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Postoperative thrombotic microangiopathy following radical cystectomy for bladder cancer.

SUMMARY

This report describes the perioperative management of disseminated intravascular coagulation occurring abruptly during a planned cystectomy for non-metastatic bladder papillary carcinoma. Peroperatively, profuse bleeding and an acute decrease in blood pressure were effectively treated by blood transfusions and fresh frozen plasma. Haematological tests indicated the presence of disseminated intravascular coagulation. On the following three days, acute renal failure, peripheral disseminated intravascular coagulation-related thrombocytopenia and haemolytic anemia with schistocytes were suggestive of thrombotic microangiopathy. Treatment by plasma exchange along with haemodialysis was commenced. An aetiological work-up remained negative. After 21 days of treatment, haemodialysis and plasma exchange were stopped. Urological outcome was favourable. The one year follow-up did not show any residual renal insufficiency and laboratory parameters returned to normal. In the absence of evidence in favour of an infectious, drug-related or immunological aetiology, we postulated that this thrombotic microangiopathy was caused by disseminated intravascular coagulation and that the tumour manipulation during the surgical procedure was the triggering factor.

Key Words: disseminated intravascular coagulation, acute renal failure, cystectomy, bladder cancer, plasma exchange

Thrombotic microangiopathy is characterized by the association of haemolytic anemia, thrombocytopenia and acute renal insufficiency secondary to the obstruction of the renal microcirculation by platelet thrombi(1,2). This is a rare disorder in the postoperative period. There are numerous aetiologies including thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS) of infectious origin, notably within the framework of diarrhoea involving Escherichia coli 0157:H7(1,2). The majority of HUS cases in adults are sepsis-related. Cases of thrombotic microangiopathy have been reported after heart or vascular surgery (3) and after colectomy for colonic carcinoma (4) and generally in the cancer patient (5).

We report a case of thrombotic microangiopathy that occurred in a 75-year-old woman after radical cystectomy for bladder cancer. The initial clinical feature was peroperative bleeding in relation to acute disseminated intravascular coagulation.

CASE HISTORY

A 75-year-old woman was hospitalized for severe haematuria. The patient's medical history was also noteworthy for arterial hypertension that was well stabilized using an angiotensin-converting enzyme inhibitor. She was not taking any other drugs. Cystoscopy demonstrated two polyps on the anterior wall of the bladder. Histological findings diagnosed stage pT2N0M0 papillary carcinoma (muscular involvement). Two months later, the patient was hospitalized for radical cystectomy and ileal conduit urinary diversion operation. The preoperative clinical and laboratory assessments were unremarkable. The patient had no fever. Her blood pressure values were normal and she indicated that she had not experienced any particular symptoms apart from the haematuria. The preoperative renal function was normal (plasma creatinine, 78 [micro]mol/l). Complete blood count was also normal. Haemoglobin concentration was 13.8 g/dl, platelet count 157,100/[mm.sup.3] and there was no coagulation disorder. Blood electrolytes were within the normal range.

The patient was anaesthetized with midazolam, sufentanil, sevoflurane and cisatracurium. Three grams of ticarcillin-clavulanic acid were administered as prophylaxis for the operation. The variations in systolic arterial pressure during mechanical ventilation ([DELTA] down) were used to detect hypovolaemia and to guide fluid replacement. Two hours after the induction of anaesthesia, cystectomy was performed; blood loss was approximately 400 ml and 500 ml of hydroxy-ethylstarch solution was administered. One hour later, during the manipulations of the ileal conduit but before closure, profuse bleeding occurred suggesting acute disseminated intravascular coagulation (DIC). Her systolic blood pressure dropped to 80 mmHg. This necessitated the transfusion of six units of packed red cells (1,800 ml), two units of platelets and three units of fresh frozen plasma (600 ml) to maintain normal [DELTA] down. The patient's temperature remained normal. During the acute phase, her platelet count fell to 63,100/[mm.sup.3], kaolin cephalin clotting time (KCCT) was 88 seconds compared to a pooled control KCCT value of 30 seconds, and the international normalized ratio (INR) was 3. Fibrinogen concentration decreased from 3.2 to 0.55 g/1 (1.65 [micro]mol/1). Fibrinogen degradation products (FDP) were 80 [micro]g/ml (normal range <5 [micro]g/ml). Haemodynamic stabilization necessitated two units of packed red cells (500 ml) and two more units of fresh frozen plasma (450 ml); two units of platelets were also administered. The use of dopamine increased urine output in the immediate postoperative period.

