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Original Study

Cancer-Related Microangiopathic Hemolytic Anemia

Clinical and Laboratory Features in 168 Reported Cases

Lechner, Klaus MD; Obermeier, Hanna Lena

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doi: 10.1097/MD.0b013e3182603598
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Abstract

INTRODUCTION

Microangiopathic hemolytic anemia (MAHA) is a typical feature of hereditary and immune-mediated thrombotic thrombocytopenic purpura (TTP)49,93 and of atypical hemolytic uremic syndrome (aHUS).105 Secondary causes of TTP/aHUS are drugs, collagen vascular disorders, surgery, infections, stem cell transplantation, and malignancies. We conducted the current review of cancer-related MAHA (CR-MAHA). CR-MAHA is usually associated with thrombocytopenia and clinical and/or pathologic evidence of microvascular thrombosis in various organs. Since it shares many features with hereditary or acquired immune TTP and/or aHUS, a popular name for this disease is “CR-MAHA with thrombocytopenia (TTP/HUS).” Others, in particular pathologists, prefer the name “thrombotic microangiopathy,” a name that emphasizes the tissue changes associated with this clinical syndrome.

To our knowledge, CR-MAHA was first described by Brain et al.16 Antman et al8 described the essential causes and clinical and laboratory features of CR-MAHA in an extensive review published in this journal in 1979. Since that review, a number of new clinical and laboratory data, pathologic findings, and treatment advances have been reported in larger43,106 and smaller case series25,38,41,48,141 or case reports. CR-MAHA has been reviewed several times,55,123 but without a data analysis of the reported cases.

We conducted the current study to analyze published data since 1979 on CR-MAHA according to predefined criteria, to get a broader view of this syndrome.

PATIENTS AND METHODS

We retrieved all reported cases of presumed CR-MAHA (TTP/HUS) since 1979 (the date of the review of Antman et al 8) from the literature using MEDLINE via PubMed (National Library of Medicine, Bethesda, MD). The search terms were “microangiopathic hemolytic anemia and cancer or specific cancer site,” “thrombotic thrombocytopenic purpura or HUS and cancer or specific cancer sites,” and “microangiopathic hemolytic anemia and lymphoma.” We also searched the reference lists of published case reports for additional cases.

The basic inclusion criterion for cases was a definite diagnosis of cancer associated with Coombs-negative hemolytic anemia with schistocytes and thrombocytopenia. We included all accessible papers published in English, German, French, Italian, and Spanish. Papers in other languages were included only if there was an extensive English abstract, and detailed laboratory data were presented in tables or figures in English. We excluded all cases in languages not mentioned above, cases published in papers that could not be retrieved, and cases with uncertain diagnosis of MAHA or insufficient data. We also excluded all cases with potentially drug-induced MAHA (patients in whom MAHA [TTP/HUS] occurred <1 year after the end of chemotherapy), except patients after autologous stem cell transplantation.

Data Collection and Definitions

Using predefined criteria, we collected and analyzed the following data: 1) Site, histology, and stage of cancer. Metastatic cancers were cancers with distant metastases. 2) Time of diagnosis of MAHA from or to cancer (prior, concurrent, postoperative, or at recurrence). 3) Relevant clinical signs such as central nervous symptoms, pulmonary symptoms, and diffuse bleeding. We counted only severe central nervous system symptoms, according to the criteria of Vesely et al.152 Pulmonary symptoms or findings included severe noncardiac dyspnea, pulmonary reticulonodular infiltrates (on X-ray), and pulmonary carcinomatous lymphangitis, tumor emboli, and pulmonary TTP (at autopsy). 4) Laboratory features such as renal abnormalities (creatinine levels), leukoerythroblastic blood presentation (defined according to Delsol et al35), hypofibrinogenemia (fibrinogen <200 mg/dL), elevated dimer or fibrin degradation products, and, in a few cases, ADAMTS 13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats, 13) activity. Disseminated intravascular coagulation (DIC) could not be classified according to the ISTH criteria,144 because thrombocytopenia and fibrin-related markers11 are often elevated in cancers without DIC and/or MAHA. We assumed overt DIC—similar to Sallahet al128—if the fibrinogen level was below 200 mg/dL and the fibrin degradation products and/or dimer was elevated. Acute renal failure was defined as an increase of creatinine by >0.5 mg/dL per day or to >4 mg/dL.152 Patients with MAHA and severe neurologic symptoms152 were classified as “MAHA (TTP like),” and those with acute renal failure, as “MAHA (HUS like).” All others were classified as “MAHA (not specified).” 5) Histologic findings (biopsy or autopsy) with particular reference to marrow infiltration, tumor emboli, and fibrin thrombi in various organs. 6) Efficacy of treatment with plasma exchange, fresh frozen plasma, hormonal treatment, cancer surgery, and/or chemotherapy. In patients undergoing hormonal treatment and/or chemotherapy, the response of MAHA to treatment was recorded.

The data extraction and analysis were made independently by the 2 authors and the final result was resolved by consensus.

Statistical Methods

For the Kaplan-Meier analysis, overall survival was taken as endpoint. If no data on survival were provided, disease-free survival was used as a substitute for overall survival. Patients undergoing chemotherapy received many different treatments. They were included in the analysis even when chemotherapy was not according to the current state of the art. Patients were included in the chemotherapy group even when they had prior plasma exchange or fresh frozen plasma. In prostate and breast cancer, hormonal treatment was also counted as chemotherapy. In the category “patients without chemotherapy,” all patients were included who had no chemotherapy, independent of whether they had no therapy at all or plasma exchange, fresh frozen plasma, or hemodialysis. The survival times of individual patients were rounded to nearest half-month intervals. Because response criteria were rarely provided, we used only the term “response,” but probably most patients had at least a partial remission.

RESULTS

Malignancies Associated With MAHA

We identified 168 cases of CR-MAHA reported since the review of Antman et al,8 154 in solid cancers and 14 in lymphoma. We did not count cancer patients with postoperative MAHA. The cancers associated with MAHA are listed in Table 1; the most common cancers were gastric, breast, prostate, lung, and cancer of unknown primary (CUP), in this order. Abdominal, genitourinary, and endocrine cancers were much less common. Abdominal cancers included 3 cases of colon cancer,79,84,106 3 of pancreatic,43,141,156, 3 of liver,106,134 and 1 case of appendix cancer. 99 Genitourinary cancers included 1 case of renal cell43 and 2 cases of ovarian cancer.63,119 MAHA occurred in a relatively small number of patients with Hodgkin disease, aggressive non-Hodgkin lymphoma (NHL), and myeloma.

TABLE 1
TABLE 1:
Malignancies Associated With MAHA

In the large majority of patients (91.8%) the solid cancer was metastatic at the time of MAHA (Table 2). However, there were some cases of gastric, lung, and prostate cancer that were apparently not metastatic at the time of MAHA. All evaluable gastric, breast, prostate, and CUP cancers; 5 of 10 abdominal cancers; and 2 of 3 evaluable genitourinary cancers were adenocarcinomas. Among the lung cancers 5 were adenocarcinomas, 4 were small cell cancers, and 2 were squamous cell cancers. In most cases MAHA was diagnosed concurrently with the first diagnosis of the cancer, but in 30 (19.4%) cases it was not diagnosed until the time of cancer recurrence. MAHA at the time of recurrence was most common in gastric and breast cancers (23/80), but much rarer in other cancers. The median time to MAHA-associated recurrence was 7 years (range, 7 mo to 13 yr) in gastric, 4 years (range, 6 mo to 10.5 yr) in breast, and 3 years (range, 14 mo to 12 yr) in prostate cancer. In a few cases of CR-MAHA at cancer diagnosis, a relapse of cancer was again associated with MAHA,33,106 but in some other cases MAHA did not recur when the cancer relapsed.70,106

TABLE 2
TABLE 2:
Clinical and Hematologic Data of Patients With CR-MAHA

The median age of gastric patients with CR-MAHA was 52 years (5 yr younger than patients without MAHA), and the female to male ratio was 1:1 (in contrast to 2–3:1 in patients without MAHA2). The median age of women with CR-MAHA and breast cancer was 54 years (range, 19–82 yr).

