The authors present a case of a 16-year-old boy, who was referred to the hospital due to thrombocytopenia, anemia, proteinuria and hyperbilirubinemia. Based on the clinical picture and the laboratory data, thrombotic thrombocytopenic purpura (TTP) was diagnosed. The adequate therapy was immediately started. TTP is quite a rare entity. The etiology and the pathogenesis are not well defined. The

authors summarize the different pathomechanisms, which may

play a role in the development of TTP. Similarity to the hemolytic uremic syndrome (HUS), therapeutic possibilities, prognosis and the outcome are also discussed. The importance of the early diagnosis of TTP in childhood, and life-saving effect of the adequate treatment are emphasized

Czinyéri, Judit

Garami, Miklós

Kovács, Gábor

Müller, Judit

Sasvári, Ildikó

English

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144 International Pediatrics/Vol. 16/No. 3/2001Moschcowitz SyndromeClinical ArticleThrombotic Thrombocytopenic Purpura, Moschcowitz SyndromeJudit Müller, MD; Judit Czinyéri, MD; Ildikó Sasvári, MD; Miklós Garami, MD; Gábor Kovács, PhDAbstractThe authors present a case of a 16-year-old boy, who was referredto the hospital due to thrombocytopenia, anemia, proteinuria andhyperbilirubinemia. Based on the clinical picture and the laboratorydata, thrombotic thrombocytopenic purpura (TTP) was diagnosed.The adequate therapy was immediately started. TTP is quite a rareentity. The etiology and the pathogenesis are not well defined. Theauthors summarize the different pathomechanisms, which mayplay a role in the development of TTP. Similarity to the hemolyticuremic syndrome (HUS), therapeutic possibilities, prognosis andthe outcome are also discussed. The importance of the early diag-nosis of TTP in childhood, and life-saving effect of the adequatetreatment are emphasized. Int Pediatr. 2001;16(3):144-149.Key words: thrombotic thrombocytopenic purpura (TTP), plasma-pheresis, plasma exchange (PEX)IntroductionThrombotic thrombocytopenic purpura (TTP) is asevere multisystemic disorder characterized by the sametetrad of clinical findings as hemolytic uremic syndrome(HUS) (thrombocytopenia, microangiopathic hemolyticanemia, fluctuating neurological symptoms and impairedrenal function) with the addition of fever.1 Although it isa disorder of unknown cause, a variety of clinical eventshave been identified as possible precipitating factors. In-fections are the most common precipitation factors, fol-lowed by pregnancy.2,3 Without treatment, TTP has amortality rate in excess of 90% due to multi-organ fail-ure.4 The authors recognized the clinical signs and thelaboratory data on a 16-year-old patient, and after settingthe diagnosis of thrombotic thrombocytopenic purpura,adequate therapy was started immediately on the basis ofthe current literature. For five months this patient hasreceived combined therapy. He is now symptom- and com-plaint-free.From Semmelweis University, Faculty of Medicine, 2nd Dep. ofPediatrics (Dr Müller, Dr Sasvári, Dr Garami, Dr Kovács) and theHeim Pal Children Hospital, Laboratory for Apheresis (Dr Czinyéri).Address reprint request to H-1094 Budapest, Tuzoltó u. 7-9, Hun-gary/Europe (Dr Müller).Case ReportA 16-year-old boy is presented. He is the first child ofhis family, after a normal delivery. At the age of 8-months,he had salmonellosis, and later varicella and mumps. Therewas no family history of an inherited disease or bleedingdisorder. Both his parents and his younger brother werehealthy. At 16 years of age, the previously healthy boyhad diarrhea. One day later he had fever and vomited.These symptoms had disappeared in three days. Twodays later, his family doctor referred him to the hospitalbecause of proteinuria. In the hospital, anemia, thromb-ocytopenia, indirect hyperbilirubinemia, severe pro-teinuria were recognized, and an unclear structure of thekidneys was seen by an abdominal ultrasound.During the first physical examination, he appearedpale, scleral and skin jaundice.  Petechia, and some ec-chymosis, and submandibular lymphadenomegaly weredetected. His liver was 2 cm under the costal arch.On his first admission at another institution, he hadprofound thrombocytopenia (18.000 G/l), anemia (Hb 9.2g/dl) with numerous schistocytes (Fig 1). The patient alsohad an elevated LDH activity (2116 U/l), indirect hyper-bilirubinemia (65 µmol/l), decreased level of serum fibrino-gen (125 mg/dl), hypocalcemia (1.9 mmol/l), and pro-teinuria. The boy’s urine sediment contained 4-5 red bloodcells and 1-1 leukocytes could be detected.Microangiopathic hemolytic anemia was diagnosedbased on the clinical findings and laboratory results. Thetreatment was symptomatic with forced fluid therapy (ina dose of 3000 ml/m2), which included infusions of freshfrozen plasma (FFP).On the second day of his admission, his hemoglobinlevel decreased, the platelet count was stable but low.Therefore a