ABSTRACT: Tumor cells from malignancies of any type—carcinoma, sarcoma, lymphoma, leukemia—may cause systemic arteriolar and capillary obstructions. The high shear rates of blood passing through these obstructions result in fragmentation of the red cells and can cause severe anemia, described as microangiopathic hemolytic anemia (MAHA). The thrombi caused by these obstructions consume platelets and can lead to severe thrombocytopenia. MAHA (defined by fragmented red cells on the peripheral blood smear and evidence of hemolysis) and thrombocytopenia are the clinical features of syndromes described as thrombotic microangiopathies (TMAs). If a malignancy is not recognized as the cause of TMA, the diagnosis of thrombotic thrombocytopenic purpura (TTP) may be considered and plasma exchange, the essential treatment for TTP, may be initiated—a critical decision because this treatment carries a high risk of serious complications. This review describes the clinical features that should suggest a search for systemic malignancy as the cause of unexpected MAHA and thrombocytopenia. Recognition of a systemic malignancy is critical to the initiation of appropriate chemotherapy and avoidance of inappropriate use of plasma exchange treatment.
Occult malignancies as a cause of unexpected microangiopathic hemolytic anemia (MAHA) and thrombocytopenia are an uncommon but critical clinical problem. The clinical problem is emphasized and illustrated by a patient whose case we have previously reported, a 52-year-old woman who presented with sudden onset of acute abdominal pain and syncope 3 years after resection of breast carcinoma and adjuvant chemotherapy. Her hematocrit was 26% with evidence of microangiopathic hemolysis (many fragmented red cells on her blood smear, increased indirect bilirubin [3.9 mg/dL] and lactate dehydrogenase [LDH; 1431 U/L] levels, negative direct Coombs test), and her platelet count was 17,000/µL. Coagulation studies, including fibrinogen level, were normal. She had been in continuous remission for the past 3 years, and computed tomographic (CT) scans showed no evidence of recurrent carcinoma. Thrombotic thrombocytopenic purpura (TTP) therefore was assumed to be the cause of this sudden illness, and plasma exchange treatment was started. The patient developed respiratory distress; spiral CT documented multiple bilateral pulmonary emboli and echocardiogram documented a dilated, akinetic right ventricle. She died 3 days after the diagnosis of TTP. I assumed that the autopsy would demonstrate multiple pulmonary emboli as the cause of her death, but I was very surprised to learn that the gross autopsy was normal. No pulmonary emboli were seen; there was no evidence of recurrent carcinoma; no cause of death was established. Therefore I assumed that she had TTP with very unusual clinical manifestations, and I assumed that the microscopic examination would demonstrate microvascular platelet thrombi in multiple organs, the characteristic pathologic abnormality of TTP. My second great surprise came several weeks later, when the pathologist called to tell me about the microscopic findings. Small intravascular clusters of metastatic carcinoma cells, consistent with breast carcinoma, were present in arterioles and capillaries of nearly every section of the lungs, brain, heart, liver, spleen, lymph nodes, and marrow. The vessels were occluded by tumor emboli and also by platelet-fibrin thrombi, which must have accumulated proximal to the tumor cells (see Figure). The platelet-fibrin thrombi were similar to the characteristic pathologic feature of TTP, however in this patient the thrombi were the result of microvascular obstruction by microscopic tumor emboli. Therefore this patient had acute and fatal malignancy-associated thrombotic microangiopathy (TMA) that was mistakenly diagnosed as TTP. The lesson I learned was that because of her atypical clinical features, we should have been more aggressive in our evaluation, which should have included a bone marrow biopsy. This might have revealed the correct diagnosis and could have enabled the patient to avoid inappropriate plasma exchange treatment.