TTP-Like, aHUS-Like, and Not Specified MAHA in Solid Tumors

In most cases of gastric, breast, lung, CUP, and abdominal cancers, the patients did not show clinical or laboratory features of TTP or aHUS, but essentially had MAHA with no or only mild signs of cerebral dysfunction and/or renal abnormalities (see Table 2). However, in each cancer category there were a few cases of typical TTP or aHUS. In prostate cancer a high proportion of patients (17/23) had an aHUS-like presentation. In some of these cases aHUS was recurrent.150

Bone Marrow Findings

In the vast majority (90/111; 81.1%) of evaluable cases, bone marrow infiltration with cancer cells was documented (see Table 2), by bone marrow biopsy or in some cases only at autopsy. Unfortunately, in a relatively large number (43/154; 28%) of cases, bone marrow biopsies were not done or were not evaluable. The extent of marrow infiltration was not described in all cases, but from a number of well-documented cases38 it is clear that the extent of infiltration was not uniform, and MAHA occurred in many cases with only limited (focal) infiltration. Most cases with bone marrow infiltration also had bone metastases. Bone marrow infiltration was sometimes associated with bone marrow necrosis25,78,109,124,135,141 or fibrosis.38,106 Tumor emboli in the marrow have been found in some cases at autopsy.141

Pulmonary Abnormalities in CR-MAHA

Clinical, radiologic, or histologic evidence of pulmonary involvement was documented in 49 cases. Clinical findings included noncardiac dyspnea and respiratory distress syndrome. Radiologic findings were reticulonodular infiltration of the lung. 43,67,89,126,135,156 Histologic findings of pulmonary involvement (most at autopsy) were pulmonary carcinomatous lymphangitis, 14,92,115,151 pulmonary microvascular tumor emboli,12,28,43,151 and pulmonary thrombotic microangiopathy.47,108,115,116,131

Thromboembolic Complications and Skin Necrosis

Venous thromboembolism (deep venous thrombosis, pulmonary embolism, cerebral sinus vein thrombosis) was observed in 5 cases,38,68,96,120,139 and skin necrosis in 2 cases.78,100

Association of CR-MAHA With Hypofibrinogenemia

Thirty-nine of 108 patients had fibrinogen levels <200 mg/dL, usually with elevated levels of fibrin degradation products or dimer (see Table 2). These patients most likely had overt DIC, although formally they did not fulfill the ISTH criteria for DIC. In most cases the fibrinogen level was not excessively reduced, and clinically none of these patients had definite signs of severe fibrinogen depletion (that is, bleeding from puncture sites). Nevertheless the bleeding rate in CR-MAHA patients was high, and many patients died from cerebral bleedings.

ADAMTS 13 Deficiency and CR-MAHA

ADAMTS 13 activity was determined in a limited number of cases. In most cases ADAMTS 13 was either normal or moderately reduced, as expected in metastatic malignancy.42,86 However, in a small number of cases,15,68,75,106 ADAMTS 13 activity was very low or absent at presentation and normalized after successful treatment of MAHA and cancer. In MAHA associated with lymphoma, ADAMTS 13 antibodies were detected in a few cases and disappeared after successful lymphoma treatment (see below).

MAHA in Endocrine Tumors

MAHA occurred in 3 cases of pheochromocytoma,51,127,132 2 cases of pituitary tumor,74,75 and 1 case of neuroendocrine tumor.38 Two of these tumors were malignant, 38,127 and both had bone marrow infiltration. Clinically, 2 cases were TTP like and 2 were HUS like. In the 2 cases of pheochromocytoma, 1 patient in whom the tumor was removed had complete remission,132 the other had complete remission of MAHA but persistent renal failure.51 Both patients with pituitary tumors had no bone marrow infiltration. Prolactin was elevated (prolactin is often secreted with growth hormone in this tumor). Plasma exchange was not effective; both patients died within a few days.

MAHA in Lymphoma: An Immune-Mediated Disease?

MAHA has been described in 4 cases of Hodgkin lymphoma,20,31,37 3 cases of intravascular lymphomatosis/angiotropic lymphoma,69,72,136 3 cases of NHL (2 with diffuse large B-cell lymphoma),20,43 3 cases of myeloma,7,61 and 1 case of hairy cell leukemia.95 In most instances, lymphoma-associated MAHA seems to be different from MAHA in solid tumors. An instructive case of MAHA (TTP like) was described in a patient with angiotropic lymphoma.72 This patient had a TTP-like clinical picture, very low ADAMTS 13 activity, and antibody to ADAMTS 13. The patient responded to fresh frozen plasma. Complete remission of lymphoma and MAHA and recovery of ADAMTS 13 was achieved after chemotherapy. The patient had a long remission (>20 mo) of lymphoma and TTP. In 2 other cases of MAHA in angiotropic lymphoma,69,136 no data on ADAMTS 13 activity were available.

Two other cases of presumably immune-mediated MAHA were described with myeloma.61 One patient with IgA kappa myeloma had a history of MAHA associated with IgA monoclonal gammopathy of undetermined significance (MGUS), which was controlled by treatment with fresh frozen plasma. Thirteen years later he developed IgA myeloma with MAHA (ADAMTS 13 activity of 0.7% and ADAMTS 13 antibody of 1 BU/mL). MAHA did not respond to plasma exchange, but complete remission of MAHA was obtained with chemotherapy (dexamethasone/bortezomide), which lasted for 5 months. However, ADAMTS 13 activity remained low. A complete remission of ADAMTS 13 activity was achieved after autologous stem cell transplantation. Five months later ADAMTS 13 activity dropped again, but without recurrence of myeloma. Another myeloma patient with IgA kappa myeloma developed MAHA (TTP like, ADAMTS 13 activity zero with an antibody titer of 1.4 BU/mL) in very good partial remission after treatment with thalidomide, dexamethasone, and lenalidomide. Drug-induced TTP cannot be excluded because the patient was treated with lenalidomide at the onset of MAHA. The patient achieved complete resolution of MAHA and complete recovery of ADAMTS 13 after plasma exchange and cyclosporine. A further progression of myeloma was not associated with ADAMTS 13 deficiency and MAHA.

MAHA occurred in 3 advanced Hodgkin cases. In 1 case31 MAHA occurred in a splenectomized (for staging) patient with active disease (stage IV with skin involvement). MAHA improved after antiplatelet therapy. In another Hodgkin case,20 MAHA developed in a patient in complete hematologic remission late after chemotherapy and improved after steroid therapy. The patient remained in complete remission for 9 years after this event. Two similar cases with MAHA in complete remission of NHL were reported.20 Both died from MAHA.

MAHA After Cancer Surgery: Not Really a Paraneoplastic Syndrome

In 5 cases MAHA occurred a few days (2–5 d) after cancer surgery in patients with glioblastoma multiforme,23 small bowel,56 endometrial,57 cecal,125 or bladder carcinoma.143 None of these cancers was metastatic, and none had bone marrow infiltration. All patients achieved complete remission of MAHA either spontaneously125 or after plasma exchange.23,57,143

Efficacy of CR-MAHA Treatment in Solid Tumors

Most patients had a variety of treatments, usually starting with fresh frozen plasma and/or plasma exchange followed by chemotherapy when the diagnosis CR-MAHA was established. An at least transient response of MAHA to antitumor therapy occurred in 42 of 56 evaluable patients with solid cancers (prostate cancer excluded) (Table 3). The overall survival in patients who received chemotherapy was superior to those without chemotherapy in cases of gastric, breast, CUP, and lung cancer combined (Figure 1). The median survival times with or without chemotherapy in gastric, breast, lung, CUP, and prostate cancers are shown in Table 4. In contrast to patients with other cancers associated with MAHA, patients with prostate cancer with MAHA had a good response to plasma exchange and fresh frozen plasma (14/16). Some of these patients received additional hormonal treatment, but from the description of the cases it is very likely that plasma exchange was the primary effective treatment.

