The diagnosis of TTP is suggested by a pentad of clinical features: thrombocytopenia, microangiopathic haemolytic anaemia, neurological and renal abnormalities, and fever. This uncommon but serious blood disorder is characterised by widespread platelet and von Willebrand factor (VWF)-rich thrombi in the capillaries and arterioles systemically.6
The mainstay of TTP treatment is plasma exchange and/or plasma infusion. Prior to the availability of this therapy, TTP was fatal in 90% of patients.7
As plasma exchange has proven efficacious in the treatment of TTP, the thresholds for clinical suspicion and when to initiate treatment have been lowered. Now, only thrombocytopenia and microangiopathic anaemia, without other apparent aetiology, are sufficient to make the diagnosis of TTP and begin appropriate therapy.2
In our patient, the aetiology of microangiopathic haemolytic anaemia and thrombocytopenia is unclear; underlying malignancy and treatment with bevacizumab could be the postulated mechanisms for microangiopathic development and immune dysfunction. Thrombotic microangiopathy can occur in almost any cancer but is seen more frequently with chemotherapy and metastases of adenocarcinoma of the pancreas, lung, prostate, stomach, colon, ovary, breast or unknown primary site.8
The hypercoagulable state of malignancy can lead to intermittent signs of DIC which can suggest a diagnosis of TTP; in our patient DIC was excluded due to normal PT, aPTT and fibrinogen values. Severe ADAMTS13 deficiency almost never occurs in cancer-associated thrombotic microangiopathy, where plasma exchange is ineffective.2 8
Bevacizumab (Avastin) inhibits angiogenesis by blocking the vascular endothelial growth factor receptor on the surface of endothelial cells. It has been approved in various solid tumours including metastatic colorectal cancer, lung cancer and breast cancer.9–13
However, in the literature, thrombotic microangiopathy has been associated with bevacizumab when used in treatment for renal cell carcinoma.14 15
Several case reports of microangiopathic haemolytic anaemia have been documented in patients with solid tumours while receiving concomitant bevacizumab and sunitinib. Of the 25 cases described, five of 12 patients at the highest sunitinib dose level exhibited laboratory findings consisted with microangiopathic haemolytic anaemia and two were diagnosed with typical cardinal signs and symptoms of TTP including severe thrombocytopenia, anaemia, reticulocytosis, reductions in serum haptoglobin, schistocytes on peripheral smear, modest increases in serum creatinine levels and severe hypertension.16 17
The clinical features improve once the medications are discontinued.16
Therefore, the microangiopathic haemolytic anaemia and thrombocytopenia in this patient were not caused by bevacizumab.
Autoimmune or idiopathic thrombocytopenic purpura is a diagnosis of exclusion, made only after other causes of thrombocytopenia have been successfully ruled out. Although detection of platelet-associated antibodies is not a defining specific characteristic of ITP, the presence of these antibodies in the serum is consistent with an autoimmune mechanism of thrombocytopenia.1 18
While TTP and ITP rarely occur simultaneously, several studies have documented the concurrent or subsequent development of TTP and ITP in the same individual, suggesting a possible immunological component in TTP.1
Although both entities can manifest similarly, the presence of the enzyme ADAMTS13 can aid in the differentiation of TTP from ITP. A disintegrin-like and metalloprotease with trombospondin type-1 motif, ADAMTS13 is an enzyme that circulates in plasma and cleaves VWF in a shear-dependent manner.18
Deficient VWF cleavage leads to the accumulation of superactive forms of VWF and VWF-platelet aggregation, explaining why a severe deficiency of ADAMTS13 causes the disseminated microvascular thromboses characteristic of TTP.2 19
The accumulation of superactive VWF also helps explain why plasmapheresis is an established and efficacious treatment modality for cases of ADAMTS13 deficient TTP.2
However, severe ADAMTS13 deficiency occurs in only 43–72% of patients with idiopathic TTP.2 19
A normal level of ADAMTS13 does not exclude the diagnosis of TTP. Although the mechanism of response is not clear, plasma exchange remains the mainstay of therapy for patients with idiopathic TTP.2
Rituximab is a human/murine chimeric monocolonal antibody that specifically targets the transmembrane protein CD20 of B cells; when bound, it leads to a significant depletion of peripheral B cells. This agent has been used in the treatment of rheumatoid arthritis, systemic lupus erythematosus, ITP, multiple sclerosis, autoimmune haemolytic anaemia, TTP, graft versus host disease, clotting factor inhibitor, Graves’ disease and B-cell lymphomas.20–23
Successful in the treatment of haematological autoimmune disorders, rituximab is only mildly toxic in comparison to combination chemotherapy, which may yield more side effects. However combination chemotherapy (ie, cytoxan, rituximab and steroids) can be more effective when compared to monotherapy with steroids or rituximab.24 25
In cases of acquired haemophilia, the combined regimen has proven to result in greater odds of remission and lower odds of death when compared to both dual therapy and steroids alone.25
While it has been used as therapy for patients with refractory ITP and TTP, to our knowledge there have been no reported cases of concurrent TTP and ITP treated with rituximab. We present the first case of concurrent TTP and ITP in a patient with metastatic NET who was successfully treated with rituximab-CVP. Whether the combination of rituximab with CVP is more effective or not remains to be studied further and confirmed.
- Thrombotic thrombocytopenic purpura (TTP) and immune thrombocytopenic purpura (ITP) are common acquired bleeding disorders that more often occur independently.
- Cases of simultaneous TTP and ITP have been reported and have mostly occurred in HIV-positive patients.
- However, to our knowledge, we present the first case of concurrent TTP and ITP in a patient with metastatic neuroendocrine tumour while receiving bevacizumab therapy.
- Also, although the patient had been refractory to fresh frozen plasma exchange and infusion, she improved haematologically with rituximab-CVP therapy.