treatment with regular plasma exchange(PEX) by plasmapheresis was initiated.Due to the daily PEX, with replacement ofcryosupernatant, a quick improvement was observed. HisLDH level became normal, serum bilirubin-level de-creased, hemolysis alleviated, and platelet count increased.Reticulocytosis was seen as a compensation of the bonemarrow (Fig 2).After the seventh PEX, severe spastic abdominal painoccurred; only opioid analgetics were effective. As a causeof this acute symptom, in addition to the manifestation ofhis primary disease, bowel ischemia, hypocalcemia, inspis-145International Pediatrics/Vol. 16/No. 3/2001Moschcowitz Syndromesated bile syndrome and gallbladder dysfunction had arise,but none of them could have been proved.PEX was given to our patient 12 times. All together,33 liters of plasma were removed, and just as manycryosupernatants were transfused. One week later, theplatelet count has decreased again without any sign forhemolysis; therefore oral corticosteroid was given. Dur-ing the third week, his nursing therapy was completedwith azathioprine and 4 times a day transfusion withcryosupernatant (Fig 3).The result of this combined therapy, the blood workand the laboratory results of our patient became normal,but still, no clinical finding was recognized. He was treatedwith methylprednisolone for 11 weeks and with azathio-prine for 19 weeks. Remarkably, at six months after set-ting the diagnosis, he had acute purulent appendicitis, andthree months later, he was admitted to the hospital be-cause of mastoiditis associated with meningitis. Duringthis period, the laboratory results were those for acutebacterial infection. At his last ambulatory control, he wassymptom- and complaint-free; his blood work and labo-ratory results were normal, with no sign of hemolysis orrelapse of the primary disease.DiscussionIn 1925 Moschcowitz observed widespread hyalinethrombi in capillaries and arterioles now established asthe pathologic hallmark of TTP. Moschcowitz regardedthese lesions as the result of circulating toxin affectingplatelets and red cells.1The etiology is unknown, but a variety of clinicalevents have been identified as possible precipitating fac-tors (serotoxin-producing enteropathogenic Escherichiacoli and Shigella dysenteriae infections,2 pregnancy or oral-contraceptive related,3 malignancy, chemotherapy, mar-row transplantation, drug-dependent antibodies and con-nective tissue disease).The pathogenesis of TTP is heterogeneous. Severalmarkers and hypothesis have been described in the litera-ture. Histological findings point to the pathological in-teraction between vascular endothelium and platelets,which leads to enhance platelet aggregation and endot-helial damage. Autopsy findings in TTP reveal multiplesmall hyalin-like thrombi occluding capillaries and arte-rioles in a variety of organs (most frequently the kidneys,brain, pancreas, heart, spleen and adrenal glands).Immunohistochemical stains have shown that thethrombi contain platelets and fibrin and frequently im-munoglobulin and complement. Cytotoxic effects on en-dothelial cells have been induced by sera from patientswith TTP.4 Abnormalities of prostacyclin (PGI2), theplatelet-inhibiting eicosanoid synthesized by endothelialcells, have also been described in TTP. Plasma from somepatients, in contrast to normal plasma, was unable tostimulate PGI2 synthesis in endothelial cells. ß-thromboglobulin, a platelet α-granule protein secretedupon platelet activation, can inhibit endothelial PGI2 syn-thesis and is a candidate for this activity in patients withTTP. Others have suggested that a PGI2 deficiency maybe caused by deficiency of a PGI2-stabilizing protein, withexcessive PGI2 degradation.5 Detection of abnormally largemultimers of the von Willebrand factor in the plasma ofpatients with TTP links endothelial cell damage with amechanism of platelet aggregation.6 These multimers arevery effective in binding to glycoproteins (Ib and II/IIIa)on the endothelial cell surface and inducing platelet ag-gregation. An intracellular cysteine protease, calpain, hasbeen found in the plasma of many patients with acuteTTP. High molecular weight kininogen is one of the pri-mary plasma inhibitors of calpain. Kelton et al observedthat the high molecular weight kininogen in plasmasamples from patients with acute TTP was proteolysed.7,8Fig 1. - Blood smear of our patient, showing red cell fragmenta-tion (schistocytosis) and marked deficiency of platelet.Fig 2. - Blood smear of our patient, showing reticulocytosis, re-flecting the bone marrow response to hemolysis.146 International Pediatrics/Vol. 16/No. 3/2001Moschcowitz SyndromeFibrinolytic activity is depressed at the site ofmicrothrombi formation. Decreased level of protein C alsohas been reported in TTP plasma. Impaired fibrinolysismay contribute to the stability of the platelet plug andenhance tissue injury.9The classic pentad of clinical findings