On postoperative day one, blood pressure was 131/85 mmHg, heart rate 82 beats.[min.sup.-1]. Haemoglobin was 100 g/1 and platelet count 80,000

/[mm.sup.3]. There was a marked reduction in renal function with plasma creatinine level at 200 [micro]mol/l. On postoperative day two, plasma creatinine level had risen to 449 [micro]mol/l, urea concentration was 18 mmol/l and potassium rose to 6.9 mmol/1. Urine output fell below 300 ml/24 hours and the patient was transfered to the nephrology unit for emergency dialysis. On postoperative day three, in addition to deteriorating renal function, blood analysis showed anaemia (haemoglobin 80 g/1) and intravascular haemolysis (serum haptoglobin lower than 0.065 g/l and schistocytes elevated to 4%). The level of serum lactate dehydrogenase was 1,390 IU/l. Thrombocytopenia persisted (44,000/[mm.sup.3]). Coombs' test was negative. The initial abnormalities of coagulation had reverted to normal (KCCT at 35 seconds for a control KCCT at 33 seconds and INR of 1.2). Fibrinogen concentration returned to normal at 3.5 g/1, but fibrinogen degradation products remained at the upper limit of normality (40-50 [micro]g/ml). The white cell count was elevated to 11,000/[mm.sup.3] including 86% neutrophils. A bone marrow aspirate was dense, with mild hyperplasia of the erythroid lineage and presence of megakaryocytes. The association of acute renal insufficiency, thrombocytopenia due to peripheral destruction of platelets, and haemolytic anaemia with the presence of schistocytes was suggestive of thrombotic microangiopathy and treatment with plasma exchange was instituted along with haemodialysis.

The laboratory work-up included investigations to look for an infectious aetiology. In particular we looked for the presence of Escherichia coli 0157:117 in stool, urine and blood specimens. These examinations were negative. No other pathogenic agent was found. During the days following the initiation of plasma exchange, the patient's condition improved quickly with resolution of thrombocytopenia, normalization of haptoglobin and disappearance of schistocytes. On the fifteenth postoperative day the patient developed Bacteroides fragilis septicaemia due to a urinary tract infection. The septicaemia resolved with specific antibiotic therapy.

After 15 days of treatment, the haemodialysis sessions were discontinued. Plasma exchange was stopped after three weeks. There was no residual renal insufficiency or laboratory evidence of haemolysis after one year of follow-up (plasma creatinine 70 [micro]mol/l). The urologic outcome was also favourable.

DISCUSSION

This patient developed profuse intraoperative bleeding due to acute DIC while undergoing radical cystectomy for bladder cancer. This was associated with features of thrombotic microangiopathy (TMA). The diagnosis of disseminated intravascular coagulation was confirmed by the combination of low platelet count, a decrease in fibrinogen and an increase of fibrinogen degradation products (6,7). The treatment of disseminated intravascular coagulation is based on the control of hypovolaemia and haemostasis by the administration of fresh frozen plasma, platelet concentrates and packed red cells (6,8,9).

The diagnosis of thrombotic microangiopathy is based on a pentad of signs and symptoms: thrombocytopenia, microangiopathic haemolytic anaemia, neurologic abnormalities, renal failure and fever. In actual practice however, the triad of thrombocytopenia, schistocytosis and elevated lactate dehydrogenase levels is often sufficient to suggest the disorder (10,11). Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are now considered variable expressions of the same disease process: when renal impairment is prominent, the disease is called HUS, whereas it is termed TTP if neurological disturbances are the predominant features (12). HUS occurs in children (haemorrhagic diarrhoea) after infection by shiga-toxin-producing microorganisms such as Escherichia coli 0157 :H7 or Shigella dysenteriae serotype 1. The mortality of E. coli-associated HUS may be high (90%) in the elderly (11,12). Various other infectious agents can induce HUS when septicaemia is involved. These include Staphylococcus aureus, Streptococcus pneumoniae, Neisseria meningitidis, Chlamydia psittachi and Mycoplasma pneumoniae. Anaesthetic agents are not known to induce HUS. Moreover, when HUS is induced by the administration of a drug, it generally appears several weeks or even several months after the beginning of treatment (1,2). HUS due directly to a neoplastic disorder is rare (13,14). An Aden carcinoma is involved in the majority of such cases, but in most cases it is actually the antimitotic agents that are at fault (mitomycin C, 5-fluorouracil, platinum-based drugs and bleomycin). Stomach cancer is found in half of the cases regardless of treatment. Cancer of the lungs, prostate, or pancreas as well as acute promyelocytic leukaemia have also been reported to cause HUS. In fact, the majority of cancers in advanced metastatic stages can be complicated by HUS of poor prognosis.

