In Practice
Thrombotic Microangiopathy, Cancer, and Cancer Drugs

https://doi.org/10.1053/j.ajkd.2015.02.340Get rights and content

Thrombotic microangiopathy (TMA) is a complication that can develop directly from certain malignancies, but more often results from anticancer therapy. Currently, the incidence of cancer drug–induced TMA during the last few decades is >15%, primarily due to the introduction of anti–vascular endothelial growth factor (VEGF) agents. It is important for clinicians to understand the potential causes of cancer drug–induced TMA to facilitate successful diagnosis and treatment. In general, cancer drug–induced TMA can be classified into 2 types. Type I cancer drug–induced TMA includes chemotherapy regimens (ie, mitomycin C) that can potentially promote long-term kidney injury, as well as increased morbidity and mortality. Type II cancer drug–induced TMA includes anti-VEGF agents that are not typically associated with cumulative dose–dependent cell damage. In addition, functional recovery of kidney function often occurs after drug interruption, assuming a type I agent was not given prior to or during therapy. There are no randomized controlled trials to provide physician guidance in the management of TMA. However, previously accumulated information and research suggest that endothelial cell damage has an underlying immunologic basis. Based on this, the emerging trend includes the use of immunosuppressive agents if a refractory or relapsing clinical course that does not respond to plasmapheresis and steroids is observed.

Section snippets

Case Presentation

A 65-year-old man with a history of metastatic pancreatic cancer is referred from the oncology clinic for weakness and fatigue, epistaxis, new skin lesions over his shins, significantly elevated blood pressure (BP), and increased serum creatinine level. His medical history is significant for osteoarthritis of the knees, mild hypertension, and pancreatic malignancy initially treated with surgery and radiation. Recurrence developed with liver and peritoneal metastases. Medications include

Chemotherapy-induced TMA: Diagnosis, Pathophysiology, and Triggering Factors

Vascular injury as a result of chemotherapy is reported with increasing frequency.8 Although a variety of clinical disorders are described, the most devastating is TMA, a term originally proposed by Symmers.9 A sudden decrease in hemoglobin level, acute kidney injury (AKI), uncontrolled hypertension, and thrombocytopenia should alert clinicians of the possibility of TMA. When TMA is suspected, evidence supporting a microangiopathic process (schizocytes and elevated lactate dehydrogenase level)

Cancer-Related TMA

In oncology patients presenting with TMA, practitioners must differentiate cancer-related TMA from medication-induced TMA. In some patients, it can be challenging to identify whether TTP/HUS is drug induced or a result of the condition for which the drug was given. However, there are some features that distinguish the 2 conditions.6, 20, 21 Up to 90% of patients with cancer-related TMA have metastatic disease,22 whereas patients with chemotherapy-induced TMA have little or no detectable

Cancer Drug–induced TMA

Chemotherapy-induced TMA is more common than cancer-related TMA. Clinically suspected drug-induced TMA has been well documented in the last few decades, although in the past, it probably accounted for <15% of cases overall.1, 45, 46 Currently, incidence has increased and antitumor therapy has become a more common cause of TMA in cancer patients. Cancer drug–induced TMA diagnosis should be considered in the presence of cytopenia. In this circumstance, anemia and thrombocytopenia can by linked to

Management of Cancer Drug–induced TMA

Effective management of drug–induced TMA first requires accurate and rapid diagnosis. As discussed, not all the drugs manifest with hematologic findings of TMA, even in the presence of severe kidney TMA on kidney biopsy. Thus, patients receiving medications associated with TMA should be monitored for new or worsened hypertension, hematuria/proteinuria, and decreased kidney function. These findings may signal isolated kidney TMA in the absence of microangiopathic hemolytic anemia (including

Conclusion

TMA is a potentially severe kidney lesion with untoward outcomes that can complicate certain malignancies and a number of cancer therapies. It is important for clinicians to differentiate TMA due to the underlying cancer from a drug-induced cause of this endothelial injury. Drugs can be classified as type I versus type II based on the clinical and pathologic presentation, severity, and response to drug discontinuation. Newer agents leading to type II cancer drug–induced TMA and pegylated

Case Review

The patient’s kidney function continued to decline despite discontinuation of gemcitabine therapy. Hemodialysis was initiated for oliguric AKI. After 3 weeks of dialysis therapy, the patient and his family decided to discontinue dialysis treatment and he went home with hospice care. The patient died 5 days later.

Acknowledgements

Support: None.

Financial Disclosure: The authors declare that they have no relevant financial interests.

References (134)

  • C.D. Flombaum et al.

    Thrombotic microangiopathy as a complication of long-term therapy with gemcitabine

    Am J Kidney Dis

    (1999)
  • T. Khansur et al.

    Case report: cisplatin-induced hemolytic uremic syndrome

    Am J Med Sci

    (1991)
  • C. Porta et al.

    Cancer chemotherapy-related thrombotic thrombocytopenic purpura: biological evidence of increased nitric oxide production

    Mayo Clin Proc

    (1999)
  • J. Palmisano et al.

    Successful treatment of cisplatin–induced hemolytic uremic syndrome with therapeutic plasma exchange

    Am J Kidney Dis

    (1998)
  • M.W. Saif et al.

