Outcomes with prophylactic anticoagulation in hemolytic anemias: A systematic review

Abstract Introduction: Venous thromboembolism (VTE) is one of the most common causes of mortality in hemolytic anemias, such as paroxysmal nocturnal hemoglobinuria (PNH) and autoimmune hemolytic anemia (AIHA). We aim to investigate outcomes with prophylactic anticoagulation in hemolytic anemias, with a particular focus on preventing thromboembolic events. Methods: Following PRISMA guidelines, a comprehensive search of PubMed, Cochrane, Embase, Google Scholar, and ClinicalTrials.gov (inception to May 2025) was conducted using MeSH terms for “emolytic anemia”, “anticoagulation”, and “prophylaxis.”  After screening and excluding review articles, meta-analyses, and studies without a patient population of interest, three studies reporting outcomes of prophylactic anticoagulation in hemolytic anemia were selected for inclusion from a total of 383 references. All four studies are described systematically. Results: A total of 219 patients from three studies were analyzed in this systematic review. Hall et al. analyzed 163 patients with PNH; 39 were prophylactically treated with warfarin. The median age of the treatment group was 44 years (range, 3-76 years). Thirty-three (85%) patients had a large clone size as determined by flow cytometry. There were no thrombotic events in the treatment group, as compared to 23% (n = 29/124) in the non-treatment group. In patients with large PNH granulocyte clones when not on warfarin, there were 19 thromboses in 511.5 patient-years off warfarin (3.7 thromboses per 100 patient-years not on warfarin) compared with no thromboses in 117.8 patient-years on primary warfarin prophylaxis (P < .05). One patient suffered from chronic subdural hematoma on warfarin but developed multiple pulmonary emboli (PE) when taken off warfarin and did well after resumption of anticoaguation. There was one reported mortality secondary to warfarin, due to spontaneous cerebral hemorrhage. Fattizzo et al., prospectively followed 170 patients with AIHA. In a subgroup of 33 patients with lactate dehydrogenase (LDH) levels 1.5 or higher than upper limit of normal, 17 patients (52%) were treated with low molecular weight heparin (LMWH) (4000-8000 units/day) and showed no thrombotic events, whereas 31% (n = 5/16) suffered from thrombotic events in non-anticoagulated group. Hendrick et al. reported an institutional follow-up of 23 patients with AIHA over a period of 16 years. The median age was 67 years (22-83). Prophylactic anticoagulation was initially administered during hospitalization, but was offered in an ambulatory setting with a fixed dose of warfarin after 3 episodes of fatal PE. In a total of 36 hemolysis episodes, the VTE rate was 5% (n = 1/21) in patients with prophylactic anticoagulation and 33% (n = 5/15) without anticoagulation (p < 0.10). Conclusion: Prophylactic anticoagulation with either warfarin or LMWH appears to reduce VTE events in patients with PNH and AIHA. However, there is a lack of high-quality data from randomized trials. Further trials are needed to consolidate efficacy and to report on complications with anticoagulation, and the overall impact on survival and mortality.