Study Identifies Risk Factors for Thrombosis in Patients With AIHA

Although thrombosis is known to be a potential complication of autoimmune hemolytic anemia (AIHA), its pathogenesis has been unclear and there are no specific indications for anticoagulant prophylaxis in these patients. A study published in Journal of Thrombosis and Haemostasis identified several potential risk factors for thrombosis in patients with AIHA and provides suggestions for prophylaxis.

In patients with AIHA, many factors play into disease severity, and thrombotic complications have been linked to increased morbidity and mortality. Although the cause of thrombosis in AIHA is not clear, it may be related to free hemoglobin release resulting in nitric oxide depletion, a patient’s proinflammatory and procoagulant autoimmune status, and interactions between the complement system and the coagulation cascade. AIHA can also be secondary to conditions that further increase the risk of thrombotic events.

The retrospective study aimed to provide insight into predictors of thrombotic episodes in patients with AIHA and potential indicators that anticoagulant prophylaxis may be beneficial to certain patients.

Data from 287 patients with AIHA receiving care at a tertiary center in Milan, Italy, and followed from June 1978 were used in the study. Further, 174 patients from the same initial cohort and experiencing relapse were prospectively studied from January 2020 to December 2021. These patients were evaluated for thrombosis occurrence and use of prophylaxis for anticoagulation.

The retrospective analysis had a median follow-up of 51 months, and 33 of the 287 patients (11.4%) experienced thrombotic complications, 70% of whom were hospitalized. Of these patients, 243 (85%) received their diagnosis between 2000 and 2022. The median time from diagnosis to initial thrombotic event was 4 months, and 16 thrombotic episodes (48%) happened within 3 months. Pulmonary embolism, deep venous thrombosis of lower limbs, splanchnic vessels thrombosis, superficial thrombophlebitis, and catheter-associated thrombosis were all observed. Three myocardial infarctions and 2 strokes were reported, and 5 patients experienced multiple thrombotic episodes. A pulmonary embolism and a stroke resulted in death.

Low-molecular-weight (LMW) heparin was started in 12 cases, oral anticoagulants in 17 cases, and antiplatelets agents in 4 cases. None of the patients who experienced thrombotic complications were receiving antithrombotic prophylaxis or antiplatelet agents at the time. Approximately half of the patients (n = 17) were undergoing therapy for AIHA, with treatments including high-dose steroids, cyclophosphamide, rituximab, intravenous immunoglobulins, cyclosporine, and recombinant erythropoietin. Two patients had splenectomies in the 6 months leading up to thrombosis. Nine of the 33 patients with thrombotic complications (27%) had conditions with potential to increase thrombotic risk.

Patients with elevated lactate dehydrogenase (LDH) levels were more likely to experience thrombotic events (HR, 3.22). Patients with infectious complications (HR, 3.57), receiving transfusions (HR, 3.06), on rituximab (HR, 3.3), and on cyclophosphamide (HR, 2.67) also had higher cumulative thrombosis incidence. Multivariable analysis found LDH levels, transfusions, rituximab, and cyclophosphamide to be independent factors for thrombotic events. Patients who experienced thrombotic events more frequently received multiple lines of treatment.

In the prospective follow-up of 174 patients, there were 70 acute hemolytic episodes in 45 patients, which included 16 new diagnoses and 29 relapses. Of those 45 patients, 33 had LDH at or higher than 1.5 times the upper limit of normal (ULN) and 17 of these patients received anticoagulant prophylaxis with LMW heparin for a median of 70 days. None of the patients with high LDH on prophylaxis experienced thrombotic events vs 5 thrombotic episodes in the other 16 patients with elevated LDH.

Study limitations included its retrospective nature, long span of observation, and potential variations in thrombophilia screening. But its prospective observation suggests administering prophylaxis to patients with AIHA and active hemolysis, defined as LDH at or above 1.5 times ULN, can help reduce the incidence of thrombotic events. The authors also strongly recommend prophylaxis in hospitalized patients who require transfusions, are on rituximab or cyclophosphamide therapy, and patients experiencing infectious complications.

“The duration of anticoagulant prophylaxis is still a matter of debate, and although most episodes happened within the first weeks, our results showed the occurrence of late-onset thrombotic events, advising to continue heparin until LDH normalization,” the authors wrote. “The results of an ongoing randomized prospective trial evaluating long-term anticoagulant prophylaxis with apixaban in AIHA patients will possibly clarify this issue.”

Reference

Fattizzo B, Bortolotti M, Giannotta JA, Zaninoni A, Consonni D, Barcellini W. Intravascular hemolysis and multitreatment predict thrombosis in patients with autoimmune hemolytic anemia. J Thromb Haemost. Published online May 30, 2022. doi:10.1111/jth.15757