Desmopressin may be hazardous in thrombotic microangiopathy

Jon Stratton, Paul Warwicker, Sylvia Watkins and Ken Farrington

Lister Hospital, Stevenage, UK



   Case
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 Case
 Discussion
 References
 
A 59-year-old woman presented in 1991 with carcinoma of the right breast. She underwent a right mastectomy and started tamoxifen 20 mg daily. In 1997 she represented with recurrent carcinoma. A left mastectomy and axillary clearance was performed. Chemotherapy was started comprising mitozantrone, methotrexate and mitomycin-C. Anaemia developed at 6 months, requiring repeated blood transfusions. She completed 9 months of treatment, then tamoxifen was increased to 40 mg daily. A relapse 9 months later required a further course of chemotherapy. At this time her serum creatinine had risen from normal to 206 µmol/l. 5-Fluorouracil, epirubicin and cyclophosphamide were prescribed. Her renal function continued to deteriorate reaching 269 µmol/l 5 months into this treatment (Figure 1Go). At this stage, the patient's platelet count fell to a nadir of 99x109/l. Bone marrow examination was normal. The chemotherapy was stopped.



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Fig. 1. Platelet and creatinine changes over time and in response to drug therapy.

 
The patient developed atypical chest pain and was admitted with a possible sub-endocardial myocardial infarction. ECG was normal and a cardiac exercise stress test did not induce ischaemic changes. The serum creatinine deteriorated to 460 µmol/l (creatinine clearance 10 ml/min) and she was referred for renal investigation. Urine dipstick showed protein +++, blood ++. Renal ultrasound was normal. A full autoimmune screen was normal. The serum C3 level was low at 0.65 (0.85–2) mg/l. Serum C4 was normal.

A renal biopsy was arranged. Screening coagulation tests were normal but the patient had a prolonged bleeding time. She therefore received Desmopressin (DDAVP) (0.4 µg/kg) according to local protocol to correct this [1]. The procedure was technically uncomplicated but within 30 min the patient suffered an acute inferior myocardial infarction complicated by nodal bradycardia. She made an uneventful clinical recovery. The renal biopsy showed features consistent with haemolytic–uraemic syndrome (HUS), including marked vessel narrowing secondary to endothelial-cell swelling. Tamoxifen and quinine were withdrawn and angiotensin-converting enzyme inhibitors introduced. Her renal function improved a little. Her low complement level returned to normal and the platelet count increased.



   Discussion
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 Case
 Discussion
 References
 
Precipitants of (D-) HUS include cancer, chemotherapeutic agents, and other drugs. All may have played a role in this case. Involvement of mitomycin C is well recognized and concurrent use of tamoxifen may be a potentiating factor [2]. Tamoxifen may well have had a role here since the decline in renal function only occurred after the dose was increased. Furthermore, renal function improved slightly after its withdrawal. Less likely is a role for quinine sulphate that can rarely cause HUS associated with antibody formation against the platelet glycoprotein complex [3].

There seems little doubt that use of DDAVP induced a myocardial infarction in this case. The association has been described in three cases, reported in cases of suspected underlying heart disease [4]. DDAVP is not recommended for use in these patients [5]. The extent of underlying ischaemic heart disease is difficult to determine in this case, but it is unlikely that her cardiac disease was severe.

In a thrombotic microangiopathy, is DDAVP more liable to induce a thrombotic complication? Endothelial activation is a constant feature of HUS. Naturally occurring endothelial anti-coagulant mechanisms are reversed and lead to a phenotype change to a pro-coagulant state. Endothelial expression of heparin, tissue plasminogen activator (t-PA), and thrombomodulin is altered, and the local endothelium secretion of inhibitors to platelet aggregation compounds (nitric oxide, adenosine, and prostacyclin) is reduced [6]. Plasma VIII: von Willebrand factor (vWF) antigen levels are elevated in HUS patients from two- to eightfold [7]. The effect of DDAVP is to raise t-PA and vWF levels still further. It is possible therefore that the endothelium in a patient with HUS is more susceptible to the effects of DDAVP, increasing the likelihood of spontaneous thrombosis.



   Notes
 
Correspondence and offprint requests to: Jon Stratton, Research Renal Registrar, Lister Hospital, Stevenage SG1 4AB, UK. Back



   References
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 Case
 Discussion
 References
 

  1. Donovan KL, Moore RH, Mulkerrin E, Mumar-Bashi W, Williams JD. An audit of appropriate tests in renal biopsy coagulation screens. Am J Kidney Dis1992; 19: 335–338[ISI][Medline]
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  3. Glynne P, Salama A, Chaudhry A, Swirsky D, Lightstone L. Quinine induced immune thrombocytopenia purpura followed by hemolytic uremic syndrome. Am J Kidney Dis1999; 33: 133–137[ISI][Medline]
  4. van Danzig JM, Düren DR, Tencate JW. Desmopressin and myocardial infarction. Lancet1989; 8639: 664–665
  5. Lowe GD. Desmopressin and myocardial infarction. Lancet1989; 8643: 895–896
  6. Warwicker P, Donne RL, Goodship THJ. Haemolytic Uraemic Syndrome. Royal College of Physicians, London, 1999; 301–306
  7. Moake JL, Byrnes JJ, Troll JH, et al. Abnormal VIII : von Willebrand factor patterns in the plasma of patients with the hemolytic uremic syndrome. Blood1984; 63: 592–598
Received for publication: 30. 5.00
Revision received 25. 8.00.



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