Clinical and laboratory features of TMA are shared by many diseases other than TTP/HUS (15) and the broad definition of TMA encompasses these diseases (Table 1). In clinical practice, TTP and HUS are clinically and pathologically indistinguishable in adults except for the severity of renal failure. Histological confirmation is not sought to avoid risks of renal biopsy. The ADAMTS13 activity (a von Willebrand factor cleaving protease) seems helpful for precise diagnosis management (16) and to predict response to plasma exchange (17). Moreover, the diagnosis, evaluation and initial management are the same. Plasma exchanges improve survival rate from 10 to 92%, creating urgency for the initiation of treatment (18,19).

Amongst the pathophysiological mechanisms leading to the occurrence of HUS, a pivotal element is the dysfunction of endothelial cells that leads to activation of platelets causing them to adhere to the damaged regions (20). This dysfunction is manifested by a reduction in the synthesis of prostacyclin and nitric oxide and an increase in the synthesis of endothelin. The von Willebrand factor normally stored in the Weibel-Palade bodies in endothelial cells is found in the form of abnormal high-molecular-weight multimers in the plasma. They disappear at remission of HUS. Endothelial cells have anticoagulation properties that act by preventing the aggregation of platelets and by stimulating fibrinolysis. Endothelial cells are the principal source of tissue plasminogen activator (t-PA) in the bloodstream and also secrete the physiological inhibitor of t-PA (PAI-1) (21). High plasma concentrations of the latter have been found in patients with HUS suggesting that it might play a role in the inhibition of fibrinolysis observed in this disease. These increases in PAI-1 and platelet aggregation appear to be the central haematologic anomalies of HUS (20). Experimental studies have shown that neoplastic urothelial cells can inhibit urokinase (t-PA) (22).

In conclusion, this case report highlights two important problems. 1) Excessive intraoperative bleeding in relation to acute disseminated intravascular coagulation is rare. Anaesthetic management includes the maintenance of adequate tissue perfusion, correction of hypothermia and anaemia. Haemostatic blood products are used according to the results of coagulation testing to correct microvascular bleeding. 2) Postoperative thrombotic microangiography, when diagnosed, needs rapid treatment by plasma exchange in order to decrease mortality. Disseminated intravascular coagulation is a possible factor in the pathogenesis of thrombotic microangiopathy (15). We postulate that the tumour manipulation has initiated the disease.

REFERENCES

(1.) Neild GH. Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura: pathophysiology and treatment. Kidney Int Suppl 1998; 64:S45-49.

(2.) Remuzzi G, Ruggenenti P The hemolytic uremic syndrome. Kidney Int Suppl 1998; 66:S54-57.

(3.) Chang J, Shipstone A, Llenado-Lee M. Postoperative thrombotic thrombocytopenic purpura following cardiovascular surgeries. Am J Hematol 1996; 53:11-17.

(4.) Robson M, Abbs I. Thrombotic thrombocytopenic purpura following hemicolectomy for colonic carcinoma. Nephrol Dial Transplant 1997; 12:198-199.

(5.) Gordon LI, Kwaan HC. Thrombotic microangiopathy manifesting a thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the cancer patient. Semin Thromb Hemost 1999; 25:217-221.

(6.) Rocha E, Paramo JA, Montes R, Panizo C. Acute generalized, widespread bleeding. Diagnosis and management. Haematologica 1998; 83:1024-1037.

(7.) Salloh S, Wang JY, Nguyin NP, Hanrahan LR, Sigounes G. Disseminated intravascular coagulation in solid tumors: clinical and pathologic study. Thromb Haemost 2001; 86:828-833.

