Thromboembolic complications, including DIC, deep venous thrombosis, and pulmonary embolism have been associated with the use of crude factor IX concentrates. MLID76229869 MLID91022651 MLID73196994 43–45 In an early series of 13 hemophilia B patients undergoing surgery, 6 patients had significant postoperative thrombosis, including 3 with deep vein thromboses and 3 with pulmonary emboli (one fatal). 46 Similar complications have occurred in nonsurgical settings, although perhaps not as frequently. In addition to thromboembolic phenomena, there are several reports of myocardial infarction occurring in young patients following the use of crude concentrates. MLID81193972 MLID84272071 46–48 Diffuse thrombosis and a peculiar myocardial necrosis have been documented on autopsy in a few patients treated with crude factor IX products. MLID83244876 49 Most patients had no sign of atherosclerosis or other cardiac disease.
Different mechanisms have been proposed for the complications of DIC or thrombosis, or both, that occur when PCCs are used. Since many of these complications are seen in patients with liver disease, it is possible that failure of the liver to clear activated clotting factors from the circulation predisposes to thrombosis. Factors VIIa, IXa, and Xa are known to be present in some but not all the products. MLID75053044 MLID80043411 MLID79166675 50–52 Factor VIIa, with a half-life of 2–4 hours, is a potential thrombogenic agent, although factor Xa-phospholipid complexes are also suspect. MLID82114107 53 These findings contrast with the absence of activated factors in the highly purified factor IX concentrates MLID93206143 MLID92119275 MLID91246863 MLID92303539 MLID91091494 33–37 (Fig. 108-3). Clinical trials of purified factor IX, including use in surgical settings, have been notable for a lack of thrombosis, validating the advantage of the pure preparations. MLID92119275 MLID91246863 MLID92303539 MLID91091494 34–38
Inhibitors to factor IX are observed in about 2–4% of severely affected hemophilia B patients, a lower prevalence than factor VIII inhibitors in hemophilia A. MLID92376744 54,55 They are highly restricted polyclonal alloantibodies (usually IgG4-k) and occur frequently in patients who have undetectable factor IX antigen. MLID88240936 56 Hemophilia B patients with inhibitors frequently exhibit partial or complete deletions in the factor IX gene, although patients with measurable but abnormal factor IX antigen also develop inhibitors. MLID88264925 MLID91011130 MLID87138319 57–59
Inhibitors are quantified by measurement of factor IX activity in mixes of serial dilutions of inhibitor-containing plasma with pooled normal human plasma (containing factor IX). The strength of inhibition of factor IX activity is expressed in Bethesda inhibitor units (BIU). MLID89059734 60,61 One BIU is defined as a 50% reduction in the activity of factor IX in the mixture under standard conditions of time and temperature. Inhibitors complicate the treatment of hemophilia B and preclude the use of conventional therapy. It is possible to overcome low titers of inhibitor (<10 BIU) with increased doses of factor IX, while in the case of high-titer inhibitor (>10 BIU) this is not possible. Therefore, the treatment of patients with inhibitors can be divided into three approaches: (1) overcoming low-titer inhibitors with increased factor IX doses, (2) providing factor IX "bypassing" activity in patients with high-titer inhibitors, and (3) removing or suppressing the inhibitor.
In the case of patients with low-titer inhibitors, higher than normal doses of purified factor IX can be administered in an effort to achieve a measurable circulating level of factor IX. If satisfactory levels of factor IX are not achieved, a trial of PCC administration (in the range of 75–100 U/kg body weight every 8–12 hours) may be of value since these crude preparations contain putative inhibitor "bypassing" activity. The risk of thrombosis related to the use of PCCs is presumably decreased by the anti-factor IX antibody, although this has not been proved. If satisfactory amounts of factor IX overcome the inhibitor, an anamnestic response may be induced so that the antibody titer increases to levels much >10 BIU. Anamnesis may occur within 5 days after initiation of treatment. An anamnestic response of >10 BIU defines a high responder patient. Those who do not respond to factor IX with an anamnestic increase in antibody are termed low responders.
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