Pathogenesis of Malignancy-Associated Microangiopathic Hemolytic Anemia (MAHA) and Thrombocytopenia
The term "microangiopathic hemolytic anemia" was used by Brain et al in their initial description of mechanical red cell destruction in 1962. They observed that "widespread intra-capillary and intra-arteriolar eosinophilic granular or amorphous thrombi" could reduce the vessel lumen to "pin-point size," causing intraluminal shearing of red cells. They described the morphologic appearance of red cell fragmentation as "burr, triangular, and helmet red cells." In their report describing 25 patients, the variety of conditions that caused MAHA, which almost always was accompanied by thrombocytopenia, was emphasized: 6 patients had TTP; 6 had malignant hypertension; 8 had acute renal diseases of multiple etiologies; and 5 had metastatic carcinomas (stomach, 3; lung, 1; prostate, 1). The pathologic picture of thrombosis in arterioles and capillaries, which is associated with swelling of endothelial cells and the subendothelial space that causes MAHA and thrombocytopenia, is described as thrombotic microangiopathy. Since the initial report of MAHA, multiple other disorders have been recognized as potential causes of TMA: hemolytic-uremic syndrome (HUS), scleroderma, antiphospholipid antibody syndrome, drug toxicity, pre-eclampsia, radiation nephropathy, renal allograft rejection, hematopoietic stem cell transplantation, and human immunodeficiency virus (HIV) infection.[3,4]
In 1979, Antman et al reported on 4 patients with cancer and MAHA and reviewed 51 previously reported cases. Although more than half of the 55 patients had coagulation abnormalities consistent with disseminated intravascular coagulation (DIC), Antman et al proposed that the primary cause of hemolytic anemia and thrombocytopenia is the mechanical factor of vascular obstruction by tumor cell emboli. Their conclusion was that systemic malignancies of many different types can cause both the pathologic and clinical features of TMA without abnormalities of coagulation.
Frequency of Systemic Malignancies That Can Cause MAHA and Thrombocytopenia Misdiagnosed as TTP
In most patients with malignancy-associated MAHA and thrombocytopenia, the systemic malignancy is already known to be the patient’s primary problem. It is uncommon for MAHA and thrombocytopenia to be the first clinical manifestation of a systemic malignancy. It is this uncommon presentation, however, that requires awareness and appropriate evaluation by the physician. A report on the experience of the Oklahoma TTP-HUS Registry described 10 patients initially diagnosed with TTP, treated with plasma exchange, and subsequently diagnosed as having MAHA and thrombocytopenia caused by a systemic malignancy. Two patients in the Registry with malignancy-associated MAHA and thrombocytopenia were not included in this report because metastatic carcinomas (one lung, one prostate) were apparent at the time that their physicians diagnosed TTP. If I had been asked, I would have advised these physicians against the use of plasma exchange, because these patients did not have the diagnostic criteria for TTP, which are MAHA and thrombocytopenia without another clinically apparent etiology. During the 5 years since the preparation of their report, no additional patients in the Oklahoma Registry have had a systemic malignancy misdiagnosed as TTP. Among the 415 patients in the Oklahoma TTP-HUS Registry who were clinically diagnosed with their initial episode of TTP over a period of more than two decades, from 1989 to 2010, only the 10 patients (2.4%) described in the report were subsequently diagnosed with an initially unsuspected systemic malignancy. Therefore this is an uncommon occurrence, with a frequency of less than 1 patient per year in a region with a population of approximately 2 million. This low frequency is consistent with our systematic literature review in 2006 that identified only 19 additional patients who were initially diagnosed with TTP, treated with plasma exchange, and then subsequently diagnosed as having a systemic malignancy as the cause of their MAHA and their thrombocytopenia.
The Variety of Systemic Malignancies That Can Cause MAHA and Thrombocytopenia Misdiagnosed as TTP
Table 1 lists 19 different systemic malignancies that have been reported to cause MAHA and thrombocytopenia. The conclusions from these data are that MAHA and thrombocytopenia are more frequently caused by the more common malignancies, but many systemic malignancies—perhaps any systemic malignancy—can cause MAHA and thrombocytopenia.