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The Oncologist, Vol. 8, No. 4, 375–380, August 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
Symptom Management and Supportive Care

Thrombotic Thrombocytopenic Purpura Associated with Bone Marrow Metastasis and Secondary Myelofibrosis in Cancer

Jae C. Changa, Tahir Naqvib

a University of California, Irvine College of Medicine and Division of Hematology/Oncology at UCI Medical Center, Orange, California, USA; b Department of Medicine, Wright State University School of Medicine, Dayton, Ohio, USA, and Hematology and Oncology Section, Good Samaritan Hospital, Dayton, Ohio, USA

Correspondence: Jae C. Chang, M.D., Division of Hematology/Oncology, Chao Family Comprehensive Cancer Center, University of California at Irvine Medical Center, 101 The City Drive, Orange, California 92868, USA. Telephone: 714-456-5153; Fax 714-456-2242; e-mail: jaec{at}uci.edu


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 References
 
To examine the relationship between cancer and development of thrombotic microangiopathy (TM), the medical records of patients with known TM were examined in one institution from January 1981 to December 2002. Nine out of 93 patients with the established diagnosis of TM had active cancer. All nine of those patients had thrombotic thrombocytopenic purpura (TTP). Among those patients, two patients received chemotherapy prior to the development of TTP. Six of the seven patients who received no chemotherapy had extensive bone marrow metastasis and secondary myelofibrosis. There were two patients each with breast cancer, lung cancer, and stomach cancer. Severe anemia and thrombocytopenia with leukoerythroblastosis were prominent clinical features in all six patients. Four patients had neurological (mental) changes and three developed fever, but none had significant renal dysfunction. Upon establishing the diagnosis of TTP, four patients were treated with exchange plasmapheresis (EP) and two patients were treated with chemotherapy because there were no neurological changes. Three patients achieved complete remission of TTP, one with EP alone and two with chemotherapy. The one patient who achieved remission with EP alone was later treated with chemotherapy and survived for 2 1/2 years. The other three patients treated with EP alone died within 2 months after the diagnosis of TTP. Since TTP occurred in association with bone marrow metastasis and myelofibrosis in six patients among seven chemotherapy-untreated cancer patients, this marrow change was considered to be the possible cause of the development of TTP. It is recommended that all cancer patients with unexplained anemia and thrombocytopenia be evaluated for the coexistence of bone marrow metastasis and TTP.

Key Words. Thrombotic thrombocytopenic purpura • Bone marrow metastasis • Secondary myelofibrosis • Microangiopathic hemolytic anemia • Thrombotic microangiopathy


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 Conclusions
 References
 
In the past two decades, in addition to idiopathic thrombotic thrombocytopenic purpura (TTP), more cases of secondary TTP have been identified, perhaps due to an enthusiasm for cure potential with an availability of exchange plasmapheresis (EP) [1]. In addition, the term thrombotic microangiopathy (TM) has been introduced to include hemolytic uremic syndrome, hemolysis with elevated liver enzyme levels and a low platelet count (HELLP) syndrome, and dyadic TTP in addition to classical TTP. Secondary TM has been known to be associated with collagen vascular diseases [2–5], use of certain drugs [6–9], transplants [10–13], surgeries [14–17], infections [18, 19], pregnancy [20, 21], and cancer [22–24]. In cancer patients, at least two causes for TM have been identified. One is the complication from chemotherapy [6, 25–31], and the other is the manifestation of the cancer itself without any relationship to chemotherapy. No specific pathologic feature, however, has been implicated for TM in the patient with cancer. In this article, we describe that TTP in cancer patients is associated with bone marrow metastasis and secondary myelofibrosis. The possible pathophysiologic mechanism of bone marrow metastasis contributing to TTP is discussed.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 Conclusions
 References
 
All identifiable cases of TM seen at the Good Samaritan Hospital in Dayton, Ohio, from January 1981 to December 1994 were documented and recorded retrospectively in the personal computer system. Cases of TM from January 1995 to December 2002 were prospectively recorded. These studies included all patients with TTP, hemolytic uremic syndrome, and HELLP syndrome. The medical records and peripheral blood and bone marrow biopsy slides of the patients among these that were diagnosed with TM simultaneously with active cancer were reviewed. The essential diagnostic criteria for TM were unexplained thrombocytopenia and microangiopathic hemolytic anemia (MAHA) [14]. The diagnosis of MAHA was based on schistocytosis, reticulocytosis, and elevated lactic acid dehydrogenase (LDH) level or decreased haptoglobin level. In some patients, additional clinical features, such as neurologic changes, renal dysfunction, and fever, were present. The identifiable causes of thrombocytopenia were excluded with the evaluation of clinical history, review of medical records, and laboratory findings, including previous history of thrombocytopenia, drug administration, blood transfusion, and evidence of infection.