(8.) Levi M, DeJonge E, Van der Poll T. New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology. Ann Med 2004; 36:4149.

(9.) Koh MBC, Hunt BJ. The management of perioperative bleeding. Blood Reviews 2003; 17:179-185.

(10.) Moake JL. Haemolytic-uraemic syndrome: basic science. Lancet 1994; 343:393-397.

(11.) Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347:589-600.

(12.) Tsai H-M. Advances in the pathogenesis, diagnosis and treatment of thrombotic thrombocytopenic purpura. Am J Soc Nephrol 2003; 14:1072-1081.

(13.) Antman KH, Sharin AT, Mayer RJ, Hargreaves HK, Canellos GP Microangiopathy hemolytic anemia and cancer: a review. Medecine (Baltimore) 1979; 58:377-384.

(14.) Muller NJ, Pestalozzi BC. Hemolytic uremic syndrome in prostatic carcinoma. Oncology 1998; 55:174-176.

(15.) Elliott MA, Nichols WL. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Mayo Clin Proc 2001; 76:1154-1162.

(16.) Lammle B, Kremer Hovinga JA, Albiero L. Thrombotic thrombocytopenic purpura. J Thromb Haemost 2005; 3:1663-1675.

(17.) Mori Y, Nada H, Gabazzo EC et al. Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity. Transfusion 2002; 42:572-580.

(18.) George JN. How I treat patient with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood 2000;96:1223-1229.

(19.) Stegmayr BG, Banga R, Berggren L, Norda P, Rydwell A, Vikersfors T. Plasma exchange as rescue therapy in multiple organ failure including acute renal failure. Crit Care Med 2003; 31:1875-1877.

(20.) Ballermann B. Endothelial cell activation. Kidney Int 1998; 53:1810-1826.

(21.) Bergstein JM, Riley M, Bang NU. Role of plasminogen-activator inhibitor type 1 in the pathogenesis and outcome of the hemolytic uremic syndrome. N Engl J Med 1992; 327:755-759.

(22.) Naito S, Kanamori T, Hisano S, Tanaka K, Momose S, Kamata N. Human renal cell carcinoma: establishment and characterization of two new cell lines. J Urol 1982; 128:1117-1121.

P. TAUZIN-FIN *, M. SESAY [dagger], A. RYMAN [dagger], P. BALLANGER [double dagger], C. COMBE [section]

Departement d'Anesthesie-Reanimation III and Service d'Urologie, Hopital Pellegrin-Tondu and Service Hematologie et Coagulation and Departement de Nephrologie, Hopital Pellegrin, Bordeaux France

* M.D., Departement d'Anesthesie-Reanimation III, Hopital Pellegrin-Tondu.

[dagger] M.D., Departement d'Anesthesie-Reanimation III, Hopital Pellegrin-Tondu.

[double dagger] M.D., Service d'Urologie, Hopital Pellegrin-Tondu.

[section] M.D., Departement de Nephrologie, Hopital Pellegrin.

Address for reprints: Dr Patrick Tauzin-Fin, DAR III, Hopital Pellegrin-Tondu, 5 place Amelie Raba-Leon, 33076 Bordeaux Cedex, France.

Accepted for publication on June 9, 2006.
TABLE 1

Differential diagnosis of thrombotic microangopathy

Haemolytic uraemic syndrome (E. coli-associated, familial,
idiopathic)

Thrombotic thrombocytopenic purpura (familial, recurrent,
idiopathic)

Malignant hypertension

Medication (cyclosporine A, tacrolimus, mitomycin,
ticlopidine, clopidogrel, etc)

Post organ/haematopoietic cell transplantation

Disseminated intravascular coagulation

Sepsis

Malignancy

Pre-eclampsia /eclampsia, HELLP syndrome

Systemic vasculitis (SLE, scleroderma, cryoglobulinaemia,
etc)

E. coli=Escherichia coli; HELLP=haemolysis elevated liver
enzymes and low platelets; SLE=systemic lupus erythematosus.
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Author:Tauzin-Fin, P.; Sesay, M.; Ryman, A.; Ballanger, P.; Combe, C.
Publication:Anaesthesia and Intensive Care
Date:Oct 1, 2006
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