campylobacter jejuni and throtnbotic throtnbocytopenic...

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Campylobacter jejuni and throtnbotic throtnbocytopenic

purpura

ROMAN JAESCHKE, MD, EJAN IRvlNE, MD, JANE MOORE, ART, jOIIN KELTON, MD

ABSTRACT: Gastrointestinal bacterial infecttons could be associated with rnul t isystem complication due to the th rombotic phenomena. This paper reports the association of Campylobacter jejuni infection and thrombotic thrombocytopenic purpurn, and describes a new test for diagnosing thrombocytopenic purpura. CanJ Gastroente rol 1990;4(4):154-156

Key W ords: Campylobacter jejuni, Hemolytic uremic syndrome, Thrombotic thrombocycopenic purpura

Campylobacter jejuni et le purpura thrombotique thrombocytopeniq ue

RESUME: Les infections gascro-imescinales d'origine bacte rienne pourraienr etre associees a unc complication agissant sur Jc multiples organes et Jue aux phenomenes thrombotiques. Cet art icle rapporte !'association existant enrre l'infecuon a Campylobacter jejuni et le purpura rhrombotique thrombocytopenique (PTT), er dccrit un test nouveau permettant de diagnostiquer le PTT.

Departments of Med1cme, Clmical E/>idemmlogy and Bwsw11srics, and Pailwlo[;Y. McMrutcr U111versi1y, Hamilwn, Onwno; and De/>arrmcnc of Medic me, St Jme/>h', Hu,fmal, Hamilton, Oniarw

Co1Tcs/mndencc and rc/irnw, Dr H Jaeschke, Si)meph\ I lo:s/nwl, roml>onnc /J~. Hamilton, Onwrw L8N 4A6 Teleplume (41 6) 525 9140e,12160

Hecci11ed fm /mbl,cwion Fehruary 6. I 990 Acee/lied March 2 l, / 990

THROMBCX ')TOPENIA AND 'iC. ·111sro.

cytic hemoly1 ic anemia characterize a group of d1 ,order, that arc uncommon but 11nportant because of their porent1ally serious outcome,. Two of these disorders, th romhotic rhrombocytopenic purpura and hemolytic uremic syndrome, share a numher of simila rities while exh1b1ting some uni

que features ( I) . Hemolytic urcm1e syndrome 1s charactcnzed by thrombocytopenia, schistocytic hemolytic anemia, and renal fai lure. Recent studies have shown that many episode, of hemolytic uremic syndrome follow infection, often with a verotoxinproducing Escherichia coli (2). Other 111·

fectious gastrointestinal organi m~. including campylobacrer, shigella and salmonella, can cause hemolytic uremic syndrome as well. Thrombonc rh rombocytopenic purpura, like hcmolync uremic syndrome, is characren:eJ hy th rombocytopenra and sch1s·

154 CAN J vASTRl)ENTLROL Vl )l 4 No 4 MA Y/jUNE 1990

p ...

* C

Figure 1) The />artem of von Willehrand f acwr obwmed with the use of crossed immunoekcrrophoresis. In C()mparison with conrrol (C), the 1,acient', serum ( P) demonstrates lack of the large m11lumers (*) and an increased row/ level of che factor

tocytic hemolytic anemia, but neurological lesions arc more frequent chan ren<11 impai rmen t. Recent studies in thrombotic thrombocycopenic purpura have focused upon the characterization of a platelet aggregating factor in the serum of these patierm (3-10). This facmr could be of pathogenetic importance if it proved to induce in vivo platelet aggreg,ition.

In chis report the authors describe the investigation of a pat ient who had a thrombotic thrombocytopenic purpura preceded by an infection which has more typically been associated with hemolytic uremic syndrome. The patient had a plate let aggregating factor present in her serum that h,is been described to occur in patien ts with spontaneously occurring thrombotic rhrombocytopen ic purpura.

CASE PRESENTATION A 73-year-old woman had a three

day history of abdo minal discomfort with cramps, vomiting and diarrhea. She was admitted to hospital and stool cultures grew Campylobacter jejuni. Treatment with erythromycin produced a partia l resolution of her

symptoms. However, over the next several days she had a progressive fall in both platelet count ( to 18 x 109/L) and hemoglobin level ( to l 05 g/L). Extensive red cell fragmenration was oh~erved on a peripheral blood fi lm. Coagulation tests were normal and showed no evidence of disseminated intra vascu l,ir coagulation. Blood cu ltures were negative. Renal function was normal :rnd a presumptive diagnosis of th rombotic thwmhocytopenic purpura was made. The patient was initia lly treated with plasma mfusion ( 100 mL/h), hut because of a fai lure to

respond she was u eated wi th plasmapheresis. A total of seven apheresis procedures of two m three plasma exchanges each, usmg stored plasma, were performed. The patient did not respond and thrombocytopenia persist ed.

