Annals of Oncology Advance Access originally published online on April 11, 2008
Annals of Oncology 2008 19(6):1204-1207; doi:10.1093/annonc/mdn160
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Purpura in a patient with disseminated breast cancer: a rapidly progressive cancer-related thrombotic thrombocytopenic purpura
case reportA 59-year-old woman with a history of primary lateral sclerosis with a right-sided foot paresis and fibrocystic mastopathy presented with tiredness, weakness, muscle pain and slight fever for the last 2 weeks. She was not taking any medication. She did not recall any malignancies or cardiovascular diseases in her family.
Clinical examination revealed a very weak and pale woman (World Health Organization performance status 3) with scleral icterus. Purpura was marked in the lowermost parts of the body, and she also had bilateral malleolar edema. A palpable mass of 2 cm diameter in the upper outer quadrant of the right breast was remarked, as well a right-sided axillary lymph node of 1.5 cm. Clinical neurological examination elicited the known foot paresis.
Routine blood analysis showed a hemoglobin value of 6.1 g/dl (normocytic normochromic), a severe thrombocytopenia (16 x 109/l) and leucocytosis (17.9 x 109/l). The direct Coombs test was negative. Schistocytes and reticulocytes were seen in the peripheral blood smear. Biochemistry revealed a normal renal function. The liver function was compromised: lactate dehydrogenase (LDH) 1076 U/l, aspartate aminotransferase (AST) 88 U/l, alanine aminotransferase (ALT) 77 U/l and indirect bilirubin 1.8 mg/dl. The C-reactive protein level was normal. Coagulopathy parameters were within normal ranges with the exception of fibrinogen (476 mg/dl; normal range 200–400 mg/dl) and D-dimers (2.5 µg/ml; normal range 0.0–0.5 µg/ml).
A bone marrow biopsy revealed metastases of a breast carcinoma as confirmed by immunohistochemistry.
The diagnosis of cancer-related thrombotic thrombocytopenic purpura (TTP) was made and she was admitted to our hospital. Because of the rapid clinical deterioration, plasma exchange (PE) and steroid therapy were started immediately and she received daily blood and platelet transfusions. In spite of the repeated PE, there was only a minimal improvement in the platelet count.
A biopsy of the mass in the right breast confirmed an invasive ductal breast carcinoma (hormone-receptor positive and HER-2/neu negative).
Initial staging revealed no other metastastatic site. Chemotherapy with weekly vincristine 1 mg and epirubicine 25 mg/m2 was started. This treatment schedule was chosen because of the compromised bone marrow, liver and renal function at that moment (LDH 11595 U/l, AST 423 U/l, ALT 175 U/l, indirect bilirubin 3.4 mg/dl, urea 248 mg/dl, serum creatinine 2.8 mg/dl).
Because of no hematological or clinical improvement, PE was stopped after 10 days and the corticosteroids were tapered.
After the first course of chemotherapy, her transfusion need of blood and platelets seemed to reduce. Her renal function stabilized and liver tests improved.
Unfortunately after the second course of chemotherapy, she developed fever. Microscopic examination showed a urinary infection. On chest radiography, a pleural effusion with parenchymal infiltrate in the lower lobe of the left lung was seen. All hemocultures remained sterile. Broad-spectrum antibiotics and variconazole were initiated without any improvement.
The patient's clinical status deteriorated rapidly with worsening of the respiratory and neurologic status and evolution to multiorgan failure. She died 1 month after diagnosis.
The performed autopsy demonstrated an invasive grade 3 ductal carcinoma with metastases to bone (marrow), lungs, spleen, ovaries, adrenal glands and lymph nodes. The kidneys were not invaded by tumor but were pathognomonic for shock. Furthermore, there was a hypercoaguability disorder with diffuse thrombi and pulmonary embolism. In addition, there was bronchopneumonia with invasive aspergillosis (Figures 1 and 2).
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discussion
clinical presentation and laboratory findings
Thrombotic microangiopathy (TMA) is a microvascular thrombosis defined by lesions of vessel wall thickening (mainly arterioles or capillaries) with intraluminal platelet thrombosis leading to partial or complete occlusion of the vessel lumina. It includes TTP, hemolytic uremic syndrome and HELLP syndrome (hemolysis with elevated liver enzyme levels and low platelets) [1].
The essential diagnostic criteria for TMA are unexplained thrombocytopenia with microangiopathic hemolytic anemia (MAHA). MAHA is a nonimmune hemolyses (negative direct antiglobulin test) with prominent red blood fragmentation or schistocytes, reticulocytosis, elevated LDH and indirect bilirubin and low levels of haptoglobin.
Most patients have neurologic symptoms, kidney dysfunction, fever and cardiac involvement. Identifiable causes of thrombocytopenia have to be excluded (previous history of thrombocytopenia, drug-induced thrombocytopenia, blood transfusion, collagen vascular diseases, surgery, pregnancy, infection and cancer). Also consumption coagulopathy has to be ruled out [1].