TABLE 3
TABLE 3:
Treatment of Patients With CR-MAHA
TABLE 4
TABLE 4:
Survival of CR-MAHA Patients With Various Cancers According to Treatment*
FIGURE 1
FIGURE 1:
Overall survival (gastric, lung, breast, CUP). X axis: months from diagnosis. Solid line: patients treated with chemotherapy or hormonal drugs. Dashed line: patients treated with plasma exchange, fresh frozen plasma, or no treatment.

DISCUSSION

Hereditary or immune-mediated TTP and aHUS are well defined disorders25,45,49,93,105,114 with established effective treatments.50 CR-MAHA is a rare cause of secondary MAHA. It is a serious, often fatal complication of malignancy. For an experienced hematologist the diagnosis of MAHA may not be difficult, but in practice the delay from the beginning of symptoms to diagnosis of TTP or aHUS is often long.43 However, making the diagnosis of CR-MAHA is important, because the usual treatment of TTP and aHUS (fresh frozen plasma, plasmapheresis) is rarely effective, but with early chemotherapy the survival of some of these patients may be considerably prolonged, with good quality of life.

In 2 studies the prevalence of CR-MAHA among patients with TTP/aHUS was 3.5%152 and 7.8%.80 Since the incidence of TTP is estimated at 4.5 persons/million per year,152 the incidence of CR-MAHA may be about 0.25 to 0.45 persons/million. There are no data on the incidence of CR-MAHA in cancers overall or in special cancer types. The incidence of CR-MAHA must be extremely low: in a recent study of breast cancer patients with bone metastasis, there was no case of CR-MAHA among 2046 patients with a median observation time of 17 months140 (AT Stopeck, personal communication).

There is no linear correlation between the frequencies of a paraneoplastic syndrome and the incidence or prevalence of a cancer. In immune-mediated paraneoplastic syndrome, the highest association is lung cancer with immune thrombocytopenia,76 renal cell cancer with autoimmune hemolytic anemia,122 prostate cancer with factor VIII antibodies,59 and small cell lung cancer with anti-HU antibodies (a type I antineural nuclear antibody).62 In general, adenocarcinoma was the most common histologic type of cancer in CR-MAHA. Gastric carcinoma was the most common cancer in the current survey, followed by breast, prostate, and lung cancer. In another study MAHA was highly associated with prostate cancer.48 The reasons for these discrepancies are unknown; they may be due to ethnic differences.145 A special feature of CR-MAHA is that, unlike in other paraneoplastic syndromes, a relatively high proportion of CR-MAHA cases occurred at the time of cancer recurrence, in particular in gastric, breast, and prostate cancers. One may speculate that this is due to clonal selection after chemotherapy. It is well known that a tumor may change its properties when it recurs.34,81,121,146,154

In most case reports and reviews, the term “CR-MAHA (TTP/aHUS)” has been used, because it is not always easy to clinically distinguish TTP and aHUS. ADAMTS 13 measurement is a powerful diagnostic test in hereditary or immune TTP, but it is not a useful diagnostic tool in CR-MAHA. Nevertheless we have tried to assign the diagnosis of TTP or aHUS (according to criteria of an experienced center) to the published cases. We found that the classical clinical and laboratory pattern of TTP or aHUS was present in only a minority of cases and in most cases the MAHA was associated with rather unspecific symptoms. Highly noteworthy and to our knowledge not yet recognized was the finding that aHUS was highly prevalent in prostate carcinoma, in contrast to other cancers.

Bone marrow was the most common site of metastasis in CR-MAHA, but a substantial number of cases had cancer-free bone marrow, and in some cases of bone marrow involvement the infiltration was only focal. In a study of 25 patients with bone marrow cancer infiltration, only half had the typical peripheral blood findings of MAHA.157 Thus, cancer infiltration of the bone marrow cannot be the only explanation for the blood abnormalities. Bone marrow necrosis or fibrosis was described in a number of CR-MAHA cases, but these abnormalities cannot be regarded as specific for CR-MAHA because they occur in many other conditions.113 CR-MAHA was highly associated with bone metastases, but the prevalence of MAHA in patients with bone metastases is very low140 (AT Stopeck, personal communication).

Signs of pulmonary thrombotic microangiopathy seem to be more common in CR-MAHA patients compared to patients with nonmalignant TTP/aHUS or patients with metastatic cancer without MAHA.106,158 This may be due to the site of tumors (lymphatic metastases). In contrast, myocardial infarction seems to be less common compared to noncancer-related TTP. 46,64,112 DIC was highly associated with CR-MAHA, in contrast to hereditary or immune-mediated TTP.

To our knowledge, MAHA in endocrine tumors was not mentioned in earlier reviews. The 3 patients with pheochromocytomas had severe hypertension. It is known that MAHA may occur in patients with malignant hypertension.149 In a 2011 study,3 7 of 16 patients with malignant hypertension had aHUS-like MAHA. All hematologic abnormalities resolved after normalization of the blood pressure. Thus, it may be that the pheochromocytoma patients did not have CR-MAHA, but had hypertension-associated MAHA. The 2 patients with pituitary tumors had high prolactin levels. High prolactin levels may be a risk factor for MAHA.85

Postoperative MAHA after cancer surgery cannot be regarded as true cancer-related MAHA because it occurs after removal of a nonmetastatic cancer and disappears spontaneously, and may occur also after noncancer surgery.130 Thus, this type of MAHA is considered a surgery-associated MAHA.

There is no doubt that there is a close association of MAHA with DIC. About one-third of patients with MAHA had laboratory signs indicative of DIC, but it was not possible to define DIC according to the ISTH criteria. It may be that in some cases, among the probably-many circulating cytokines, clotting activators play an important role. The degree of hypofibrinogenemia is modest in most cases, which may be due to a low fibrinolytic activity. The generation of small vessel platelet thrombi in patients with MAHA may be increased by simultaneous DIC. It is interesting to compare the tumors that are associated with MAHA and DIC without MAHA. Prostate cancer is highly prevalent in both conditions, but gastric and breast cancers are much less prevalent in DIC.6,138 The low prevalence of thrombosis in CR-MAHA with or without DIC may be surprising, but may be due to the short observation time, severe anemia and thrombocytopenia, and nondetection of silent thrombi.

It is well established that in hereditary and acquired TTP, ADAMTS 13 activity is more or less reduced.30,45,152 Reduced ADAMTS 13 activity has also been found in a number of CR-MAHA patients, but the interpretation of these data is difficult because reduced ADAMTS 13 levels are not uncommon in metastatic cancer patients.42,44,86,107 In the vast majority of cancer patients, ADAMTS 13 was above 20%.

Severe immune-mediated deficiency of ADAMTS 13 may occur in some patients with lymphoproliferative disorders. aHUS in prostate cancer could be antibody mediated because of the good response to plasmapheresis.36

In contrast to hereditary and immune TTP or aHUS, the pathogenesis of CR-MAHA is largely unknown. In CR-MAHA in solid cancers, the most likely cause may be red cell fragmentation and platelet destruction in small vessels of cancerous tissue—in particular in the bone marrow, the lung, and/or other organs. This does not explain the absence of CR-MAHA in most patients with the same metastatic pattern. Cytokine production by tumor cells may play a role, but we are not aware of a cytokine that experimentally produces the typical symptoms of CR-MAHA. The endothelial cells play a critical role in all types of thrombotic microangiopathy. As long as endothelial cells are functionally intact, even patients with severe congenital defects predisposing to thrombotic microangiopathy may remain asymptomatic, whereas a severe injury of endothelial cells such as in cancer may trigger thrombotic microangiopathy.53

CR-MAHA is a serious disease with a very poor prognosis. Almost half (46.5%) of all evaluable patients in the current series died, with or without treatment, within 1 month. Chemotherapy is the only effective therapy (in cancers that respond to chemotherapy). However, it is known from case reports 63,82,106,126 that the hematologic response of CR-MAHA to chemotherapy may be fast, and complete remission may be obtained after 1 chemotherapy cycle. Because almost all the cancers are metastatic, the remission duration and overall survival are short, but some patients responding to chemotherapy may enjoy life with good quality for many months or even years. However, the overall survival of breast cancer patients with MAHA treated with chemotherapy (4 mo) is definitely inferior to that of chemotherapy-treated breast cancer patients without MAHA (11.0–33.5 mo).19 The median survival of chemotherapy-treated gastric cancer patients with CR-MAHA is about 3 months, which was similar to that of patients with bone marrow involvement without MAHA,157 but definitely inferior to patients with metastases at other sites.2 In patients with prostate cancer with aHUS, the prognosis seems to be better. A number of these patients had complete resolution of MAHA after plasmapheresis and enjoyed many years with good quality of life.