On J ay 13, there was a sudden and dramatic deterioration in neurological status with coma and a right hemiparcsis. Computed tomographic investigation of the brain was reported as normal. The patient a lso developed progressive oliguric renal fail ure anJ was treated with peritoneal dialysis.

CAN J GASTROENTEROL VOL 4 No 4 MA Y/)UNE 1990

Campylobacter jejuni and TTP

The patient died on Jay 21 having been unresponsive to p lasma infusion, plasmapheresis, vincristinc, corticosteroids, acetylsa licylic acid an<l Jipyridamole. Post mo rtem examination demonstrated r lmeler th rombi in the sm::ill vessels of rhe heart, kidneys, pancreas, adrenals, parathyroid glands, pituitary, lymph nodes, uterus and ovaries. G ross Hnd microscopic ex;:imina rion of the brain was normal.

SPECIAL LABORATORY INVESTIGATIONS

The mulrimcric pattern of the patient 's von WillehrnnJ factor ( vWF) was studied using crossed immunoelectrophoresis. The tota l amoun t w,h increase<l slightly ( l.9 iu/mL, with upper limit of normal range 1.6), and there was loss of large multimcrs of vWF at rhe time of the acute thromhocytopenic episode (Figure I).

To determine if there was a plate let aggregating factor present, the ability of the patient's p lasma to induce the relea~c of 14C-serotonin from 14C-seroronin-radiolabelleJ normal platelets wa:, measure<l. Calcium-dependent cysteine protease (calpain) act ivity was confirmed by inhibition of this reaction by known inhibitors to calpain (leupeptin and iodoacetic acid ). In addition, the nbilit y of the calpain in the patient\ serum ro cleave the glycoca licin component of glycoprotein lb from normal platelets was measured (4,5).

The patient haJ calpain prc~ent in the plasma during the thrombocytopcnic episode. Previous experi mcn u, have ~hown that calpain activity is nor pre~ent in patients with other thrombocytopen ic disorders including idiopathic thrombocyropenic purpura and dissem inated intravascular coagulation. Via the same metho<ls, ca lpain activity was no t detectable in the supernatant from the C jejuni cultures.

DISCUSSION Over the past several years major

strides have been made in the improvement of o ur understanding of thrombotic th rombocytopenic purpura and hemolytic uremic syndrome. Although

155

JAESCHKE er al

these disorders have considerable clinical similarities in that borh arc associated wilh thrombocycopenia and schistocyric hemolytic anemia, different organs arc rrimarily affected: the brain is frequently affected in thromhoLic thrombocytopcnic purpura versus the kidneys in hemolyLic uremic syndrome. Studies examining Lhe rathogenesis of the two diw rJe rs have focused on the differences rather than the s imilarities of the disorders: hemolytic uremic syndrome is frequendy preceded by an cntcric infection and a number of recent reports have documented the high frequency of a verotoxin-producing E coli in epidemic outbreaks of this disorder. C jejuni

enteritis h as also been implicated in the pathogenesis of hemolytic uremic syndrome ( I l - 15). In contrast, thrombotic

ACKNOWLEDGEMENTS: Th i. study was partially supported hy a grant from the I lean and S troke Foundation of Ontario.

REFERENCES l. Bram l ,--:;, Kelton JG. 1lm1mbmic

thrombocycopcnic purpura and the hemolytic uremic syndrome. In: Brain M, McCulloch P, eds. C urrent Therapy in Hematology-Oncology. Philadelphia: BC Decker Inc 1983: I 93-6.

2. Aster RH. Thrombocytopenia due tu enhanced platelet destruction. In: Williams WJ, Beutler E, Erslev AJ, Lichtman MA, eds. Hematology, 3rd edn. New York: McGraw Hill Bonk Company, 1983: !034-9.

3. Lian EC-Y, Harkne;,s DR, Bumes JJ , Wallach H, Nunez R. The presence of platelet aggregating factor in the plasma of patients with thrombotic thrombocytopcnic purpura and its mhibition by normal plasma. Blood !979;53:333-8.

