Bleeding Patterns and Clinical Outcomes in Patients With Systemic AL Amyloidosis‐Related Acquired Factor X Deficiency

Bleeding patterns and clinical outcomes in patients with systemic AL amyloidosis-related acquired factor X deficiency. Systemic light chain (AL) amyloidosis is caused by clonal plasma cells, which produce amyloidogenic immunoglobulins. These immunoglobulins circulate and aggregate into oligomers and amyloid fibrils, which accumulate in tissues, leading to organ dysfunction [1]. Bleeding symptoms are frequent in AL amyloidosis, and the underlying mechanisms include: increased vascular fragility and vasculopathy secondary to amyloid deposition; reduced coagulation factor production secondary to hepatic dysfunction; acquired von Willebrand syndrome; and acquired factor X (aFX) deficiency attributed to adsorption of this coagulation factor onto amyloid fibril deposits, [1, 2]. The impact of aFX deficiency on bleeding symptoms and patient outcomes, as well as its management, is not well established, especially in the context of contemporary regimens targeting plasma cells. Here, we describe the association between baseline aFX deficiency and clinical characteristics, as well as the impact of plasma cell targeting therapies on FX activity in a large cohort of patients evaluated at our tertiary amyloidosis center. We conducted a retrospective analysis of patients evaluated at the Boston University Amyloidosis Center between 2000 and 2023. FX activity was systematically measured at diagnosis, before any treatment initiation, using a modified prothrombin time assay with single-donor FX-deficient plasma (HemosIL, Instrumentation Laboratory, Bedford, MA) on an ACL TOPS Coagulation Analyzer. Patients receiving anticoagulation therapy, including warfarin or direct oral anticoagulants, were excluded. aFX deficiency (FX activity ≤ 50%) was categorized based on FX activity as mild (41%–50%), moderate (21%–40%), or severe (≤ 20%). All patients had histologically confirmed AL amyloidosis with typing of the amyloidogenic protein by either immunohistochemistry, immunogold electron microscopy, or liquid chromatography–tandem mass spectrometry. All patients consented to the use of clinical data in research, and the Institutional Review Board approved the study according to the standards of the Declaration of Helsinki. Statistical differences were assessed using the independent samples t-test, Mann–Whitney U test, chi-square test, or ANOVA, as appropriate. Correlations were evaluated using Pearson or Spearman correlation analyses. Multivariable linear regression was performed to analyze predictors of FX activity improvement, with hematologic response and treatment type as independent variables; results are reported as unstandardized coefficients (B) with 95% confidence intervals (CI). A p value of < 0.05 (two-sided) was considered statistically significant. Of 1956 patients, 88 (4.4%) had aFX deficiency, and their baseline characteristics are shown in Table 1. Prior studies reported the prevalence of FX deficiency to range from 6% to 14% among patients with AL amyloidosis [2-5]. The lower prevalence observed in our study likely reflects a stricter definition for aFX deficiency, careful exclusion of patients on anticoagulation, earlier-stage diagnosis in contemporary patients, and potential referral bias. Subsequently, we analyzed the clinical correlates of FX activity. FX activity showed a negative correlation with hepatic involvement (r = −0.291, p = 0.006) and multi-organ disease (r = −0.239, p = 0.025), indicating that a more severe aFX deficiency was associated with these clinical features. Conversely, FX activity showed a positive correlation with age at diagnosis (r = 0.418, p < 0.001), suggesting that younger patients were more likely to have more severe aFX deficiency. While statistically significant, the strength of these correlations was modest (Table S1). Although patients with more severe aFX deficiency had higher rates of multi-organ involvement—particularly hepatic, reflecting more extensive amyloid load and advanced disease—57% of those with severe deficiency did not have hepatic involvement. This suggests that factors other than amyloid burden also contribute to the pathophysiology of aFX deficiency. In our cohort, 56% (n = 49/88) of patients reported at least one bleeding manifestation at or near the time of diagnosis, predominantly cutaneous (Table 1). Patients with severe aFX deficiency tended to have a higher frequency of bleeding symptoms (71% [10/14]) compared to those with moderate (64% [21/33]) or mild deficiency (44% [18/41]). However, this difference was not statistically significant (p = 0.102). Previous studies reported similar rates of bleeding symptoms, with more severe aFX deficiency generally associated with higher frequency and greater severity. Despite this trend, most patients—both in our cohort and in previous studies—remain asymptomatic or experience only minor symptoms; life-threatening bleeding is uncommon [2, 5, 6]. Therefore, only a subset of patients with aFX deficiency develops significant bleeding, highlighting the multifactorial nature of bleeding risk in AL amyloidosis. Longitudinal follow-up data on hematologic response and FX activity were available for 32% of patients (n = 28/88), which limits our study and may introduce selection and surveillance biases. Nonetheless, baseline characteristics were largely similar between patients with and without follow-up measurements (Table S2). First-line therapy regimens included high-dose melphalan followed by autologous stem cell transplantation (HDM/SCT, n = 10); bortezomib-based regimens (n = 9) such as cyclophosphamide, bortezomib, and dexamethasone (CyBorD, n = 7) and bortezomib with dexamethasone (Vd, n = 2); daratumumab-based regimens (n = 7) such as daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD, n = 6) and daratumumab monotherapy (n = 1); and melphalan with dexamethasone (Mel-Dex, n = 2). At the first follow-up, FX activity was reassessed a median of 11 months (range, 6–20) after initiation of clone-directed therapy (Tables S3 and S4). Patients who achieved complete hematologic response (hemCR) had a significantly higher median FX improvement of 42% (range, −15 to 112), compared to a median improvement of 14% (range, −10 to 64) in those who did not achieve hemCR (p = 0.028, Figure 1a), consistent with previous findings [4]. Interestingly, FX activity normalized in 2 patients without hematologic response suggesting