The current study has important limitations, as is the case with all retrospective studies. The clinical evaluations and the laboratory examinations were not uniform, and often not all relevant data were provided, but overall the quality of data was sufficient for this analysis. We included only patients in whom the diagnosis of CR-MAHA was well established. Bone marrow biopsies were not done in a substantial number of patients, in particular in patients with prostate cancer. The efficacy of plasmapheresis was difficult to evaluate, because this treatment was often stopped as soon the diagnosis of CR-MAHA was established and chemotherapy and/or hormonal therapy was started. Because of the retrospective nature of the study, no statistical analyses were performed except for the Kaplan-Meier plot. We want to emphasize that the treatment results shown in Figure 1 were not based on results of prospective phase II or III studies.

A strength of our data is that patients came from various ethnic groups and were probably less selected than in prospective studies. We also provide some evidence that CR-MAHA in prostate cancer is different from CR-MAHA in other solid cancers with regards to clinical presentation and response to treatment.

There are 2 challenges for the future treatment of CR-MAHA. The first is to improve treatment of the acute phase of CR-MAHA to prevent early deaths and make patients fit for chemotherapy. There are a few new potential treatment options available, such as treatment with concentrates of recombinant ADAMTS 13118 or anti-Willebrand factor aptamer (ARC 1779),66 which may be effective even in patients without ADAMTS 13 deficiency. For patients with aHUS, eculizumab, a monoclonal complement inhibitor licensed for the treatment of paroxysmal nocturnal hemoglobinuria, may be an attractive option; it has already shown efficacy in some cases of aHUS.26,73,159 The second challenge is to improve the long-term prognosis of patients who survive the acute phase. Finding new effective treatments for the underlying cancer is the only way to prolong the life of patients with CR-MAHA.

ACKNOWLEDGMENTS

The authors thank Dr. Stopeck for providing additional information on the Denosumab trial140 and Prof. Schneider for help with the statistical analysis.

