Thrombotic Microangiopathy Induced by Hyperthermal Intraperitoneal Chemotherapy with Mitomycin C

doi:10.4236/ss.2011.24037

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Surgical Science, 2011, 2, 173-174

doi:10.4236/ss.2011.24037 Published Online June 2011 (http://www.SciRP.org/journal/ss)

Thrombotic Microangiopathy Induced by Hyperthermal

Intraperitoneal Chemotherapy with Mitomycin C

Mahir Köksal1, Robert J. van Ginkel2, Jan G. Zijlstra1

1Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

2Department o f S urg e ry, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

E-mail: [email protected]

Received January 26, 2011; revised February 21, 2011; accepted Febr u ary 28, 2011

Abstract

A patient with pseudomyxoma peritonei underwent Hyperthermal Intraperitoneal Chemotherapy (HIPEC)

with Mitomycin C after which she developed thrombotic microangiopathy. This syndrome mimicked possi-

ble surgical complications. Treatment with plasma exchange resolved the syndrome and the patient recov-

ered completely. This is the first description of thrombotic microangiopathy early after a single dose intrap-

eritoneal Mitomycin C.

Keywords: HIPEC, Toxicity, HUS-TTP

1. Introduction

Hyperthermal Intraperitoneal Chemotherapy (HIPEC) is

an established therapy in peritoneal malignancies and

advocated as standard therapy in pseudomyxoma peri-

tonei. [1,2] With careful selection and optimal periopera-

tive care morbidity and mortality are comparable to other

major gastrointestinal surgery. [3] Mortality is mainly

due to sepsis and multi-orgaan failure as a result of sur-

gical complications. Systemic toxicity of HIPEC also

occurs in about 20% and is mainly haematological or

renal toxicity. [3] We describe a potentially lethal but

most times curable complication of HIPEC that can eas-

ily be mistaken for a surgical complication or haemato-

logical toxicity.

A 65-year old woman was admitted to the ICU for

postoperative care after abdominal surgery with Hyper-

thermal Intraperitoneal Chemotherapy (HIPEC). She had

a pseudomyxoma peritonei with a primary tumour in the

appendix. Peritonectomy, splenectomy, cholecystectomy,

hemicolectomy (cecum and colon ascendens), appen-

dectomy, hysterectomy, bilateral salpingectomy, resec-

tion of both the omentum majus and omentum minus,

diathermia of the liver capsula, and stripping of both

hemidiaphragmata and the pelvic peritoneum was per-

formed. She received HIPEC with a total Mitomycine-C

(MMC) dose of 63 mg.

On admission to the ICU she was haemodynamically

and respiratory stable. She remained somnolent and feb-

rile but could be extubated the same day. Four days

postoperatively she developed oliguric renal failure with

sUrea 20.4 mmol/l (normal range 2.5 - 7.5 mmol/l) and

sCreatinin 213 µmol/l (normal range 0 - 90 µmol/l) lev-

els). Lactate Dehydrogenase (LDH) increased to 1653 U/l

(normal range 0 - 250 U/l) and a marked thrombocyto-

penia developed (39 × 109 E/l; normal range 150 - 350 ×

109 E/l). Schizocytes were highly positive and hap-

toglobulin decreased (<0, 2 g/l; normal range 0.3 - 2.0 g/l).

Coagulation tests were normal and Coombs test was

negative. Blood cultures were negative. ADAMTS13

activity was 45% (normal range 30% - 200%). The di-

agnosis atypical haemolytic uremic syndrome, a disorder

from the wide spectrum of the thrombotic microan-

giopathy (TMA) syndrome, was made. Immediate treat-

ment with twice daily plasma exchange with 40 ml Fresh

Frozen Plasma (FFP) per kilogram body weight was

started. Sixteen days after admission to our department,

she could be transferred to the ward in an alert, stable

condition with normal thrombocytes and regained renal

function. She was readmitted once to the ICU because of

sick sinus syndrome requiring a pacemaker. There were

no signs of TMA.

TMA is a disorder characterized by haemolytic anae-

mia, thrombocytopenia, purpura, renal failure and neu-

rological impairment. [4] It is life-threatening; left un-

treated the mortality rate is up to 95%. The central

pathophysiological feature is the formation of hyaline

thrombi resulting in hemolysis and micro infarction in

174 M. KÖKSAL ET AL.

several organs. The underlying mechanism is a dysbal-

ance between von Willebrand factor (vWf) and von

Willebrand processing factor. [5] A local increase in vWf

is seen in classic haemolytic uremic syndrome (HUS), or

hamburger disease, where thrombi are mainly formed in

the kidney, resulting in renal failure and minimal sys-

temic symptoms. In familiar thrombotic thrombocyto-

penic purpura (TTP) the processing factor ADAMTS13

is decreased and systemic symptoms prevail. Between

these two ends of the spectrum there is a range of clinical

presentations. Cause, genetic make-up of the patient and

many other factors determine the presenting symptoms.

Causes are mainly infectious diseases and medication

related. The therapy is based on supply of vWf process-

ing factor by FFP. To supply enough FFP plasma ex-

change is required. In this patient MMC is the most

probable cause. [6] Our patient presented with haemo-

lytic anaemia, thrombocytopenia, renal failure and som-

nolence. The later developing sick sinus can also be due

to micro infarction of the heart. After excluding sepsis,

immune mediated hemolysis, and disseminated in-

travascular coagulation the diagnosis atypical HUS was

made. [6] MMC induced TMA has been described after

intravenous dosing. [4 ,7-9] It has been sugg ested that the

chance of developing TMA is related to the cumulative

dose. Below 36mg/m2 MMC no TMA is seen. [10] The

mechanism is not clear although direct endothelial dam-

age has been suggested. [4,7,11] MMC induced TMA

has never been described after a single HIPEC procedure.

We have no serum levels of MMC but considerable ab-

sorption is possible because of the large wound surface

created by the extensive surgery. However, systemic

toxicity was limited because no toxic leucopenia oc-

curred. MMC induced TMA is considered a late compli-

cation because toxicity has mainly been described after

repeated doses reaching the cumulative dose after weeks

or months. Our patient received more than the suggested

maximal dose in a single gift presuming that limited ab-

sorption from the abdomen would occur. Our patient

shows several other unique features. TMA occurred im-

mediately after a single intraperitoneal dose and re-

sponded well to th erapy. [6]

Patients treated with HIPEC are prone to surgical

complications and to systemic toxicity of the chemo-

therapy. [3] Both have many symptoms in common with

TMA syndrome. Subscribing these symptoms to toxicity

or complications is imminen t and a potentially lethal but,

when recognized, treatable disease can easily be missed.

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