of hemophilic synovitis. IL-6, interleukin 6; IL-1a, interleukin 1a; SMC, synovial mesenchymal cell; TNFa, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor. (Adapted from Valentino LA, Hakobyan N, Rodriguez N, et al. Pathogenesis of haemophilic synovitis: experimental studies on blood-induced joint damage. Haemophilia 2007;13(3):10–3; with permission.)
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Pediatr Clin N Am 55 (2008) xiii-xi
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Pediatr Clin N Am 55 (2008) 287-304
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DECISION ANALYSIS IN PEDIATRIC HEMA
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Nietert et al [30] Treatment of sic
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VENOUS THROMBOEMBOLISM IN CHILDREN
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Page 32 and 33: VENOUS THROMBOEMBOLISM IN CHILDREN
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Page 42 and 43: PEDIATRIC ARTERIAL ISCHEMIC STROKE
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Page 58 and 59: CARE OF PATIENTS WITH VASCULAR ANOM
Page 74 and 75: 358 RODRIGUEZ & HOOTS Fig. 1. X-lin
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Page 92 and 93: 376 RODRIGUEZ & HOOTS [42] Carcao M
Page 94 and 95: 378 ROBERTSON et al von Willebrand
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Page 102 and 103: 386 ROBERTSON et al Type 2M Type 2M
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Page 106 and 107: 390 ROBERTSON et al References [1]
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Page 110 and 111: 394 BLANCHETTE & BOLTON-MAGGS A key
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416 BLANCHETTE & BOLTON-MAGGS [16]
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422 FASANO & LUBAN of storage and t
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424 FASANO & LUBAN Leukocyte reduct
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426 FASANO & LUBAN RBCs is decrease
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Table 1 Blood component characteris
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430 FASANO & LUBAN Alloimmunization
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432 FASANO & LUBAN of individual un
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434 FASANO & LUBAN patients have an
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436 FASANO & LUBAN adults; therefor
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438 FASANO & LUBAN [21]. Meta-analy
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440 FASANO & LUBAN Pretransfusion m
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442 FASANO & LUBAN [55,56]. This is
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444 FASANO & LUBAN [20] Roseff SD,
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THALASSEMIA UPDATE 449 hypochromia
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THALASSEMIA UPDATE 451 Fig. 1. Chan
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THALASSEMIA UPDATE 453 delivery of
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THALASSEMIA UPDATE 455 thromboses i
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THALASSEMIA UPDATE 457 On the basis
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THALASSEMIA UPDATE 459 [31] Kan YW,
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ORAL IRON CHELATORS 463 large iron-
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ORAL IRON CHELATORS 465 of 50 child
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ORAL IRON CHELATORS 467 Table 2 Com
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ORAL IRON CHELATORS 469 use in Nort
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ORAL IRON CHELATORS 471 needed to d
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ORAL IRON CHELATORS 473 in liver fi
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ORAL IRON CHELATORS 475 in the lowe
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ORAL IRON CHELATORS 477 Other oral
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ORAL IRON CHELATORS 479 [12] Borgna
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ORAL IRON CHELATORS 481 [55] Wonke
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HYDROXYUREA FOR CHILDREN WITH SICKL
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Fig. 1. Guideline for initiating, m
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504 TRACY & RICE congenital spheroc
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506 TRACY & RICE and antibodies aga
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508 TRACY & RICE limited splenic vo
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510 TRACY & RICE constitutes the pi
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512 TRACY & RICE German experience
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514 TRACY & RICE Table 1 Effect of
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516 TRACY & RICE decreased bilirubi
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518 TRACY & RICE [13] Bader-Meunier
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