REFERENCE

1. Abdel Samie A, Sandritter B, Theilmann L. Severe microangiopathic hemolytic anemia as first manifestation of a CUP syndrome. Rapid hematologic remission under polychemotherapy. Med Klin (Munich). 2004; 99: 148–153.
    2. Ajani JA, Rodriguez W, Bodoky G, Moiseyenko V, Lichinitser M, Gorbunova V, Vynnychenko I, Garin A, Lang I, Falcon S. Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010; 28: 1547–1553.
    3. Akimoto T, Muto S, Ito C, Takahashi H, Takeda S, Ando Y, Kusano E. Clinical features of malignant hypertension with thrombotic microangiopathy. Clin Exp Hypertens. 2011; 33: 77–83.
    4. Alexopoulou A, Dourakis SP, Nomikou E. Case of thrombotic thrombocytopenic purpura associated with disseminated gastric cancer. Am J Clin Oncol. 2002; 25: 632.
      5. Ali N, Kamran N, Adil S, Pervez S. Metastatic signet ring gastric adenocarcinoma presenting with microangiopathic hemolytic anemia. Indian J Gastroenterol. 2007; 26: 185–186.
        6. Al-Mondhiry H. Disseminated intravascular coagulation: experience in a major cancer center. Thromb Diath Haemorrh. 1975; 34: 181–193.
        7. Alpay N, Uzun S, Bahat G, Yavuz S, Erten N, Tascioglu C. Thrombotic thrombocytopenic purpura associated with multiple myeloma. Blood Coagul Fibrinolysis. 2008; 19: 439–441.
        8. Antman KH, Skarin AT, Mayer RJ, Hargreaves HK, Canellos GP. Microangiopathic hemolytic anemia and cancer: a review. Medicine (Baltimore). 1979; 58: 377–384.
        9. Arkenau HT, M¨ssig O, Buhr T, Jend HH, Porschen R. Microangiopathic hemolytic anemia (MAHA) as paraneoplastic syndrome in metastasized signet ring cell carcinomas: case reports and review of the literature. Z Gastroenterol. 2005; 43: 719–722.
          10. Ataga KI, Graham ML. Microangiopathic hemolytic anemia associated with metastatic breast carcinoma. Am J Hematol. 1999; 61: 254–255.
            11. Ay C, Pabinger I. Tests predictive of thrombosis in cancer. Thromb Res. 2010; 125 (Suppl 2): S12–15.
            12. Bastecký J, Langr F, Chrobák L, Hlava A, Kvasnicka J. [Tumor microembolization in the lungs—a cause of marked dyspnea, syncope, hemolytic syndrome and disorders of hemocoagulation. ] Vnitr Lek. 1992; 38: 505–512.
            13. Bhagwati N, Seno R, Dutcher JP, Oleksowicz L. Fulminant metastatic melanoma complicated by a microangiopathic hemolytic anemia. Hematopathol Mol Hematol. 1998; 11: 101–108.
              14. Bisetti A, Lalicata M, Jacot-des-Combes E. [Occult gastric adenocarcinoma with pulmonary carcinomatous lymphangitis and microangiopathic hemolytic anemia in a young adult. ] Schweiz Med Wochenschr. 1985; 115: 561–564.
              15. Blot E, Decaudin D, Veyradier A, Bardier A, Zagame OL, Pouillart P. Cancer-related thrombotic microangiopathy secondary to Von Willebrand factor-cleaving protease deficiency. Thromb Res. 2002; 106: 127–130.
              16. Brain MC, Azzopardi JG, Baker LR, Pineo GF, Roberts PD, Dacie JV. Microangiopathic haemolytic anaemia and mucin-forming adenocarcinoma. Br J Haematol. 1970; 18: 183–193.
              17. Calvo Villas JM, Hernández JM, Cueto M, Cuenca C. [Microangiopathic anemia and leukoerythroblastic reaction associated with a pulmonary adenocarcinoma. ] An Med Interna. 1996; 13: 356–357.
                18. Caramello V, Dovio A, Caraci P, Berruti A, Angeli A. Thrombotic thrombocytopenic purpura in advanced prostate cancer: case report and published work review. Int J Urol. 2007; 14: 150–152.
                  19. Cardoso F, Bedard PL, Winer EP, Pagani O, Senkus-Konefka E, Fallowfield LJ, Kyriakides S, Costa A, Cufer T, Albain KS; ESO-MBC Task Force. International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy. J Natl Cancer Inst. 2009; 101: 1174–1181.
                  20. Carey RW, Harris N. Thrombotic microangiopathy in three patients with cured lymphoma. Cancer. 1989; 63: 1393–1397.
                  21. Carr DJ, Kramer BS, Dragonetti DE. Thrombotic thrombocytopenic Purpura associated with metastatic gastric adenocarcinoma: successful management with plasmapheresis. South Med J. 1986; 79: 476–479.
                    22. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 26-1984. Microangiopathic hemolytic anemia in a 53-year-old woman with metastatic breast cancer. N Engl J Med. 1984; 310: 1728–1736.
                      23. Cataland SR, Jin M, Smith E, Stanek M, Wu HM. Full evaluation of an acquired case of thrombotic thrombocytopenic purpura following the surgical resection of glioblastoma multiforme. J Thromb Haemost. 2006; 4: 2733–2737.
                      24. Chang JC, Naqvi T. Thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer. Oncologist. 2003; 8: 375–380.
                        25. Chang JC. The understanding of thrombotic thrombocytopenic purpura: Dyadic, triadic, pentadic, and other manifestations. J Clin Apher. 2004; 19: 2–4.
                        26. Chatelet V, Fremeaux-Bacchi V, Lobbedez T, Ficheux M, Hurault de Ligny B. Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. Am J Transplant. 2009; 9: 2644–2645.
                        27. Chevalet P, Moreau A, Muller F, Berthelot JM, Hamidou M, Prost A. [Extensive bone marrow necrosis and thrombotic microangiopathic anemia revealing disseminated adenocarcinoma. ] Presse Med. 1998; 27: 1213–1215.
                          28. Cohan M, Pittman G, Hoffmann GC. Hemolytic anemia, tumor cell emboli, and intravascular coagulation. Arch Pathol. 1972; 93: 305–307.
                          29. Collins PW, Jones L, Pocock C, Newland AC. Microangiopathic haemolysis associated with occult carcinoma. Clin Lab Haematol. 1991; 13: 245–249.
                            30. Coppo P, Schwarzinger M, Buffet M, Wynckel A, Clabault K, Presne C, Poullin P, Malot S, Vanhille P, Azoulay E, Galicier L, Lemiale V, Mira JP, Ridel C, Rondeau E, Pourrat J, Girault S, Bordessoule D, Saheb S, Ramakers M, Hamidou M, Vernant JP, Guidet B, Wolf M, Veyradier A; French Reference Center for Thrombotic Microangiopathies. Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience. PLoS One. 2010; 5: e10208.
                            31. Crain SM, Choudhury AM. Thrombotic thrombocytopenic purpura in a splenectomized patient with Hodgkin’s disease. Am J Med Sci. 1980; 280: 35–40.
                            32. Crespo-Valades E, Espinosa-Magro MP, Marco-Schulke C. [Metastatic gastric adenocarcinoma with microangiopathic hemolytic anemia. ] Rev Esp Enferm Dig. 2010; 102: 511–512.
                              33. Davis S, Rambotti P, Grignani F, Steinhouse K. Microangiopathic hemolytic anemia and pulmonary small-cell carcinoma. Ann Intern Med. 1985; 103: 638.
                              34. Deganello A, Franchi A, Sardi I, Pignataro L, Leemans CR, Gallo O. Genetic alterations between primary head and neck squamous cell carcinoma and recurrence after radiotherapy: recurrence, genetically related cancer, or second primary? Cancer. 2010; 116: 1291–1297.
                              35. Delsol G, Guiu-Godfrin B, Guiu M, Pris J, Corberand J, Fabre J. Leukoerythroblastosis and cancer frequency, prognosis, and physiopathologic significance. Cancer. 1979; 44: 1009–1013.
                              36. Dragon-Durey MA, Blanc C, Garnier A, Hofer J, Sethi SK, Zimmerhackl LB. Anti-factor H autoantibody-associated hemolytic uremic syndrome: review of literature of the autoimmune form of HUS. Semin Thromb Hemost. 2010; 36: 633–640.
                              37. Dumoulin-Lagrange M, Tulliez M, Diebold J, Samama M, Bousser J. [Thrombotic thrombopenic purpura associated with Hodgkin’s disease. ] Nouv Rev Fr Hematol. 1983; 25: 275–276.
                              38. Elliott MA, Letendre L, Gastineau DA, Winters JL, Pruthi RK, Heit JA. Cancer-associated microangiopathic hemolytic anemia with thrombocytopenia: an important diagnostic consideration. Eur J Haematol. 2010; 85: 43–50.
                              39. Eugene M, Deray G, Cacoub P, Achour A, Baumelou A. Hemolytic uremic syndrome and prostatic adenocarcinoma. Clin Nephrol. 1987; 27: 46.
                                40. Ferretti G, Petti MC, Carlini P, Zeuli M, Picardi A, Meloni G, Bria E, Papaldo P, Fabi A, Cognetti F. Zoledronic acid-associated thrombotic thrombocytopenic purpura. Ann Oncol. 2004; 15: 1847–1848.
                                  41. Fontana S, Gerritsen HE, Kremer Hovinga J, Furlan M, Lammle B. Microangiopathic haemolytic anaemia in metastasizing malignant tumours is not associated with a severe deficiency of the von Willebrand factor-cleaving protease. Br J Haematol. 2001; 113: 100–102.
                                  42. Franchini M, Montagnana M, Targher G, Lippi G. Reduced von Willebrand factor-cleaving protease levels in secondary thrombotic microangiopathies and other diseases. Semin Thromb Hemost. 2007; 33: 787–797.
                                  43. Francis KK, Kalyanam N, Terrell DR, Vesely SK, George JN. Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: A report of 10 patients and a systematic review of published cases. Oncologist. 2007; 12: 11–19.
                                  44. Fujimura Y, Matsumoto M. Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara Medical University during 1998-2008. Intern Med. 2010; 49: 7–15.
                                  45. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer I, Aumann V, Mittler U, Solenthaler M, Lammle B. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998; 339: 1578–1584.
                                  46. Gami AS, Hayman SR, Grande JP, Garovic VD. Incidence and prognosis of acute heart failure in the thrombotic microangiopathies. Am J Med. 2005; 118: 544–547.
                                  47. Geissler RG, Ganser A, Hubner K, Hor G, Hoelzer D. [47-year-old patient with pulmonary hypertension, anemia and thrombocytopenia. ] Internist (Berl). 1995; 36: 385–388.