other factors contribute to recovery. FX activity increase tended to be higher after HDM/SCT and daratumumab-based regimens, with a median of 28% for HDM/SCT and 24% for non-SCT daratumumab-based regimens, compared to 14% for non-SCT non-daratumumab-based regimens. However, these differences were not statistically significant (p = 0.505, Figure 1b). Multivariable linear regression analysis demonstrated that hematologic response (hemCR vs. non-hemCR) was significantly associated with greater improvement in FX activity (B = 33.40, 95% CI: 11.26–55.54, p = 0.007), independently of treatment type. In contrast, treatment type (HDM/SCT vs. non-HDM/SCT) was not significantly associated with improvement in FX activity (B = 13.23, 95% CI: −8.89 to 35.35, p = 0.251). Although treatment type was not a significant predictor, daratumumab-based regimens warrant particular attention, as daratumumab has become a standard of care therapy after its introduction and federal regulatory agency approval in 2021 for AL amyloidosis. Its role in ameliorating aFX deficiency is not yet established. Our study included seven patients treated with daratumumab-based regimens, who demonstrated a median increase in FX activity of 24%. While this is the largest series to date of patients with aFX deficiency treated with contemporary regimens, larger cohorts are necessary to determine whether daratumumab-based regimens can achieve sustained FX responses, comparable to or exceeding those of HDM/SCT, while minimizing the risk of bleeding. During follow-up, with a median duration of 46 months (range, 6–172), FX activity normalized to greater than 50% in 75% (n = 21/28) of patients. The median time to normalization of FX activity after initiating clone-directed therapy was 7 months (range, 6–37). Among these 21 patients, 19 achieved FX normalization to > 50% after first-line therapy and two after second-line therapy (Table 5). FX activity remained > 50% throughout the follow-up period for 86% (n = 18/21) of patients and dropped back down to < 50% in 14% (n = 3/21) of patients. The number of FX activity measurements and the duration of follow-up after normalization were similar between patients who maintained FX activity above 50% (n = 18; median follow-up, 1.95 years; 3 measurements) and those whose levels later declined to < 50% (n = 3; median follow-up, 2.8 years; 4 measurements). All three patients who experienced a decline in FX activity to < 50% during follow-up had either hematologic relapse or persistence of amyloid-related major organ dysfunction, underscoring the importance of monitoring FX activity serially, as well as its potential role as a surrogate marker of disease status. Although an uncommon phenomenon, aFX deficiency related to AL amyloidosis can have important clinical implications, and early diagnosis is critical. During follow-up, we observed bleeding events in a subset of patients. Among 10 patients with aFX deficiency treated with HDM/SCT at our center, four experienced bleeding complications within the first month of treatment (three grade 3, one grade 1); however, no bleeding-related deaths occurred in this group during follow-up. In contrast, although no bleeding complications were observed among patients receiving non-SCT regimens, the two bleeding-related deaths in our cohort occurred in this group during follow-up. Notably, both patients had uncontrolled disease and were receiving active treatment at the time of the hemorrhagic events. One patient with severe deficiency died from uncontrolled gastrointestinal bleeding, while the other, with moderate deficiency, died from postoperative complications following spinal surgery. In conclusion, this study confirmed that aFX deficiency is a rare manifestation in the context of AL amyloidosis, and its severity is associated with younger age and multi-organ involvement. FX activity tends to improve after clone-directed therapy in most patients, especially those achieving a hemCR. HDM/SCT provides high rates and magnitudes of FX improvement but should be used carefully in selected patients, due to the risk of bleeding. Interestingly, the severity of aFX deficiency is not significantly associated with bleeding symptoms, highlighting the complexity of bleeding risk assessment in this population. Our practice is to screen every patient for aFX deficiency irrespective of bleeding symptoms; to avoid the use of antiplatelet aggregation and anticoagulation agents; and to utilize higher thresholds for platelet transfusion during the period of thrombocytopenia during clone-directed therapies. Preventive and supportive measures—such as higher platelet transfusion thresholds, antifibrinolytics, fresh frozen plasma, prothrombin complex concentrates, or recombinant coagulation factors—are essential to minimize complications. These strategies are particularly important for invasive procedures, which should be postponed when possible until FX activity improves. Nevertheless, rapid-acting interventions are still needed for major bleeding. High-purity FX concentrates may be useful in this setting, although not currently approved for aFX deficiency. Future larger and longitudinal studies evaluating the impact of daratumumab-based regimens and optimal supportive care are needed. O.C. and R.S. designed the study, performed data analysis, and wrote the manuscript. O.C., A.S., P.T., and R.S. collected the data. A.S., R.S., J.M.S., and V.S. performed the research and provided clinical care to the patients. All authors critically reviewed and approved the manuscript. The authors thank the current and past members of the Amyloidosis Center, Stem Cell Transplant Program, and Center for Cancer and Blood Disorders. This research was supported by the Amyloid Research Fund. The authors declare no conflicts of interest. The data are available upon request from the corresponding author. Table S1: Correlation between FX activity (lower value signifies more severe deficiency) and clinical features in patients with AL amyloidosis-related aFX deficiency. Table S2: Comparison of patients with and without longitudinal FX measurements. Table S3: Hematologic responses and FX activity changes after HDM/SCT: median 1-year retesting (range 6–20 months). Table S4: Hematologic responses and FX activity changes after non-SCT: median 1-year retesting (range 6–16 months). Table S5: FX activity parameters in patients achieving normalization at any time during follow-up. 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.