Pertinent laboratory studies were also performed and their results were reviewed. Consumption coagulopathy was ruled out by a normal fibrinogen level, prothrombin time, and activated partial thromboplastin time and a negative result of fibrin split products when this diagnosis was a possibility. Heparin-induced thrombocytopenia was excluded according to criteria described previously [32] and with a lack of heparin-induced platelet aggregation, a normal 14C serotonin release assay [33], or the absence of platelet factor 4 and heparin-associated antibodies [34] when these tests became available. Thrombocytopenia caused by infection, such as sepsis or pneumonia, or by blood transfusion was ruled out by appropriate examinations, including blood cultures, roentgenographic and imaging studies, and clinical information.

The diagnosis of cancer was established on the basis of clinical, laboratory, and pathologic examinations. In all active cancer patients presenting with anemia and thrombocytopenia, bone marrow studies, both aspiration and biopsy, were reviewed when available. The bone marrow samples were studied for the extent of the metastasis and secondary myelofibrosis, since these were the consistent abnormalities.

Hematologic data reviewed were the hemoglobin, hematocrit, platelet count, reticulocyte count, LDH level, and haptoglobin level. Reports of peripheral blood films were also reviewed and blood smears were examined. The degree of schistocytosis was estimated as follows [14]: the score of 0 was given for a finding of <1% of schistocytes among red blood cells; 1+ was given for 1%-2%; 2+ was given for 2%-5%; 3+ was given for 5%-10%; and 4+ was used for findings of >10%.

The treatments, both EP and chemotherapy regimens, of TM associated with cancer and their final outcomes were recorded.


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 Conclusions
 References
 
There were 93 patients with the diagnosis of TM between 1981 and 2002 in our institution. The primary diagnosis of TTP was present in 77 patients, hemolytic uremic syndrome was diagnosed in eight, and HELLP syndrome was the primary diagnosis in another eight. Among these patients, nine patients with TM had active cancer, and all of those had TTP (Table 1Go). Six patients had the classical triad of TTP, but three patients had only dyadic TTP with thrombocytopenia and MAHA. The neurologic manifestation was mostly mental changes, such as confusion, disorientation, lethargy, and visual disturbance. Four patients had breast cancer, two had lung cancer, two had stomach cancer, and one had unknown primary cancer. The histological types of cancer were adenocarcinoma in seven patients, small-cell anaplastic carcinoma in one patient, and positive cytology of non-small cell type from an unknown primary in pericardial fluid in one patient. Two patients with breast cancer were receiving chemotherapy when TTP developed: patient 2 with mitomycin C and vinblastine for metastatic disease and patient 9 with doxorubicin and cyclophosphamide in the neoadjuvant setting. Patient 9 was unusual in that TTP occurred following the insertion of a life-port after the second cycle of doxorubicin and cyclophosphamide. This patient had no evidence of cancer beyond the breast. Seven other patients had not taken any chemotherapy within 3 months prior to the diagnoses of TTP, although two patients with breast cancer were on hormonal therapy: patient 1 with megestrol acetate until 8 weeks prior to the diagnosis of TTP and patient 4 with tamoxifen.


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  		Table 1. Clinical data in all patients with cancer
 
Among the seven patients who had TTP in the absence of chemotherapy during the three preceding months, six had bone marrow metastasis with secondary myelofibrosis. None of those patients was known to have idiopathic myelofibrosis prior to the diagnosis of TTP and splenomegaly was not present. One patient who had pericardial effusion with positive cytology from an unknown primary showed neither hematologic abnormalities nor evidence of bone marrow metastasis. Tables 2Go–4 show the hematologic data, treatment modalities, and outcomes of the six patients who had active cancer with bone marrow metastasis. All patients had clear evidence of MAHA and unexplained thrombocytopenia when evaluated by hematologists. The degree of anemia was severe, and levels of hemoglobin fluctuated because of multiple blood transfusions. Platelet counts ranged from 7–96 x 103/µl. Peripheral blood slides showed mild-to-moderate schistocytosis as reported in the examinations by technologists and hematologists. Schistocytosis, reticulocytosis, and elevated levels of LDH with decreased haptoglobin levels confirmed the diagnosis of MAHA in all six patients. All had a varying degree of leukoerythroblastosis in the peripheral blood and extensive metastasis to the bone marrow when bone marrow biopsy specimens were examined (Table 3Go). Additionally, secondary myelofibrosis was present in all six patients. According to the isotopic bone scan, bone metastasis, however, was present only in three patients.


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  		Table 2. Hematologic data from patients with bone marrow metastasis
 

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  		Table 3. Blood and bone marrow findings from patients with active cancer and bone marrow metastasis
 
As soon as the diagnosis of TTP was established, four patients were started on EP and two patients were treated with chemotherapy, one with etoposide and carboplatin (EC) and the other with paclitaxel (T) since those patients had only dyadic TTP without neurologic manifestation (Table 4Go). Only one patient treated with EP achieved complete remission (CR) of the TTP. This was followed by combination chemotherapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) with a good partial response, and that patient survived 31 months. Three patients gained no benefit from EP due to advanced cancer as well as advanced TTP, and they died within 2 months. Two patients who were treated with chemotherapy achieved CR of their TTP, although their cancers showed only partial remission. One survived 10 months and the other survived 11 months after their diagnoses of TTP.