                                  48. Généreau T, De Cagny B, Branger B, Chérin P, Bentata M, Brivet F, Korach JM, Guillevin L. [Microangiopathic hemolytic anemia associated with cancers. Symptomatic treatment by plasma exchange. ] Ann Med Interne (Paris). 1994; 145: 365–368.
                                  49. George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006; 354: 1927–1935.
                                  50. George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010; 116: 4060–4069.
                                  51. Gillett MJ, Arenson RV, Yew MK, Thompson IJ, Irish AB. Diagnostic challenges associated with a complex case of cystic phaeochromocytoma presenting with malignant hypertension, microangiopathic haemolysis and acute renal failure. Nephrol Dial Transplant. 2005; 20: 1014.
                                  52. Girard P, Tardy B, Page Y, Mosnier JF, Tardy-Poncet B, Bertrand JC. [Thrombotic thrombocytopenic purpura disclosing cancer: apropos of 2 cases. ] Presse Med. 1995; 24: 175–178.
                                    53. Goldberg RJ, Nakagawa T, Johnson RJ, Thurman JM. The role of endothelial cell injury in thrombotic microangiopathy. Am J Kidney Dis. 2010; 56: 1168–1174.
                                    54. González N, Ríos E, Martín-Noya A, Rodríguez JM. Thrombotic thrombocytopenic purpura and bone marrow necrosis as a complication of gastric neoplasm. Haematologica. 2002; 87: ECR01.
                                      55. Gordon LI, Kwaan HC. Thrombotic microangiopathy manifesting as thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the cancer patient. Semin Thromb Hemost. 1999; 25: 217–221.
                                      56. Gusakova I, Mermershtain W, Cohen Y, Ariad S. Small bowel adenocarcinoma in Crohn disease patient complicated by microangiopathic hemolytic anemia. Am J Clin Oncol. 2003; 26: 483–485.
                                      57. Hamilton CA, Kao JM, Coutre SE, Teng NN. Acute postoperative thrombotic thrombocytopenic purpura following hysterectomy and lymphadenectomy for endometrial cancer. Gynecol Oncol. 2007; 106: 423–426.
                                      58. Hansen RM, Hanson GA. Gastric carcinoma in young people. A case report and review of the literature. Am J Gastroenterol. 1980; 74: 497–503.
                                        59. Hauser I, Lechner K. Solid tumors and factor VIII antibodies. Thromb Haemost. 1999; 82: 1005–1007.
                                        60. Himmelmann A, Schefer H. Microangiopathic haemolytic anaemia in a patient with metastatic breast cancer. Br J Haematol. 2009; 146: 231.
                                          61. Hofmeister CC, Jin M, Cataland SR, Benson DM, Wu HM. TTP disease course is independent of myeloma treatment and response. Am J Hematol. 2010; 85: 304–306.
                                          62. Honnorat J. Onconeural antibodies are essential to diagnose paraneoplastic neurological syndromes. Acta Neurol Scand Suppl. 2006; 183: 64–68.
                                          63. Horne MK III, Cooper B. Microangiopathic hemolytic anemia with metastatic adenocarcinoma: response to chemotherapy. South Med J. 1982; 75: 503–504.
                                          64. Hughes C, McEwan JR, Longair I, Hughes S, Cohen H, Machin S, Scully M. Cardiac involvement in acute thrombotic thrombocytopenic purpura: association with troponin T and IgG antibodies to ADAMTS 13. J Thromb Haemost. 2009; 7: 529–536.
                                          65. Hussain S, Chui S. Gastric carcinoma presenting with extensive bone metastases and marrow infiltration causing extradural spinal haemorrhage. Br J Radiol. 2006; 79: 261–263.
                                            66. Jilma-Stohlawetz P, Gorczyca ME, Jilma B, Siller-Matula J, Gilbert JC, Knöbl P. Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb Haemost. 2011; 105: 545–552.
                                            67. Kadikoylu G, Barutca S, Tataroglu C, Kafkas S, Erpek H, Meydan N, Yavasoglu I, Bolaman Z. Thrombotic thrombocytopenic purpura as the first manifestation of metastatic adenocarcinoma in a young woman. Transfus Apher Sci. 2010; 42: 39–42.
                                            68. Kaidar-Person O, Nasrallah H, Haim N, Dann EJ, Bar-Sela G. Disseminated carcinoma diagnosed by bone marrow biopsy in patients with microangiopathic hemolytic anemia and thrombocytopenia: a report of two cases with gastric cancer and a review of the literature. J Gastrointest Cancer. 2010; 42: 123–126.
                                            69. Kamesaki H, Matsui Y, Ohno Y, Amano H, Imanaka T, Takahashi Y, Kobashi Y, Kawakami K, Kita K. Angiotropic lymphoma with histologic features of neoplastic angioendotheliomatosis presenting with predominant respiratory and hematologic manifestations. Report of a case and review of the literature. Am J Clin Pathol. 1990; 94: 768–772.
                                            70. Kanesvaran R, Phipps C, Cheng CW, Chan MM, Khoo D, Tan MH. Management of thrombotic thrombocytopenic purpura in metastatic prostate cancer with only endocrine therapy. Ann Acad Med Singapore. 2010; 39: 580–582.
                                            71. Kanou T, Nosou Y, Yoshinaka K, Yanagawa E, Niimoto M, Hattori T, Miura K, Kuramoto J. [Microangiopathic hemolytic anemia associated with gastric cancer. ] Gan No Rinsho. 1986; 32: 1029–1034.
                                              72. Kawahara M, Kanno M, Matsumoto M, Nakamura S, Fujimura Y, Ueno S. Diffuse neurodeficits in intravascular lymphomatosis with ADAMTS13 inhibitor. Neurology. 2004; 63: 1731–1733.
                                              73. Köse O, Zimmerhackl LB, Jungraithmayr T, Mache C, N¨rnberger J. New treatment options for atypical hemolytic uremic syndrome with the complement inhibitor eculizumab. Semin Thromb Hemost. 2010; 36: 669–672.
                                              74. Kouides PA, Phatak PD, Cramer SF. Fatal thrombotic thrombocytopenic Purpura (TTP) presenting concurrently with metastatic multiple endocrine neoplasia (MEN) type I. Hematopathol Mol Hematol. 1996; 10: 161–170.
                                              75. Kovacs K, Garvey MB. Thrombotic thrombocytopenic purpura associated with a prolactin-producing pituitary adenoma. Am J Hematol. 2003; 74: 55–59.
                                              76. Krauth MT, Puthenparambil J, Lechner K. Paraneoplastic autoimmune thrombocytopenia in solid tumors. Crit Rev Oncol Hematol. 2012; 81: 75–81. Epub 2011 Apr 22.
                                              77. Lakshminarayana G, Rajesh R, Seethalekshmy NV, Kurian G, Unni VN. Thrombotic microangiopathy with severe renal failure in adenocarcinoma. Indian J Nephrol. 2008; 18: 74–76.
                                                78. Laso FJ, González-Díaz M, Paz JI, De Castro S. Bone marrow necrosis associated with tumor emboli and disseminated intravascular coagulation. Arch Intern Med. 1983; 143: 2220.
                                                79. Lee JL, Lee JH, Kim MK, Cho HS, Bae YK, Cho KH, Bae SH, Ryoo HM, Lee KH, Hyun MS. A case of bone marrow necrosis with thrombotic thrombocytopenic purpura as a manifestation of occult colon cancer. Jpn J Clin Oncol. 2004; 34: 476–480.
                                                80. Levandovsky M, Harvey D, Lara P, Wun T. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients. J Hematol Oncol. 2008; 1: 23.
                                                81. Liedtke C, Broglio K, Moulder S, Hsu L, Kau SW, Symmans WF, Albarracin C, Meric-Bernstam F, Woodward W, Theriault RL, Kiesel L, Hortobagyi GN, Pusztai L, Gonzalez-Angulo AM. Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol. 2009; 20: 1953–1958.
                                                82. Lin YC, Chang HK, Sun CF, Shih LY. Microangiopathic hemolytic anemia as an initial presentation of metastatic cancer of unknown primary origin. South Med J. 1995; 88: 683–687.
                                                83. Litt MR, Bell WR, Lepor HA. Disseminated intravascular coagulation in prostatic carcinoma reversed by ketoconazole. JAMA. 1987; 258: 1361–1362.
                                                  84. Majhail NS, Hix JK, Almahameed A. Carcinoma of the colon in a patient presenting with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Mayo Clin Proc. 2002; 77: 873.
                                                  85. Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood. 2001; 98: 2730–2735.
                                                  86. Mannucci PM, Karimi M, Mosalaei A, Canciani MT, Peyvandi F. Patients with localized and disseminated tumors have reduced but measurable levels of ADAMTS-13 (von Willebrand factor cleaving protease). Haematologica. 2003; 88: 454–458.
                                                  87. Marcoullis G, Abebe L, Jain D, Talusan R, Bhagwati N, Wiernik PH. Microangiopathic hemolysis refractory to plasmapheresis responding to docetaxel and cisplatin: a case report. Med Oncol. 2002; 19: 189–192.
                                                    88. Mariette X, Oberlin F, Brigant S, Koeger AC, Camus JP. [Microangiopathic hemolytic anemia in cancers. A case with remission after chemotherapy. ] Rev Med Interne. 1988; 9: 297–299.
                                                      89. Mauron H, Streuli R. [Anemia, subcutaneous bleeding and weight loss. Disseminated metastasizing, mucinous adenocarcinoma of the stomach. ] Praxis (Bern 1994). 2000; 89: 1568–1572.
