A Single-Center Study of Patients with Isolated Acquired Clotting Factor Deficiency: Clinical Features, Treatments, and Prognosis

Introduction and aim:

As a group of rare hemorrhagic disorders, isolatedacquired clotting factor deficiency (ACFD) is mainly caused by the existence of anti-factor antibodies or substances with absorbability of clotting factors. The most widely spread isolated ACFD is the acquired FVIII deficiency known as acquired hemophilia (AHA), and the remaining factors of deficiency are much less prevalent. Isolated ACFD is characterized by bleeding diathesis ranging from mild to life-threatening bleeding events. Their rarity and heterogeneity may lead to difficulty in diagnosis and management. We performed a retrospective study to analyze the characteristics of isolated ACFDs other than AHA, including acquired factor (F) II, FV, FIX, FX, FXI, FXII, FXIII, and VWF deficiencies, to enhance our understanding of these diseases.

Methods:

All patients with isolated ACFD other than AHA admitted to the Blood Disease Hospital, Chinese Academy of Medical Sciences, from July 1997 to December 2021, were retrospectively enrolled in the present study. The follow-up time started from when the patient was admitted to our center till March 2022. Clinical information, such as demographics, associated diseases, manifestations, laboratory tests, treatments, and prognosis, was collected.

Results:

A total of 54 patients with isolated ACFD admitted to our center were enrolled in our final analysis, including 28 males and 26 females. Acquired factor V deficiency (AFVD) was the most frequently diagnosed (20/54, 37.0%) isolated ACFD, followed by acquired factor X deficiency (AFXD) (n=16, 29.6%). The median age at diagnosis of all isolated ACFD patients was 55 (4-78) years. However, all four patients with acquired FII deficiency (AFIID) were young women (< 20 years). The median time from presenting bleeding diathesis or being found with an abnormal laboratory test to be diagnosed as isolated ACFD for all patients was 60 (2-2555) days.

Underlying conditions were found in 35 (64.8%) patients with isolated ACFD, including malignancies (n=19, 35.2%), autoimmune diseases (n=12, 22.2%), and infections (n=4, 7.4%). Of the 19 patients associated with malignancies, 18 patients were secondary to hematologic malignancies. Plasma cell dyscrasias were the primary etiologies for patients with AFXD, with a proportion of 75.0% (12/16). A total of 44 (81.5%) patients with isolated ACFD experienced at least one bleeding episode. Subcutaneous hemorrhage was the most common bleeding phenotype affecting 61.4% (27/44) of patients. One acquired factor IX deficiency (AFIXD) patient and one AFXIID patient showed venous thromboembolism (VTE).

Anti-factor neutralizing antibodies were detected in about half of the patients with isolated ACFD (24/54, 44.4%). Inhibitors were not found in two (10.0%) AFVD patients, one (6.3%) AFXD patient, two (50.0%) acquired factor XI deficiency (AFXID) patients, and five (100.0%) acquired factor XII deficiency (AFXIID) patients (Figure 1).

Prothrombin complex concentrate (PCC) was administered to 20 (37.0%) isolated ACFD patients and fresh frozen plasma (FFP) was administered to 33 (61.1%) isolated ACFD patients. Thirty-seven (37/54, 68.5%) isolated ACFD patients underwent immunosuppressive therapy (IST). In addition, chemotherapy was administered to six (6/16, 37.5%) AFXD patients with light chain (AL) amyloidosis and four (4/5, 80%) AFXIID patients with hematologic malignancies to treat primary diseases.

Overall, a majority of isolated ACFD patients achieved a high CR rate (≥ 50.0%) other than patients with AFXD, who achieved an extremely low CR rate of 18.2%. The efficiency of IST varied among different types of isolated ACFDs, ranging from 20.0% to 100.0%. The factor levels normalized in one (1/6, 16.7%) AFXD patient and all (4/4, 100.0%) AFXIID patients after receiving chemotherapy. The median time to achieve CR was shorter for AFVD patients compared with the AFXD patients (p < 0.05). Four (4/17, 23.5%) AFVD patients, four (4/11, 36.4%) AFXD patients, and one (1/2, 50.0%) acquired FXIII deficiency (AFXIIID) patient died. Four bleed-related deaths occurred in two AFVD patients, one AFXD patient, and one AFXIIID patient.

Conclusions:

Isolated ACFD is underestimated, delayed diagnosed, and lacks effective therapy. Therefore, clinicians should raise awareness for recognizing and managing isolated ACFD patients to avoid morbidity and mortality.