Introduction: Idiopathic Thrombocytopenic Purpura (ITP), Thrombotic Microangiopathy (TMA) and Disseminated Intravascular Coagulation (DIC) are hematologic disorders characterized by disruption in coagulation pathways. In ITP, antibodies are formed that target platelet surface antigens, causing thrombocytopenia that is often asymptomatic but can become life-threatening in rare cases occasionally requiring splenectomy in cases refractory to systemic steroids (Provan et. al., 2022). Eltrombopag and Romiplostim, thrombopoietin receptor agonists, were approved by the FDA in 2008 for ITP treatment. TMA is characterized by the formation of microthrombi within small blood vessels and most subtypes can be divided into immune-mediated and complement-mediated etiologies. Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is usually responsive to plasma exchange to remove anti-ADAMTS13 antibodies, for example, while complement-mediated hemolytic uremic syndrome (cm-HUS) is usually refractory to plasma exchange (Masias et. al., 2017). Eculizumab was approved by the FDA in 2007 for treatment of paroxysmal nocturnal hemoglobinuria and in 2011 for cm-HUS. There are other etiologies of TMA, including sepsis, malignant hypertension and post-hematopoetic transplant TMA (TM-TMA), with some epistemic overlap with DIC, a severe coagulopathy characterized by rapid consumption and depletion of clotting factors. There were no new approvals specific for treatment of DIC from 1999 to 2023 and treatment remains supportive and focused on the underlying, typically severe systemic illness (Popescu et. al., 2022). We examined the age-adjusted mortality rate (AAMR) for each condition from 1999 to 2023 with attention towards the trends before and after the approvals of eltrombopag, romiplostim, and eculizumab.

Methods: National mortality trends from 1999 to 2023 in the United States were exported from the CDC WONDER database, specifically the “underlying cause of death” function, using the ICD codes D65 (Disseminated Intravascular Coagulation), the ICD code D69.3 (Idiopathic Thrombocytopenic Purpura), and the ICD code M31.1 (Thrombotic Microangiopathy) which encompasses TTP and cm-HUS. AAMRs were calculated per 10-year cohort starting from age 25 and were reported as deaths per 1,000,000 population. Standard errors for death rates were calculated using the CDC WONDER functionality. AAMRs were then stratified by census regions, sex and race to observe any underlying trends within each group.

Results: The AAMR from DIC per 1,000,000 decreased from 1999 (3.52) to 2007 (2.41), then remained in a similar range with a slight overall decrease through 2023 (2.24). Between 1999 and 2023, the AAMR fell in the Northeast (3.87 to 2.21), Midwest (3.32 to 1.98), South (4.07 to 2.59), and West (2.24 to 1.48). In females, the AAMR fell from 1999 (3.42) through 2023 (2.21). In males the AAMR fell from 1999 (3.60) through 2023 (1.97). In Blacks, the AAMR fell from 1999 (6.62) through 2023 (4.04). In Whites, the AAMR fell from 1999 (3.19) through 2023 (1.93). The AAMR from ITP per 1,000,000 decreased from 1999 (1.74) through 2008 (1.45), the year when Eltrombopag was approved, then rapidly fell through 2023 (0.39). Stratification by census regions, sex and ethnicity showed similar proportional declines in all groups. The greatest absolute declines from 1999 to 2023 were appreciated in males (2.09 to 0.43) and Whites (1.78 to 0.41). The AAMR from TMA per 1,000,000 decreased from 1999 (2.07) through 2007 (1.29), the year when Eculizumab was approved, then continued to fall through 2023 (0.64). Overall there was no appreciable step change around the time of approval of Eculizumab. This was also conserved across census regions, sex and ethnicity, with the greatest absolute declines in AAMR from 1999 to 2023 appreciated in females (2.56 to 0.88) and Blacks (5.28 to 1.68).

Conclusion: We found a consistent decrease in AAMR for DIC, TMA and ITP (31.5% for DIC through 2007, 37.7% for TMA through 2007, 16.7% for ITP through 2008). Interestingly, the decrease in AAMR for TMA and ITP correlated with the approvals for Eculizumab (2007, then 2011 specifically for cm-HUS) and Eltrombopag and Romiplostim (2008 for ITP). Following these approvals, there was a rapid decrease in the AAMR for ITP among all groups (73% from 2007-2023), the AAMR from TMA continued its downward trajectory at a similar pre-Eculizumab rate and there was only a slight decrease in the AAMR for DIC.

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2025
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