    Oxaliplatin-mediated autoimmune thrombocytopenia

    Clin Colorectal Cancer

    (2009)
  • F.M. Foss et al.

    Chimeric fusion protein toxin DAB486IL-2 in advanced mycosis fungoides and the Sezary syndrome: correlation of activity and interleukin-2 receptor expression in a phase II study

    Blood

    (1994)
  • C. Frangie et al.

    Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma

    Lancet Oncol

    (2007)
  • E. Kapiteijn et al.

    Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome

    Ann Oncol

    (2007)
  • R. Pisoni et al.

    Drug-induced thrombotic microangiopathy; incidence, prevention, and management

    Drug Saf

    (2001)
  • T.C. Nguyen et al.

    Bench-to-bedside review: thrombocytopenia-associated multiple organ failure: a newly appreciated syndrome in the critically ill

    Crit Care

    (2006)
  • H.C. Kwaan

    Miscellaneous secondary thrombotic microangiopathy

    Semin Hematol

    (1987)
  • W.T. Hanna et al.

    Renal disease after mitomycin C therapy

    Cancer

    (1981)
  • J.J. Byrnes et al.

    Thrombotic thrombocytopenic purpura subsequent to acute myelogenous leukemia chemotherapy

    Am J Hematol

    (1986)
  • J.B. Lesesne et al.

    Cancer-associated hemolytic uremic syndrome: analysis of 85 cases from a national registry

    J Clin Oncol

    (1989)
  • H. Izzedine et al.

    Anti-VEGF associated kidney diseases: an 8-year monocentric observational study

    Medicine (Baltimore)

    (2014)
  • D.C. Doll et al.

    Vascular toxicity associated with antineoplastic agents

    J Clin Oncol

    (1986)
  • W.C. Symmers

    Thrombotic microangiopathic haemolytic anemia

    Br Med J

    (1952)
  • Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 Published May 28, 2009 (v4.03: June 14, 2010). US...
  • G.G. Levy et al.

    Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura

    Nature

    (2001)
  • A. Richards et al.

    Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome

    Proc Natl Acad Sci U S A

    (2003)
  • V. Fremeaux-Bacchi et al.

    Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome

    J Med Genet

    (2004)
  • J. Monteagudo et al.

    Investigation of plasma von Willebrand factor and circulating platelet aggregating activity in mitomycin C-related hemolytic-uremic syndrome

    Am J Hematol

    (1990)
  • D. Charba et al.

    Abnormalities of von Willebrand factor multimers in drug-associated thrombotic microangiopathies

    Am J Hematol

    (1993)
  • V. Eremina et al.

    VEGF inhibition and renal thrombotic microangiopathy

    N Engl J Med

    (2008)
  • J.E. Cantrell et al.

    Carcinoma-associated hemolytic–uremic syndrome. A complication of mitomycin C chemotherapy

    J Clin Oncol

    (1985)
  • R. Sheldon et al.

    A syndrome of microangiopathic hemolytic anemia, renal impairment, and pulmonary edema in chemotherapy-treated patients with adenocarcinoma

    Cancer

    (1986)
  • K. Lechner et al.

    Cancer-related microangiopathic hemolytic anemia

    Medicine (Baltimore)

    (2012)
  • A.J. Murgo

    Thrombotic microangiopathy in the cancer patient including those induced by chemotherapeutic agents

    Semin Hematol

    (1987)
  • J.C. Chang et al.

    Thrombotic thrombocytopenic purpura associated with bone marrow metastasis and secondary myelofibrosis in cancer

    Oncologist

    (2003)
  • K.K. Francis et al.

    Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: a report of 10 patients and a systematic review of published cases

    Oncologist

    (2007)
  • T.L. Werner et al.

    Management of cancer-associated thrombotic microangiopathy: what is the right approach?

    Am J Hematol

    (2007)
  • J.N. George

    Systemic malignancies as a cause of unexpected microangiopathic hemolytic anemia and thrombocytopenia

    Oncology (Williston Park)

    (2011)
  • C. Robier et al.

    Thrombotic microangiopathy and disseminated intravascular coagulation associated with carcinocythemia in a patient with breast cancer

    J Clin Oncol

    (2011)
  • R.W. Colman et al.

    Disseminated intravascular coagulation due to malignancy

    Semin Oncol

    (1990)
  • Y. Chang et al.

    Breast cancer with an unusual leukemia-like presentation: case report and literature review

    Med Oncol

    (2008)
  • M.C. Brain et al.

    Microangiopathic haemolytic anaemia and mucin-forming adenocarcinoma

    Br J Haematol

    (1970)
  • L. Oleksowicz et al.

    Deficient activity of von Willebrand’s factor-cleaving protease in patients with disseminated malignancies

    Cancer Res

    (1999)
  • P.M. Mannucci et al.

    Patients with localized and disseminated tumors have reduced but measurable levels of ADAMTS-13 (von Willebrand factor cleaving protease)

    Haematologica

    (2003)
  • S. Fontana et al.

    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)
  • K. Siami et al.

    Thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation: an autopsy study

    Transplantation

    (2008)
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