                                                      90. McGregor AR, Moore ML, Bailey RR, Robson RA, Lynn KL. Disseminated prostatic carcinoma presenting with acute interstitial nephritis and microangiopathic haemolytic anaemia. Aust N Z J Med. 1990; 20: 170–172.
                                                        91. Microangiopathic anemia and disseminated intravascular coagulation in an elderly woman. Am J Med. 1983; 74: 1052–1060.
                                                          92. Mizuno I, Izeki O, Nakahara S, Kawamoto K, Onga T, Matsuoka H, Sugimoto T, Matsui T, Itoh H, Chihara K. [Disseminated carcinomatosis of the bone marrow occurring 11 years after subtotal gastrectomy for gastric cancer. ] Rinsho Ketsueki. 1998; 39: 670–675.
                                                          93. Moake J. Thrombotic microangiopathies: multimers, metalloprotease, and beyond. Clin Transl Sci. 2009; 2: 366–373.
                                                          94. Morishita T, Matsumoto M, Honoki K, Yoshida A, Takakura Y, Fujimura Y. Successful treatment of primitive neuroectodermal tumor-associated microangiopathy with multiple bone metastases. Jpn J Clin Oncol. 2007; 37: 66–69.
                                                            95. Moses J, Lichtman SM, Brody J, Wisch N, Moake J. Hairy cell leukemia in association with thrombotic thrombocytopenic purpura and factor VIII antibodies. Leuk Lymphoma. 1996; 22: 351–354.
                                                            96. Muller NJ, Pestalozzi BC. Hemolytic uremic syndrome in prostatic carcinoma. Oncology. 1998; 55: 174–176.
                                                            97. Mungall S, Mathieson P. Hemolytic uremic syndrome in metastatic adenocarcinoma of the prostate. Am J Kidney Dis. 2002; 40: 1334–1336.
                                                              98. Narita M, Nakao K, Ogino N, Emoto T, Nakahara M, Yumiba T, Tsujimoto M. A case of microangiopathic hemolytic anemia associated with breast cancer: improvement with chemoendocrine therapy. Breast Cancer. 1997; 4: 39–42.
                                                                99. Neidhardt B, Hartwich G, Preiss G, Schneider M. [Microangiopathic hemolytic anemia in metastasizing appendiceal carcinoma. ] Med Welt. 1979; 30: 1822–1826.
                                                                100. Ng HJ, Crowther MA. Malignancy-associated venous thrombosis with concurrent warfarin-induced skin necrosis, venous limb gangrene and thrombotic microangiopathy. Thromb Haemost. 2006; 95: 1038–1039.
                                                                101. Niscola P, Palmieri MB, Scaramucci L, Vischini G, Giovannini M, Ferrannini M, Palumbo R, Fratoni S. Fulminant thrombotic microangiopathy as a clinical presentation of an occult signet-ring cell carcinoma of the lung and misdiagnosed as idiopathic thrombotic thrombocytopenic purpura. Saudi Med J. 2010; 31: 581.
                                                                  102. Nishimura M, Komori A, Matsushita M, Fukutani A, Fujiyama Y, Bamba T. Malignant gastrointestinal stromal tumor of the small intestine: rare complication of acute disseminated intravascular coagulation without hematogenous metastasis. Dig Dis Sci. 1998; 43: 2271–2277.
                                                                    103. Noda N, Sano T, Shirao K, Ono H, Katai H, Sasako M, Maruyama K. A case of bone marrow recurrence from gastric carcinoma after a nine-year disease-free interval. Jpn J Clin Oncol. 1996; 26: 472–475.
                                                                      104. Nordstrom B, Strang P. Microangiopathic hemolytic anemias (MAHA) in cancer. A case report and review. Anticancer Res. 1993; 13: 1845–1849.
                                                                        105. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009; 361: 1676–1687.
                                                                        106. Oberic L, Buffet M, Schwarzinger M, Veyradier A, Clabault K, Malot S, Schleinitz N, Valla D, Galicier L, Bengrine-Lefevre L, Gorin NC, Coppo P; Reference Center for the Management of Thrombotic Microangiopathies. Cancer awareness in atypical thrombotic microangiopathies. Oncologist. 2009; 14: 769–779.
                                                                        107. Oleksowicz L, Bhagwati N, DeLeon-Fernandez M. Deficient activity of von Willebrand’s factor-cleaving protease in patients with disseminated malignancies. Cancer Res. 1999; 59: 2244–2250.
                                                                        108. Ortega Marcos O, Escuin F, Miguel JL, Gómez Fernández P, Pérez Fontán M, Selgas R, Sanchez Sicilia L. Hemolytic uremic syndrome in a patient with gastric adenocarcinoma: partial recovery of renal function after gastrectomy. Clin Nephrol. 1985; 24: 265–268.
                                                                        109. Otrock ZK, Taher AT, Makarem JA, Kattar MM, Nsouli G, Shamseddine AI. Thrombotic thrombocytopenic purpura and bone marrow necrosis associated with disseminated gastric cancer. Dig Dis Sci. 2007; 52: 1589–1591.
                                                                        110. Ozg¨roglu M, Demirelli F, Mandel NM. Microangiopathic hemolytic anemia as an early predictor of recurrence in gastric cancer. Am J Clin Oncol. 1999; 22: 214.
                                                                          111. Pasquini E, Gianni L, Aitini E, Nicolini M, Fattori PP, Cavazzini G, Desiderio F, Monti F, Forghieri ME, Ravaioli A. Acute disseminated intravascular coagulation syndrome in cancer patients. Oncology. 1995; 52: 505–508.
                                                                            112. Patschan D, Witzke O, D¨hrsen U, Erbel R, Philipp T, Herget-Rosenthal S. Acute myocardial infarction in thrombotic microangiopathies—clinical characteristics, risk factors and outcome. Nephrol Dial Transplant. 2006; 21: 1549–1554.
                                                                            113. Paydas S, Ergin M, Baslamisli F, Yavuz S, Zorludemir S, Sahin B, Bolat FA. Bone marrow necrosis: clinicopathologic analysis of 20 cases and review of the literature. Am J Hematol. 2002; 70: 300–305.
                                                                            114. Peyvandi F, Palla R, Lotta LA. Pathogenesis and treatment of acquired idiopathic thrombotic thrombocytopenic purpura. Haematologica. 2010; 95: 1444–1447.
                                                                            115. Pietra CD, Gudat F, Obrecht P, Hartmann D. [Microangiopathic hemolytic anemia in malignant tumors. 2 cases. ] Schweiz Med Wochenschr. 1978; 108: 357–362.
                                                                            116. Pinckard JK, Wick MR. Tumor-related thrombotic pulmonary microangiopathy: review of pathologic findings and pathophysiologic mechanisms. Ann Diagn Pathol. 2000; 4: 154–157.
                                                                            117. Pirrotta MT, Bucalossi A, Forconi F, Bocchia M, Mazzotta S, Sammassimo S, Gozzetti A, Lauria F. Thrombotic thrombocytopenic purpura secondary to an occult adenocarcinoma. Oncologist. 2005; 10: 299–300.
                                                                              118. Plaimauer B, Kremer Hovinga JA, Juno C, Wolfsegger MJ, Skalicky S, Schmidt M, Grillberger L, Hasslacher M, Knöbl P, Ehrlich H, Scheiflinger F. Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost. 2011; 9: 936–944.
                                                                              119. Pogliani EM, Fowst C, Maffé P, Marozzi A, Stefani M, Polli E. CNS metastasis in ovarian cancer with microangiopathic hemolytic anemia associated with diffuse intravascular coagulation. Tumori. 1988; 74: 731–736.
                                                                              120. Polukhin E, Balla A, Chary K, Mezhir J. Microangiopathic hemolytic anemia as the first manifestation of lung adenocarcinoma. South Med J. 2001; 94: 550–551.
                                                                              121. Pusztai L, Viale G, Kelly CM, Hudis CA. Estrogen and HER-2 receptor discordance between primary breast cancer and metastasis. Oncologist. 2010; 15: 1164–1168.
                                                                              122. Puthenparambil J, Lechner K, Kornek G. Autoimmune hemolytic anemia as a paraneoplastic phenomenon in solid tumors: A critical analysis of 52 cases reported in the literature. Wien Klin Wochenschr. 2010; 122: 229–236.
                                                                              123. Qu L, Kiss JE. Thrombotic microangiopathy in transplantation and malignancy. Semin Thromb Hemost. 2005; 31: 691–699.
                                                                              124. Rauh MJ, Al Habeeb A, Chang H. Microangiopathic hemolytic anemia and leukoerythroblastic blood film heralding bone marrow metastatic gastroesophageal adenocarcinoma. Pathol Res Pract. 2011; 207: 121–123.
                                                                              125. Robson MG, Abbs IC. Thrombotic thrombocytopenic purpura following hemicolectomy for colonic carcinoma. Nephrol Dial Transplant. 1997; 12: 198–199.
                                                                              126. Rodenburg CJ, Nooy MA, Briët E. Microangiopathic haemolytic anaemia with advanced breast carcinoma: improvement with chemotherapy. Neth J Med. 1985; 28: 169–171.
                                                                              127. Sakai C, Takagi T, Oguro M, Wakatsuki S, Kuwahara T. Malignant pheochromocytoma accompanied by microangiopathic hemolytic anemia: a case report. Jpn J Clin Oncol. 1994; 24: 171–174.