is (1) fever, (2)thrombocytopenia, (3) microangiopathic hemolytic ane-mia, (4) neurologic abnormalities, and (5) renal involve-ment (Table 1). This disease is similar to HUS exceptthat it occurs most often in young adults, involves moreorgan systems, neurologic symptoms are prominent, renaldysfunction is less severe, and the mortality rate is higher(Table 2). A variety of manifestations due to damage ofmultiple organs are present. Damage to the central ner-vous system is most common. Headaches, confusion, sei-zures and coma reflect cerebral lesions. Symptoms may bereversible, if treated early. Jaundice reflects both hemoly-sis and liver damage. The widespread thrombotic processresults in visual defects, heart failure, abdominal pain, anddamage to the pancreas and adrenal glands.Four different types of TTP have been recognized: (1)single-episode TTP (most common); (2) relapsing TTP,which characterized by episodes that recur after healthyperiods of months or years; (3) chronic TTP, which ischaracterized by very frequent recurrent episodes; (4)childhood/familial TTP, which is very rare.Laboratory FindingsTTP is usually apparent from the initial blood countand examination of blood film. The hemoglobin is usu-ally less than 10.5 g/dl (average 8 to 9 g/dl). MCV may beFig 3. -  Time course of platelet count and LDH values during the hospital courses of our patient with different treatment modalities.147International Pediatrics/Vol. 16/No. 3/2001Moschcowitz Syndromenormal; decreased, if there is marked erythrocyte fragmen-tation; or increased, depending on the degree of reticulo-cytosis. MCH and MCHC are normal. Reticulocytes areincreased, and nucleated erythrocytes are found in theperipheral blood, reflecting the bone marrow response tohemolysis. The most striking blood finding is the abun-dance of schistocytes (Fig 4).Thrombocytopenia is typically severe (8 to 44 /µl) dueto consumption of platelets in the formation ofmicrothrombi. Platelet survival is very short, and plateletsequestration studies demonstrate hepatosplenic uptake.Megakaryocytes are abundant in the bone marrow. Thebleeding time may be prolonged if the platelet count isless than 100 G/l. Leukocytosis with counts more than 20G/l occur in 50% of patients and usually accompanied bya shift to the left. Hemoglobinemia, hemoglobinuria, de-creased haptoglobin levels and increased serum bilirubinare direct evidence of intravascular hemolysis. Coagula-tion tests are usually normal or only mildly disturbed inTTP, which helps to differentiate TTP from disseminatedintravascular coagulation.TreatmentDue to the rarity of the condition, several differenttreatment modalities have been used. Among them,plasma exchange recently became the standard therapeu-tic management for this disease.10 Plasma exchange regi-ments for TTP should begin with single plasma volumeexchange (40 ml/kg body mass) on a daily basis. Dailytreatments should continue until the resolution of thethrombocytopenia, neurological abnormalities, the stabi-lization of the hemoglobin, and the normalization of LDHlevel. The standard replacement fluid is FFP, however sev-eral recent reports described successful use ofcryosupernatant (which is the residual plasma fraction afterthe separation of cryoprecipitate and is mostly depletedof vWF, fibrinogen, fibronectin and factor XIII).11Solvent-detergent processing of plasma also removesthe highest multimers of vWF, so this product may also beparticularly suitable for the treatment of TTP.12 Patientsundergoing plasma exchange have shown a higher re-sponse rate and lower mortality rate than those given onlyplasma infusions.13 Antiplatelet agents such as acetylsali-Table 1. - Evolution of diagnostic criteria for TTPClinical signs Percent of patientsAmorosi et al18 Ridolfi et al19 Rock et al13Microangiopathic hemolytic anemia 96 98 100Thrombocytopenia 96 96 100Neurologic symptoms 92 84 63Renal disease 88 76 59Fever 98 59 24Table 2. - Differences between HUS and TTP.HUS TTPPeak age incidence 1-4 years 20-25 yearsMale:Female ratio 1 : 1 1 : 2Prodromal illness Usual VariableFever Rare UsualNeurologic abnormalities Variability Usualrelated to renalfailureRenal disease Usual UsualRenal failure Common RareHypertension Common RareMajor organs affected Kidneys Kidneys, brain, heart, pancreas, adrenalsPrognosis Relatively good Relatively poor148 International Pediatrics/Vol. 16/No. 3/2001Moschcowitz Syndromecylic acid and dipyridamole have widespread use as plate-let-inhibitor drugs. Vincristine, in combination with glu-cocorticoids and plasma, also has been used. Splenectomyand intravenous immunoglobulin have been reported tolead to remission in TTP patients who did not respond toplasma exchange, or those who had relapsed.14-16Supportive TreatmentThe prompt administration of appropriate therapy isessential.13 It is equally important to recognize that plate-let transfusions are contraindicated, despite the