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Prognostic markers in autoimmune TTP
tioned biomarkers, and patient outcomes were deter- mined. On univariate analysis, the following variables were significantly associated with in-patient mortality: an inability to normalize platelet count within seven days of TPE (i.e., platelet count of ≥150x109/L) (Online SupplementaryTable S2), failure to significantly reduce serum LDH after five days of treatment (P=0.03), low serum albumin (P=0.03), and high troponin levels at ED (P=0.008) and after being admitted to hospital prior to TPE (P=0.01) (Table 3). Additionally, Cox regression analysis demonstrated that high levels of total serum protein or albumin on admission were associated with a reduced risk of in-hospital mortality (HR, 0.37 or 0.21, P=0.032 or 0.003), while prolonged aPTT (HR 2.03, P=0.02), increased fibrinogen (HR 1.9, P=0.03), elevated LDH at day five (HR 2.93, P=0.04), high plasma Bb (HR 1.3, P=0.04), and sC5b- 9 (HR 1.54, P=0.05) were all found to be the significant markers of mortality (Table 4). When the achievement of clinical remission was used as an outcome, the normaliza- tion of platelet count within seven days (P<0.001) and absence of SLE diagnosis (P=0.038) were found to be the significant prognostic factors for remission (Online Supplementary Table S2). Together, our results demonstrate that lack of admission coagulopathy, low serum tropin level, absence of lupus, platelet recovery in seven days, and marked reduction of LDH in five days, patient overall well-being, and low levels of complement activation markers appear to associate with a good outcome in patients with acute iTTP.
Discussion
The Alabama cohort represents a distinct, yet unde- scribed, iTTP patient population. Our patients were pre- dominantly of African American descent (77%); currently, African Americans only make up 25% of the current pop- ulation in Alabama (https://cber.cba.ua.edu/rbriefs/ black.html). This overrepresentation of African-Americans may be in part attributed to the strict inclusion criteria that required the presence of plasma ADAMTS13 activity <5 U/dL and either positive inhibitors or elevated anti- ADAMTS13 IgG in the appropriate clinical context. Patients of African American descent have been shown to have reduced frequency of a protective HLA DRB1*04 allele, which renders them more susceptible to the devel- opment of autoantibodies against ADAMTS13.26
Since 2015, we have seen approximately 17 new cases of iTTP per year at the UAB Medical Center, which serves as the major referral center for diagnosis and management of TMA in the Southeastern United States. With a popu- lation of ~4.9 millions in the State of Alabama, the inci- dence rate is estimated to be ~3.5 cases per million per year, fairly similar to that reported in the literature.27,28 This incidence rate is most likely underestimated due to patients who may expire prior to reaching our institution or being enrolled in the study.
Data from the Ohio Registry suggest that there are dif- ferences in race, neurological symptoms, platelet counts, LDH, ADAMTS13 activity, and total number of TPE required between patients with an initial episode and those with relapses, despite no major difference in out- come.29 Our data do not show a difference in patients with an initial episode or relapse regarding admission neurolog- ic symptoms, hemoglobin, platelet count, LDH, inhibitor,
anti-ADAMTS13 IgG, and/or any of the novel biomarkers evaluated.
To date, the diagnosis of iTTP relies on laboratory find- ings of severe deficiency of plasma ADAMTS13 activity (i.e., <5 U/dL, or <10 U/dL depending on the lab cut-off) with a positive inhibitor, and/or elevated anti- ADAMTS13 IgG levels in an appropriate clinical context (i.e., thrombocytopenia and microangiopathic hemolytic anemia without other explanations).1,30 All patients in this study had an ADAMTS13 activity <5 U/dL when only the pre-treatment plasma samples were interrogated. Of note, all patients, including 5 with negative inhibitors (<0.4 U/mL), had significantly elevated levels of anti- ADAMTS13 IgG by ELISA . These results suggest that the ELISA-based binding assay may be more sensitive than the functional assays for the diagnosis of iTTP. Therefore, we recommend that any patient with severe deficiency of plasma ADAMTS13 activity (<10 U/dL), but a negative functional inhibitor, should undergo anti-ADAMTS13 IgG ELISA testing. While anti-ADAMTS13 IgG may be detect- ed in plasma of healthy individuals, their levels are not sufficient to inhibit ADAMTS13 activity.31 Findings of high concentrations of anti-ADAMTS13 IgG in addition to low ADAMTS13 antigen levels appear to predict adverse outcomes in patients with iTTP according to the UK registry data.13
The hallmark of iTTP is the autoantibody-mediated inhibition of plasma ADAMTS13 activity. This leads to the inability to cleave newly released ultra-large VWF multimers released from and anchored on the endotheli- um,32 in the circulating blood,33 or at the site of thrombus formation.34 Subsequently, the accumulated ultra-large VWF multimers may spontaneously agglutinate platelets in small arterioles and capillaries, leading to end organ damage.2 Data supporting this hypothesis include signifi- cant elevation of plasma levels of VWF antigen and colla- gen-binding activity in acute iTTP patients despite the slightly reduced ratios of VWF activity to VWF antigen in these patients during the acute setting – consistent with the partial consumption of ultra large VWF multimers dur- ing active thrombus formation. In 1982, Moake et al. showed that ultralarge VWF multimers are only detectable in chronic and relapsing TTP patients during remission, not during the acute disease.33 Plasma from Adamts13–/– mice appear to have ultra-large VWF multimers when the animals are well or not stressed.35 Nevertheless, the increased levels of plasma VWF antigen, but not VWF activity, correlate with increased levels of serum LDH, suggesting that either plasma VWF antigen or serum LDH may be used as a biomarker of end-organ damage.
Infection, inflammation, and pregnancy are known to be complement-amplifying conditions, presumably through activation of the alternative pathway.36 Consistent with our previous findings,8,20 plasma levels of HNP1-3, histone/DNA complexes, Bb, and iC3b were also signifi- cantly increased in this cohort of iTTP patients; plasma HNP1-3, histone/DNA complexes, Bb, and iC3b correlate with the markers of organ damage, including serum LDH, creatinine and/or troponin. There was a strong correlation between plasma sC5b and serum LDH. Rapid reduction in LDH was correlated with survival, consistent with a previous report.37 The elevated plasma levels of Bb and sC5b-9 were found to be predictive of mortality in the Cox regression analysis. These results suggest that both neutrophil and complement activation may participate in
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