4. Kelton JG, Moore JC, Murphy WG. Studie:, investigating platelet aggregat-ing and release initiated hy scra from patien ts with rhromboric thrombo-

156

rhrombocytopenic purpura is nnt usually associated with a preceding infection (16). Recent research activity concerning thrombotic thrombocytopcnic purpura has focused upon attempts to identify the platelet aggregating factor found in these patients' plasma. O ne group has reported a 3 7 kilodalcon protein that can be ne utra lized by IgG (6,7). Another group of investigators found evide nce of unregulated calpain activity in the scra of these patients (8- I 0). The current case report suggests the possibility of a link between an infecting coterie organism that frequently triggers hemolytic uremic syndrome and the development and presence of calpain activity in the plasma. However, a direct causal association could not be proven. Altho ugh it is like ly that C jejuni triggered the t hrombotic

cytorcn1c purpura. Blood 1987;69:924-8.

5. Murphy WG, Moore JC, Kelton JG. Calcium-dependent cysteme protease act ivity in the sera of patient, with thrombotic thrombocytopenic purpurn. Blood 1987;70: 1683-7.

6. Siddiqui FA, Lian EC-Y. Novel platelet agglutinating protein from a thrombotic thrombocytopcnic purpura plasma. J Clin lnveM 1985;76: 1330-7.

7. Lian EC-Y, Mui PT, Siddiqui FA, Chiu A Y, C hiu LL. Inhibition of platelet-aggregating activity in throm-boric thrombocytopernc purpura plas-ma by normal adult immunoglobulin G. J C lin Invest I 984;7 3:548-55.

8. Murphy WG, Moore JC, Kelton JG. Calcium-dependent cyste ine protease activ ity in the scra of patients with thrombotic thrombocyropenic purpura. Bloo<l 1987;70:1683-7.

9 . Kelton JG, Moore J, Sanms A, Sheridan D. Detection of a platelet-agglutinating factor in thrombotic thrombocyropenic purpura. Ann Intern Med !984; 10 1:589-93.

10. Murphy WG, Moore JC, Barr RD, Pai MKR, Kelton JG. Relationship between platelet aggregating factor and

thrombocytopenic purpura episode m this patient, the organism by itself does not produce calpain, as tested using two d ifferent bioassays. Thus, although this study suggests a link between the infection and the development of thrombotic thrombocytopenic purpura via release of calpain, it does not elucidate the linkage itself. It is po~sible that an infecting organism triggers a complex immunological response that in some way results in the generation of unregulated calpain in the plasma of patient~ with thrombotic t hrombocytopcn,c purpura. The calpa in activity, in turn, could cause platelet aggregation and the clinical syndrome of thrombonc thrombocytopenic purpura. Studies ar~ c urrently underway to try and identify the link between infection and the generation of calpain.

von WillebrnnJ focmr in thrombotic chrnmbocytope111c purpura. Br J Haemarol 1987;66:509-13.

11. Chamovitz RN, Hanstein Al, Alexander SR, Terry AB, Shnrt P, K.iton R. Camp)•lohaccer jej1mi-associ-aced hemnlytic-uremic syndrome in a mother an<l daughter. Pediatrics 1983;71:253-6.

12. Denneberg T , Friedberg M, Holmberg L, er al. C0mhineJ plasmapheresi, and hemodialysis t reatinenc for ,evere hemolytic-uremic syndrome fo llowing campylobacter col itis. Acta Paediatr Scand 1982;71:243-5.

13. Schulman ST, Moel D. Campylohactcr infection. Pediamcs 1981;72:437.(Lctt)

14. Delan:, RJ, Riuso JD, Saba SR, Ramirez G. Hemolytic uremic syndrome after campylobacter-inJuccd <liarrhca in adu lt. Arch Intern Med 1984; 144: I 074-6.

15. Ashraful JH, Akbar MS. Hemolytic-uremic syndrome and campylobacter. Med J Aust 1985;142:662-3. (Len)

16. Morton A R, Yu R, Waldck S, Holme, AM, C raig A, Mundy K. Campylob1c-tcr mduced thrombotic throm-bocytopenic purpura. L,mcet l 985;ii: 11 33-4. (Lett)

CAN J GASTROENTEROL Vo1 4 No 4 MAY/JUNE 1990

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