thrombotic microangiopathy is an uncommon but well - described complication of solid malignancies , and has been reported in association with gastric , breast , prostate , and other cancers . it typically occurs late in the course of disease , in the setting of malignant infiltration of bone marrow , or as a side - effect of chemotherapeutic agents . the resulting microangiopathic hemolytic anemia ( maha ) normally presents with marked thrombocytopenia , and can be clinically indistinguishable from thrombotic thrombocytopenic purpura ( ttp ) or from the hemolytic uremic syndrome ( hus ) . unlike classic ttp , cancer - associated maha may have normal or variable levels of adamts13 activity , and does not respond to therapeutic plasma exchange . like ttp - hus , cancer - associated maha involves platelet aggregation and thrombus formation , resulting in platelet consumption , impaired microvascular blood flow , and mechanical destruction of erythrocytes . since this process is associated with metastatic involvement of bone marrow , the culprit disease is typically advanced and readily apparent , but rarely maha is the presenting feature of an undiagnosed malignancy . in some instances a patient will be misdiagnosed with primary ttp , and subsequently found to harbor an underlying cancer . in 75% of cases , cancer - associated maha will respond to medical therapy directed at the underlying tumor . the other described form of malignancy - associated hemolysis is a paraneoplastic form of autoimmune hemolytic anemia ( aiha ) , reported commonly in the setting of chronic lymphocytic leukemia , and rarely in association with solid tumors . the direct coombs or direct antiglobulin test ( dat ) is considered sensitive for aiha , though dat can be negative in patients with low levels of the offending autoantibody . the hemolytic process may or may not respond to corticosteroid therapy , but cancer - associated aiha that is refractory to steroids frequently resolves with resection of the primary tumor . a 75-year - old female presented complaining of progressive fatigue and dyspnea over several months . laboratory studies showed macrocytic anemia with a hemoglobin of 8.2 g / dl , hematocrit of 25.3% , and mean corpuscular volume of 103.7 fl ; these values had been within normal limits one year prior . her platelet count was 188,000/ml and white blood cell count was 10,000/ml , both normal , as were tests of renal and hepatic function , coagulation , and micronutrient levels including iron , folate , and vitamin b-12 . the reticulocyte index was 2.4 , but only 1.6 after correction for maturation factor , showing a suboptimal response to anemia . lactate dehydrogenase was elevated at 549 iu / l ( normal range 90 - 250 ) and haptoglobin was undetectable , consistent with a hemolytic process . d - dimer was mildly elevated at 1.04 g / ml , and fibrinogen was within normal limits at 363 mg / dl . a peripheral blood smear contained schistocytes and spherocytes , suggesting hemolysis , and also showed leukoerythroblastosis , with polychromasia , nucleated red blood cells , and immature granulocytes ( figure 1 ) . dat was negative on two separate occasions , a cold agglutinin assay was negative , and hemoglobin electrophoresis and serum protein electrophoresis were normal . as part of the patient s workup for anemia , upper endoscopy was performed and found no source of bleeding , but did recover a sessile 10 mm polyp from the gastric fundus , which was found to contain a microscopic focus of adenocarcinoma . a bone marrow biopsy revealed poorly differentiated signet ring adenocarcinoma , raising concern for a metastatic gastric cancer ( figure 2 ) . at this point cytotoxic therapy with capecitabine was initiated . the patient s anemia continued to worsen , requiring several red blood cell transfusions , and she was given darbepoetin alfa to promote erythropoiesis . she developed an indirect hyperbilirubinemia of 2.7 mg / dl , while maintaining normal platelet counts and appropriate reticulocytosis , with a corrected reticulocyte index as high as 8.4 . a six - week trial of corticosteroids , given as empiric treatment for possible dat - negative aiha , similarly produced no improvement in anemia or in laboratory markers of hemolysis . after starting treatment for presumed gastric cancer , a palpable breast mass was discovered . biopsy revealed signet ring adenocarcinoma that was histologically similar to both bone marrow and gastric polyp findings , with strong estrogen receptor positivity ( figure 3 ) . additional immunohistochemical staining of the initial bone marrow sample was performed at this time , and was positive for estrogen receptor , e - cadherin , and gata-3 , consistent with primary breast cancer . pet - ct imaging showed diffusely mottled osseous structures consistent with an infiltrative process , but no other metastatic foci . in light of these findings , this was followed by a rapid improvement in anemia , allowing blood transfusions and darbepoetin alfa treatments to be stopped . the patient survived 28 months from initial presentation with no evidence of recurrent hemolysis , before succumbing to progression of breast cancer . this is an unusual case of isolated intravascular hemolysis causing transfusion - dependent symptomatic anemia , in the setting of estrogen receptor positive breast adenocarcinoma metastatic to bone marrow . a causal link between the hemolytic process and the underlying malignancy is supported by the dramatic resolution of hemolysis after the initiation of cancer - directed hormone therapy . although reticulocytosis at presentation was muted , it responded appropriately to an erythropoiesis - stimulating agent , suggesting that the anemia was primarily attributable to erythrocyte destruction rather than impaired production . key features of thrombotic microangiopathy were absent : the patient s platelet count remained within the normal range , and she did not develop renal dysfunction or neurologic symptoms . however , the presence of numerous schistocytes in peripheral blood is highly suggestive of mechanical hemolysis , especially in the setting of malignant infiltration of bone marrow . the hemolytic process observed in this case therefore appears to represent an atypical form of maha without associated thrombocytopenia . the reason for the preserved platelet count is unclear . despite the advanced stage of the patient s breast cancer , the malignant signet ring cells found in bone marrow were wrongly deemed to represent primary gastric cancer ; staining for hormone receptors could have provided important diagnostic information , and should have been performed at the time of the first biopsy . the initial misdiagnosis caused a delay in the initiation of estrogen suppression , which allowed observation of ongoing hemolysis as a manifestation of the uncontrolled cancer . subsequently , there was marked improvement in response to aromatase inhibitor therapy , demonstrating that hemolysis in malignancy may be reversible with effective treatment of the underlying disease . hemolytic anemia of unclear etiology , with or without thrombocytopenia , should trigger clinical suspicion for occult malignancy and consideration for bone marrow biopsy . in a patient with known cancer , hemolysis should raise concern for disseminated disease with bone marrow involvement , and is a poor prognostic sign .
hemolysis is an uncommon and usually late complication of malignancy , and very rarely the presenting feature . 
 cancer - associated hemolysis may be immune - mediated , or may result from thrombotic microangiopathy accompanied by thrombocytopenia . 
 we describe an unusual case of isolated hemolysis in the setting of occult metastatic breast cancer . 
 the patient initially presented with symptomatic anemia , with evidence of hemolysis but with negative direct antiglobulin testing and a normal platelet count . 
 subsequent investigation discovered metastatic adenocarcinoma of the breast involving bone marrow . 
 hemolysis worsened despite initial treatment with cytotoxic chemotherapy and a trial of corticosteroids , but later resolved with aromatase inhibitor therapy .