frequentlyencountered severe thrombocytopenia, which may aggra-vate the disease.11 Red blood cell replacement is frequentlynecessary before the abatement of the hemolysis withplasma exchange therapy. The requirement is proportionalto the degree of hemolysis. The packed red blood cells aredepleted of platelets and can be given safely.Acute renal failure is the result of severe injury to therenal vasculature, as a result of the primary endothelialinjury or of a heavy presence of the microthrombotic le-sions characteristic of TTP. The renal failure may oftenbe severe and requires frequent hemodialysis. Renal vas-cular lesions in TTP leads to ischemia results in the acti-vation of the renin-angiotensin system. In the case of se-vere involvement of the kidney, this activation is maxi-mal and prompt control of severe hypertension by angio-tensin converting enzyme inhibitors is needed to preventacute hypertensive complications.PrognosisBefore the late 1970s, almost all patients with TTPdied of their illness within days or weeks. Since the intro-duction of corticosteroids, platelet-inhibitor drugs andsplenectomy, the survival rate increased almost 50%. Bymeans of supportive care and a variable combination oftherapeutic modalities (currently including intensiveplasma exchange), as many as 85-90% of patients withTTP may eventually recover. However, Sumack et al havepublished that more than one third of patients who sur-vive an acute episode of TTP will have at least one re-lapse during the following ten years.17In conclusion, TTP is a rare, but life-threatening dis-order. Prognosis is good with immediate diagnosis andadequate treatment with plasma exchange.References1. Moschcowitz E. An acute febrile pleiochromic anemia with hya-lin thrombosis of the terminal arterioles and capillaries. Arch In-tern Med. 1925;36:89-93.2. Su C, Brandt LJ. Escherichia coli O157:H7 infection in humans.Ann Int Med. 1995;123:698-714.3. Egerman RS, Witlin AG, Friedman SA, et al. Thrombotic throm-bocytopenic purpura and hemolytic uremic syndrome in preg-nancy. Am J Obstet Gynecol. 1996;75:950-956.4. Ahn YS, Jy W, Kolodny L, et al. Activated platelet aggregates inthrombotic thrombocytopenic purpura: decrease with plasma in-fusions and normalization in remission. Br J Med. 1996;95:408-415.5. Wu KK, Hall ER, Rossi EC, Papp AC. Serum prostacyclin bind-ing defects in thrombotic thrombocytopenic purpura. J Clin In-vest. 1985;75:168-174.6. Baker KR, Moeke JL. Thrombotic thrombocytopenic purpura andhemolytic-uremic syndrome. Curr Opin Pediatr. 2000;12:23-28.7. Kelton JG, Moore JC, Warkentin TE, et al. Isolation and charac-terization of cysteine proteinase in thrombotic thrombocytopenicpurpura. Br J Med. 1996;93:421-426.8. Pavord S, Kelton JG, Warner MN, et al. Proteolytic degradationof high molecular weight kininogen in acute thrombotic throm-bocytopenic purpura. Br J Med. 1997;97:762-767.9. Kwaan HC. Role of fibrinolysis in thrombotic thrombocytopenicpurpura. Semin Hematol. 1987;24:101-109.10. Kwaan HC, Soff GA. Management of thrombotic thrombocy-topenic purpura and hemolytic uremic syndrome. Semin Hematol.1997;34:159-166.11. Rock G Shumak KH, Sutton DM, et al. Cryosupernatant as re-placement fluid for plasma exchange in thrombotic thrombocy-topenic purpura. Br J Haematol. 1996;94:383-386.12. Evans G, Llewelyn C, Luddington R, et al. Solvent/detergentfresh frozen plasma as primary treatment of acute thromboticthrombocytopenic purpura. Clin Labor Haemat. 1999;21:199-223.13. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasmaexchange with plasma infusion in the treatment of thromboticthrombocytopenic purpura. N Engl J Med. 1991;325:393-397.14. Winslow GA, Nelson EW. Thrombotic thrombocytopenic pur-pura: Indications for and results of splenectomy. Am J Surg.1995;170:558-563.15. Crowther MA, Heddle N, Hayward C, et al. Splenectomy doneduring hematologic remission to prevent relapse in patients withthrombotic thrombocytopenic purpura. Ann Int Med.1996;125:294-296.Fig 4. - Scanning electron micrograph of formation of fragmentederythrocytes by fibrin strands in an in vitro model (x2100). Bull etal. Blood. 1970;53:104.20149International Pediatrics/Vol. 16/No. 3/2001Moschcowitz Syndrome16. Kondo H, Imamura T. Effects of intravenous immunoglobulin ina patient with intermittent thrombotic thrombocytopenias pur-pura. Br J Haematol. 2000;108:880-882.17. Shumak KH, Rock GA, Nair RC, et al. Late relapses in patientssuccessfully treated for thrombotic thrombocytopenic purpura.Ann Int Med. 1995;122:569-572.18. Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic pur-pura: Report of 16 cases and review of the literature. Medicine.1965;45:139-143.19. Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura.Report of 25 cases and review of the literature. Medicine.1981;60:413-428.20. Bull BS, Kuhn IN. The production of schistocytes by fibrin strands.Blood. 1970;34:104-111.© Miami Children’s Hospital 2001