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  		Table 4. Treatment, outcome, and survival of patients with active cancer and bone marrow metastasis
 

   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
Conclusions
 References
 
In the past two decades, with the availability of EP as an effective treatment, more cases of TTP, including atypical and secondary cases, have been recognized and treated with better outcomes in clinical practice [35–37]. In patients with cancer, various cancer chemotherapeutic agents have been implicated; mitomycin C [6, 25–26] has been most commonly associated with both TTP and hemolytic uremic syndrome, and other agents, including cisplatin [27], deoxycoformycin [28], the regimen of cisplatin, bleomycin, and a vinca alkaloid [29], the combination of daunorubicin and cytosine arabinoside [30], and combination regimens containing cisplatin [31], have also been implicated. In addition, cancer itself has been suspected to cause TTP [22–24], but neither a clear link between cancer and the development of TTP nor a risk factor for TTP in cancer patients has been identified.

We attempted to address this issue by reviewing all the known cases of TTP in patients with active cancer in our institution for a period of more than 20 years. In our series, only two cases were associated with chemotherapy: one with the combination of mitomycin C and vinblastine for metastatic breast cancer and the other after the insertion of a life-port following neoadjuvant chemotherapy of a second cycle of doxorubicin and cyclophosphamide. In the second patient, acute TTP was temporally related to the insertion of a life-port that was placed for the purpose of chemotherapy and was considered not to be a complication of chemotherapy, since the patient had no evidence of TTP after the first cycle. The relationship between acute TTP and the vascular procedure is not certain in this patient. However, it is known that vascular procedures can initiate acute TTP [14]. In six active cancer patients in this study, TTP occurred in association with extensive bone marrow metastasis and secondary myelofibrosis. The primary sites of cancer origin were the breast, lung, stomach, and an unknown primary, and pathologic type was adenocarcinoma in all but two patients. In view of this observation, bone marrow metastasis of cancer with myelofibrosis is suspected to be the main feature associated with the development of TTP. In the literature, reported cases of TTP and hemolytic uremic syndrome in cancer have been associated with severe anemia and advanced cancer [38, 39]. It is quite conceivable that those patients could indeed have had unrecognized bone marrow metastasis with myelofibrosis.

The pathogenesis of TTP is still not well understood. Recent studies, however, have shed some light on the understanding of its pathophysiologic process. Relatively consistent findings have been the deficiency of a von Willebrand factor (vWF)-cleaving protease (ADAMTS 13) due to an inhibitor(s) or congenital deficiency [40–42] and the detection of unusually large (uL)vWF multimers in some patients with TTP [43]. It is also known that the protease cleaves uLvWF multimers to smaller ones, and uLvWF multimers, if not cleaved, promote the activation and aggregation of platelets [44]. In a disease or injury involving the endothelial cell, uLvWF multimers may be released into the circulation, and these multimers, if the vWF-cleaving protease is not available, promote the activation and aggregation of platelets in the arteriolar capillaries, resulting in thrombocytopenia and MAHA

As seen in the metastasis of cancer to other organs, metastasis within the bone marrow may also be associated with increased angiogenesis for the growth of cancer. It is speculated that, in addition to abnormal angiogenesis in the marrow, aggressive growth of tumors and secondary myelofibrosis may injure endothelial cells of the vessels in the marrow by direct encroachment. These changes, it is speculated, could cause the release of uLvWF multimers, and with a possible decrease in the availability of the uLvWF-cleaving protease through undetermined mechanisms, such as decreased production or immune reaction, in advanced cancer may contribute to the aggregation of platelets. Since TTP has been seen mostly in adenocarcinoma, this pathology could be another contributing factor, perhaps related to the production of mucin, which may exert a direct detrimental effect on the pathologic endothelial cell to change endothelial function.

TTP associated with cancer might have responded poorly to EP due to delayed diagnosis of TTP and advanced cancer. Since our two patients who were treated with chemotherapy alone and the one treated with EP without chemotherapy showed complete remission of TTP, both EP and chemotherapy seem to be effective treatments in some patients with TTP and cancer.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
References
 
TTP can be associated with cancer, but only in a very small fraction of cancer patients. Nonetheless, it is important to recognize the diagnosis early, since hematologic abnormalities in cancer may be the presentation of the combination of bone marrow metastasis and TTP and unnecessary diagnostic procedures, including extensive laboratory and imaging studies to determine the cause of thrombocytopenia and mental changes, may be spared if TTP can be recognized in a timely fashion. The prognosis of TTP in cancer patients is poor, but early diagnosis, as seen in patient 1 in this study, and effective chemotherapy, as seen in patients 5 and 7, may alter the course of the disease. It is recommended that all cancer patients presenting with unexplained anemia and thrombocytopenia be evaluated not only for bone marrow metastasis, but also for coexistence with secondary TTP.


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 Conclusions
 References
 

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Received February 6, 2003; accepted for publication April 30, 2003.




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