Risk and triggering factors for diffuse alveolar hemorrhage in primary antiphospholipid syndrome. An observational follow-up study and a systematic review of the literature.

Background: Diffuse alveolar hemorrhage (DAH) represents a serious, life-threatening complication of primary antiphospholipid syndrome (PAPS), a thrombophilic disorder mainly characterized by vascular thrombosis and/or pregnancy morbidity. Risk factors for DAH in PAPS patients and the comorbidities that may trigger DAH were investigated here in the effort to identify possible independent predictors of DAH in PAPS patients.

Methods: Only PAPS patients fulfilling the Sydney criteria were taken into consideration. The DAH diagnosis was based on the patient's clinical presentation (acute illness manifesting with dyspnoea, hypoxia, cough, anemia and less frequently hemoptysis and fever), the presence of transient lung infiltrates on chest radiographs, a rapidly changing ground-glass appearance on computed tomography, and a positive response to high dose steroid therapy prescribed during an acute phase. The PAPS patients manifesting DAH signs and symptoms were considered the study group; the remaining served as the control group. The following comorbidities were investigated: i) left-sided heart valve diseases, ii) left heart failure and iii) hemolytic anemia. The clinical and laboratory characteristics and comorbidities of the PAPS-associated DAH patients were recorded and compared with those of the control group and those of the PAPS-associated DAH patients identified by a literature review.

Results: The subjects considered for inclusion were 197 PAPS patients (142 women and 55 men) all suffering from thrombosis, which was associated with pregnancy morbidity in 30 (21.1 %) of the women. Eight (4.1 %) of these patients (five men and three women) experienced one or more episodes of DAH. When the clinical and laboratory characteristics of the PAPS-associated DAH patients were compared with those of the controls a significant prevalence of the male gender (p = 0.0399), of the multiple types of vascular involvement profile (p = 0.0048) and of high antiphospholipid antibody (aPL) titers (p = 0.0011) was noted in the former. Triple aPL positivity and microcirculation thrombosis were also more frequent in that group, although not to a significant degree. The prevalence of comorbidities including left-sided heart valve diseases, left heart failure and hemolytic anemia was likewise significantly higher in the PAPS-associated DAH patients (p = 0.0253, 0.0451 and 0.0358, respectively). According to logistic regression analysis, multiple types of vascular involvement profile, left-sided heart valve diseases and hemolytic anemia were found to be independent risk factors for DAH (p = 0.030, 0.022 and 0.007, respectively). Twenty-four studies (one case-control, three small case series, and 20 case reports) reporting on 55 PAPS-associated DAH patients were identified by a review of the literature. The clinical and laboratory characteristics and comorbidities of our PAPS-associated DAH patients were not significantly different from those of the DAH patients identified by literature review. Only hemolytic anemia was significantly less frequent in the literature-review DAH patients than in ours.

Conclusion: Some risk factors and comorbidities characterizing PAPS-associated DAH patients were identified when the clinical and laboratory characteristics of a group of these subjects were compared with those of a control group and of PAPS-associated DAH patients pinpointed by a literature review. In the event that these results are confirmed by larger multicenter studies, they could contribute to identifying PAPS patients at risk of developing DAH.