Activated platelet aggregates in thrombotic thrombocytopenic purpura: decrease with plasma infusions and normalization in remission.

An acute febrile pleiochromic anemia with hyalin thrombosis of the terminal arterioles and capillaries.

Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura.

Cryosupernatant as replacement fluid for plasma exchange in thrombotic thrombocytopenic purpura.

Escherichia coli O157:H7 infection in humans. Ann Int Med.

Isolation and characterization of cysteine proteinase in thrombotic thrombocytopenic purpura.

Proteolytic degradation of high molecular weight kininogen in acute thrombotic thrombocytopenic purpura.

Role of fibrinolysis in thrombotic thrombocytopenic purpura. Semin Hematol.

Serum prostacyclin binding defects in thrombotic thrombocytopenic purpura.

Soff GA. Management of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Semin Hematol.

Solvent/detergent fresh frozen plasma as primary treatment of acute thrombotic thrombocytopenic purpura. Clin Labor Haemat.

Splenectomy done during hematologic remission to prevent relapse in patients with thrombotic thrombocytopenic purpura. Ann Int Med.

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in pregnancy.

Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. Curr Opin Pediatr.

Thrombotic thrombocytopenic purpura: Indications for and results of splenectomy.

Thrombotic Thrombocytopenic Purpura, Moschcowitz Syndrome

Thrombotic Thrombocytopenic Purpura, Moschcowitz Syndrome

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