Clotting factor concentrate use and occurrence of thrombotic events in patients with hemophilia: A nationwide and 15-year cohort study
Authors: Yu‐Tse Tsan, Jiaan‐Der Wang, Wei‐Cheng Chan, Kwok‐Man Tong
Journal: American Journal of Hematology (2016)

To the Editor: Hemophilia A and B are inherited bleeding disorders that result from the absence or deficiency of clotting factors. It is plausible that a hypocoagulable state, such as that present in persons with hemophilia (PWH), have a protective effect on thrombus formation, which precipitates thrombotic events (TEs) 1-3. Since clotting factor concentrates (CFCs) are widely used in PWH, it is unknown whether CFC use neutralizes the protective effect of hemophilia, and is associated with TE occurrence. This study analyzed a population-based database to investigate CFC use and TE occurrence in hemophilia patients. The study was approved by the Institutional Review Board of Taichung Veterans General Hospital in Taiwan. Data pertaining to 1,105 male PWH, comprising 917 patients with hemophilia A and 188 with hemophilia B, were collected from Taiwan's National Health Insurance Research Database (NHIRD) between 1997 and 2011. Because patients' clotting factor levels were not recorded in the NHIRD, all PWH were categorized into two groups, 896 (81.1%) PWH who did and 209 (18.9%) who didn't need replacement therapy according to the use of CFC. TEs comprised both arterial and venous thrombosis. Arterial thrombosis includes ischemic heart disease, ischemic stroke, and peripheral arterial occlusive disease. Venous thrombosis includes superficial and deep vein thrombosis and pulmonary embolism. The mean annual dose of CFC use in each patient was calculated. The annual dose of CFCs used was compared between PWH with and without TE. To examine the relationship between CFC use and TE occurrence, we adopted a case-crossover design, to control for potential confounders within subjects. We divided the 180 days prior to TEs into 6 × 30-day periods for each person, and the amount of CFC use within 30 days prior to TE in each patient was compared to that in the other periods. The characteristics of all PWH are presented in Supporting Information Table IS. A total of 86 (7.8%) PWH developed a high-titer inhibitor of clotting factors and required treatment with bypassing agents. A total of 57 (5.2%) PWH experienced 64 newly diagnosed events of arterial thrombosis, which occurred after 1998; these included 32 with ischemic heart disease, 25 with ischemic stroke, and 7 with peripheral artery occlusive disease (Supporting Information Table IIS). The study indicated that PWH who did not need replacement therapy had more TE occurrence than those who need replacement therapy, 34 of 209 and 30 of 896, respectively (P < 0.001). Only five PWH had venous thrombosis. None of them had concurrent thrombophilia. Three patients were PWH who did not need replacement therapy. No PWH developed pulmonary embolism. During the study period, the total amount of CFC use was 584,630,500 IU of clotting factor (CF) VIII, 86,110,500 IU of CF IX, 93,481 mg of recombinant factor VIIa, and 26,337,500 IU of activated prothrombin complex concentrate. The annual doses of clotting factor VIII used by hemophilia A patients with ischemic heart disease and ischemic stroke were lower than those used by hemophilia A patients without TE (P = 0.047 and P = 0.049, respectively; Table 1). Among 10 PWH on bypassing therapy with TE, the dose was not different from those who did not have TEs. Among the five patients with venous thrombosis, none had received bypassing agents. The amount of CFC use before the occurrence of TEs was further investigated among 64 arterial and 5 venous TEs. The dose of CFC used within 30 days prior to ischemic heart disease or ischemic stroke occurrence in hemophilia A or B patients was not significantly increased in comparison to their previous dose (Supporting Information Table IIIS). Importantly, among the seven patients with peripheral arterial disease, no CFC use was recorded within 180 days prior to the event. None of five patients with venous thrombosis had received CFC within 30 days prior to the event. No aPCC was used within 180 days prior to any of the TEs. Moreover, no increased dose of rVIIa was used within 30 days prior to ischemic heart disease or ischemic stroke occurrence. The current study indicated that PWH who needed replacement therapy have less TE occurrence than those who did not need replacement therapy. In addition, the annual dose of CFCs used in PWH with TE is lower than that in PWH without TE. Since prophylaxis with CFCs in hemophilia patients was not started until July 2014 in Taiwan, the amount of CFC use in this study was generally correlated with hemophilia severity. In addition, in order to elicit whether lower dose in PWH with TE was due to significantly decreased consumption after the event, the amount of CFC use analyzed was in the entire time period before the event. Therefore, the occurrence of TEs was inversely related to the severity of hemophilia. Acute formation of a thrombus precipitates a TE, which may be caused by CFC administration. Systemic analysis of the safety data from 60 studies, involving 5,168 patients with hemophilia A or hemophilia B receiving 27 different CFCs showed that 13 TEs were probably related to CFC infusions; all of these involved superficial thrombophlebitis 4. A retrospective cohort study during 2008 to 2013 to evaluate the occurrence of same-day TEs for different clotting factor products revealed the occurrence of 15 TEs in 2,349 patients with inherited bleeding disorders 5. However, our current analyses revealed that the amount of CFC used was not increased prior to TE. In a review of all reported cases of non-catheter-associated venous thrombosis events among PWH, the most cited risk for thrombosis was treatment with bypassing agents 6. In contrast to these findings, our results showed that none of the PWH in whom venous thromboses occurred had used bypassing agents. In conclusion, our data showed that the annual dose of CFC use was lower in PWH with than without TE. It implied that TE occurrence was inversely related to the severity of hemophilia. Additionally, the amount of CFC used was not increased prior to TE. JW, WC, and YT designed the study and collected the data. WC and YT were responsible for the statistical analysis; KT collected and analyzed the data; JW and YT analyzed the data and wrote the manuscript. Yu-Tse Tsan1,2, Jiaan-Der Wang3,4*, Wei-Cheng Chan1, Kwok-Man Tong3 1Division of Occupational Medicine, Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan 2School of Medicine, Chung Shan Medical University, Taichung, Taiwan 3Department of Paediatrics, Taichung Veterans General Hospital, Center for Rare Disease and Hemophilia, Taichung, Taiwan 4School of Medicine, China Medical University, Taichung, Taiwan Additional Supporting Information may be found in the online version of this article. Supporting Information Table 1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.