In cancer patients, there are two main causes of TMA: one is a complication of chemotherapy and the other is a manifestation of the cancer itself, especially bone marrow invasion and secondary myelofibrosis [1–3].
pathogenesis
Von Willebrand factor (VWf) is synthesized in endothelial cells and assembled in larger multimers that are present in normal plasma. The larger multimers are rapidly degraded in the circulation into the normal size range of VWf multimers by a specific VWf cleaving protease (cleaving metalloproteinase called ADAMTS13). It is well known that in congenital TTP, there are mutations in the ADAMTS13 gene, resulting in a deficiency that could lead to an accumulation of large VWf multimers, platelet aggregation and platelet clumping. Normally, plasma ADAMTS13 activity ranges between 50% and 178% [1, 4] and its activity is often reduced in liver diseases, disseminated malignancies, chronic metabolic and inflammatory conditions, pregnancy, cancer therapy and disseminated intravascular coagulation (secondary TTP). In familial or acquired idiopathic TTP, the ADAMTS13 activity is <5% of normal activity. ADAMTS13 deficiency is a major risk to develop TTP, but is not a prerequisite [1]. The ADAMTS13 activity in our patient was 20%.
Nevertheless ADAMTS13 deficiency seems to play a role in the pathogenesis of cancer-associated TTP, although the exact mechanism is not well understood. One of the most considered hypotheses in cancer-associated TTP is injury to the endothelial cells of vessels in the bone marrow by direct tumor invasion. Abnormal angiogenesis, aggressive tumor growth and secondary myelofibrosis may all be involved in injuring the endothelial cells of vessels in the marrow. This can cause a release of ultra large von Willebrand factor (ULVWf), and this, together with a possible decrease of ADAMTS13 (through undetermined mechanisms, such as formation of autoantibodies against VWf cleavage protein in advanced cancer), may contribute to the aggregation of platelets [1, 3, 5]. Another explanation for the MAHA in cancer-related TMA is red blood cell fragmentation due to direct contact with tumor emboli within blood vessels or intraluminal fibrin thrombi [6].
TTP has been mostly seen in mucin-producing adenocarcinomas, such as in this case in breast cancer. Mucin probably has a direct detrimental effect on the pathologic endothelial cells causing them to change their endothelial function and thus increases the production of ULVWf multimers [1, 3].
treatment
The treatment of choice remains PE therapy to remove the ULVWf and autoantibodies.
Although it is often difficult to determine the exact cause of poor outcomes in patients with complicated illnesses, platelet transfusion should generally be avoided in patients with TTP. Platelet transfusion can cause severe exacerbations secondary to increased microvascular thrombi formation induced by circulating platelet aggregates which results in multiorgan failure and death [7].
In patients receiving PE at the time of platelet transfusion, no adverse effects were seen, suggesting that PE may prevent the exacerbation of thrombosis [8].
However, cancer-related TTP neither responds well to PE with or without platelet transfusion nor is immunosuppression therapy any help, most likely because of the lack of severe deficiency of ADAMTS13 [5].
Treatment of the underlying cancer is therefore important in the management of secondary TTP.
conclusion
There should be a high index of suspicion for an underlying malignant process in patients who present with a clinical feature consistent with TTP. Their clinical and radiological work-up must be initiated and in the meantime PE should be started. Failure to diagnose disseminated malignancy is accompanied by the risk of delaying appropriate chemotherapy. On the other hand, omission of PE (with platelet transfusion) in a patient with TTP may result in death.
The prognosis of cancer-related TTP is poor, with the majority of patients dying within weeks of diagnosis.
1 Department of Oncology
2 Department of Pathology, University Hospital of Antwerp, Belgium
* E-mail: sevilay.altintas{at}uza.be
References
1. Chang J, Naqvi T. The thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer. Oncologist (2003) 8:375–380.
2. Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int (2001) 60:831.[CrossRef][Web of Science][Medline]
3. Werner T, Agarwal N, Carney H, et al. Management of cancer accociated thrombotic microangiopathy: what is the right approach? Am J Hematol (2006) 81:1–4.[CrossRef][Web of Science][Medline]
4. George JN. The role of ADAMTS 13 in the pathogenesis of thrombocytopenic purpura-hemolytic uremic syndrome. Clin Adv Hematol Oncol (2005) 3:627–632.[Medline]
5. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med (1998) 339:1585–1594.
6. Brain MC, Azzopardi JG, Baker LR, et al. Microangiopathic haemolytic anaemia and mucin forming adenocarcinoma. Br J Haematol (1970) 18:183–192.[Web of Science][Medline]
7. McCarthy LJ, Danielson CF, Graves V, et al. Do platelet transfusions to patients with TTP influence their survival? Blood (1994) 84:669a.
8. de la Rubia J, Plumé G, Arriaga F, et al. Platelet transfusion and thrombotic thrombocytopenic purpura. Transfusion (2002) 42:1384–1385.[CrossRef][Web of Science][Medline]
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