                                                                              128. Sallah S, Wan JY, Nguyen NP, Hanrahan LR, Sigounas G. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study. Thromb Haemost. 2001; 86: 828–833.
                                                                              129. Salmeron M, Perrenoud JJ, Baumann RP. [Disseminated intravascular coagulation with microangiopathic hemolytic anemia and bone necrosis associated with a prostatic microcarcinoma. ] Schweiz Med Wochenschr. 1978; 108: 1549–1552.
                                                                                130. Saltzman DJ, Chang JC, Jimenez JC, Carson JG, Abolhoda A, Newman RS, Milliken JC. Postoperative thrombotic thrombocytopenic purpura after open heart operations. Ann Thorac Surg. 2010; 89: 119–123.
                                                                                131. Sato Y, Marutsuka K, Asada Y, Yamada M, Setoguchi T, Sumiyoshi A. Pulmonary tumor thrombotic microangiopathy. Pathol Int. 1995; 45: 436–440.
                                                                                132. Schweizer H, Boehm J, Winterer JT, Wild D, Neumann HP, Wiech T, Stubanus M, Kuehn EW. Phaeochromocytoma and thrombotic microangiopathy: favourable outcome despite advanced renal failure. J Clin Pathol. 2010; 63: 754–756.
                                                                                133. Sennesael JJ, Vanden Houte KM, Spapen HD, de Bruyne RM, Verbeelen DL. Recurrent hemolytic uremic syndrome and metastatic malignancy. Am J Nephrol. 1987; 7: 60–64.
                                                                                  134. Seo DW, Lee YS, Chae JG, Lee MG, Choe GY, Chi HS, Min YI. Hepatocellular carcinoma associated hemolytic uremic syndrome unrelated to chemotherapy. J Korean Med Sci. 1994; 9: 254–258.
                                                                                  135. Sevinc A, Kalender ME, Pehlivan Y, Sari I, Camci C. Thrombotic thrombocytopenic purpura and bone marrow necrosis as the initial presentation of lung cancer. Clin Appl Thromb Hemost. 2007; 13: 449–452.
                                                                                  136. Sill H, Höfler G, Kaufmann P, Horina J, Spuller E, Kleinert R, Beham-Schmid C. Angiotropic large cell lymphoma presenting as thrombotic microangiopathy (thrombotic thrombocytopenic purpura). Cancer. 1995; 75: 1167–1170.
                                                                                  137. Solenthaler M, Lámmle B. [Severe hemorrhage, lymphocytosis and leukoerythroblastic blood picture—disseminated intravascular coagulation in metastatic prostate carcinoma and chronic lymphatic leukemia. ] Ther Umsch. 1999; 56: 533–536.
                                                                                    138. Spero JA, Lewis JH, Hasiba U. Disseminated intravascular coagulation. Findings in 346 patients. Thromb Haemost. 1980; 43: 28–33.
                                                                                    139. Spoormans I, Altintas S, Van den Brande J, Luijks A, Vermorken JB. Purpura in a patient with disseminated breast cancer: a rapidly progressive cancer-related thrombotic thrombocytopenic purpura. Ann Oncol. 2008; 19: 1204–1207.
                                                                                    140. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010; 28: 5132–5139.
                                                                                    141. Susano R, Caminal L, Ferro J, Rubiales A, de Lera J, de Quirós JF. [Microangiopathic hemolytic anemia associated with neoplasms: an analysis of 5 cases and a review of the literature. ] Rev Clin Esp. 1994; 194: 603–606.
                                                                                    142. Takeuchi R, Kuto M, Katayama N, Kamio N, Tsuda M, Nagano T, Tomeoku M, Wada H, Murashima S, Deguchi K, et al.. [Carcinomatosis associated with microangiopathic hemolytic anemia and disseminated intravascular coagulation: 12 years after gastrectomy for gastric adenocarcinoma. ] Rinsho Ketsueki. 1983; 24: 1423–1429.
                                                                                      143. Tauzin-Fin P, Sesay M, Ryman A, Ballanger P, Combe C. Postoperative thrombotic microangiopathy following radical cystectomy for bladder cancer. Anaesth Intensive Care. 2006; 34: 672–675.
                                                                                      144. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001; 86: 1327–1330.
                                                                                      145. Terrell DR, Vesely SK, Hovinga JA, Lämmle B, George JN. Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes. Am J Hematol. 2010; 85: 844–847.
                                                                                      146. Thompson AM, Jordan LB, Quinlan P, Anderson E, Skene A, Dewar JA, Purdie CA; the Breast Recurrence in Tissues Study Group. Prospective comparison of switches in biomarker status between primary and recurrent breast cancer: the Breast Recurrence In Tissues Study (BRITS). Breast Cancer Res. 2010; 12: R92.
                                                                                      147. Trpin L, Molinari E, Ascari E. [Microangiopathic haemolytic anaemia in prostatic cancer. ] Haematologica. 1977; 62: 185–192.
                                                                                        148. Turitto G, Annunziata M, Barletta E, Lombardi R, Tinessa V, Daniele B. Thrombotic thrombocytopenic purpura in patient with metastatic occult adenocarcinoma. A case report. Recenti Prog Med. 2006; 97: 197–199.
                                                                                          149. van den Born BJ, van der Hoeven NV, Groot E, Lenting PJ, Meijers JC, Levi M, van Montfrans GA. Association between thrombotic microangiopathy and reduced ADAMTS13 activity in malignant hypertension. Hypertension. 2008; 51: 862–866.
                                                                                          150. Van der Merwe WM, Collins JF. The haemolytic uraemic syndrome and prostatic carcinoma. N Z Med J. 1987; 100: 483–485.
                                                                                          151. Vasko R, Koziolek M, Fuzesi L, König F, Strutz F, M¨ller GA. Fulminant plasmapheresis-refractory thrombotic microangiopathy associated with advanced gastric cancer. Ther Apher Dial. 2010; 14: 222–225.
                                                                                          152. Vesely SK, George JN, Lammle B, Studt JD, Alberio L, El-Harake MA, Raskob GE. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood. 2003; 102: 60–68.
                                                                                          153. von Bubnoff N, Sandherr M, Schneller F, Peschel C. Thrombotic thrombocytopenic purpura in metastatic carcinoma of the breast. Am J Clin Oncol. 2000; 23: 74–77.
                                                                                            154. Watzka SB, Rauscher-Pötsch I, Nierlich P, Setinek U, Kostler WJ, Potschger U, Muller MR, Attems J. Concordance between epidermal growth factor receptor status in primary non-small-cell lung cancer and metastases: a post-mortem study. Eur J Cardiothorac Surg. 2010; 38: 34–37.
                                                                                            155. Werner TL, Agarwal N, Carney HM, Rodgers GM. Management of cancer-associated thrombotic microangiopathy: what is the right approach? Am J Hematol. 2007; 82: 295–298.
                                                                                              156. Wolff D, Brinkmann B, Emmrich J, Steiner M. Metastatic pancreatic carcinoma presenting as thrombotic thrombocytopenic purpura. Pancreas. 2003; 26: 314.
                                                                                              157. Wong KF, Chan JK, Ma SK. Solid tumour with initial presentation in the bone marrow—a clinicopathologic study of 25 adult cases. Hematol Oncol. 1993; 11: 35–42.
                                                                                              158. Yokomine T, Hirakawa H, Ozawa E, Shibata K, Nakayama T. Pulmonary thrombotic microangiopathy caused by gastric carcinoma. J Clin Pathol. 2010; 63: 367–369.
                                                                                              159. Zimmerhackl LB, Hofer J, Cortina G, Mark W, W¨rzner R, Jungraithmayr TC, Khursigara G, Kliche KO, Radauer W. Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N Engl J Med. 2010; 362: 1746–1748.
                                                                                              160. Zupancic M, Shah PC, Shah-Khan F. Successful splenectomy in cancer-associated TTP. Am J Hematol. 2007; 82: 250–251.
                                                                                                Keywords:

                                                                                                ADAMTS = a disintegrin-like and metalloprotease with thrombospondin type 1 repeats; aHUS = atypical hemolytic uremic syndrome; CR-MAHA = cancer-related microangiopathic hemolytic anemia; CUP = cancer of unknown primary; DIC = disseminated intravascular coagulation; MAHA = microangiopathic hemolytic anemia; NHL = non-Hodgkin lymphoma; TTP = thrombotic thrombocytopenic purpura

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