Clinical Presentation and Follow-up of Eighteen Patients with Thrombotic Thrombocytopenic Purpura Received in: March 2007 Accepted in: 14/1/2010

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1 Clinical Presentation and Follow-up of Eighteen Patients with Thrombotic Thrombocytopenic Purpura Received in: March 2007 Accepted in: 14/1/2010 Dr. Ahmed Khudair Yaseen Elmeshhedany * Dr. Ahmed Abdulmajeed Elsaffar** Abstract Background and Objectives: Major advances achieved during the past 30years in understanding the pathophysiology of Thrombotic Thrombocytopenic Purpura ( TTP ). More recently treatment outcomes were revolutionized by the introduction of plasma exchange. In this study a descriptive analysis of clinical presentation and treatment outcomes with a modified Plasma Exchangee protocol (PE) is presented. Methods: During the period from November 2004 to July 2006, eighteen patients with acute episode of TTP were enrolled. After clinical and Laboratory evaluation, patients were assigned to receive modified low volume plasma exchange, and their response was monitored for a mean of 64 weeks. Results: The classical Pentad of TTP was only documented in 27% cases. Of patients enrolled, one died before starting PE, while of the remaining 17 put on PE Complete remission (CR) was achieved in 70% with a mean follow up of 64 weeks. Four patients died during the first few days of starting PE. Of patients who achieved CR none had a relapse. Conclusions: The classical pentad of TTP is present in small proportion of patients at presentation. Our results with the modified low volume exchange may suggest that even small volume of plasma exchange can be life saving. Key words: Thrombotic thrombocytopenic purpura, Iraq. Plasma Exchange. Introduction Thrombotic Thrombocytopenic Purpura ( TTP ) is a microvascular occlusive disorder characterized by systemic aggregation of platelets, thrombocytopenia and mechanical injury to erthrocytes. 1 It was first described by Moschcowitz in 1924 when he reported the presentation of a 16years old female with fever, anemia, central nervous system dysfunction, renal impairment and cardiac failure 1,2. The disorder is uncommon but not rare, and its incidence may be rising. TTP is more common in women than men (ratio 2:1) and has peak incidence in people between 30 and 40 years 3. Although TTP has been classically linked to a pentad of symptoms and signs consisting of microangiopathic hemolytic anemia neurological abnormalities,fever and renal impairment, However, for the time being appears that the classical pentad is infrequently seen particularly in the early stages of disease1. The pathophysiology of TTP has been linked to defective processing of Unusually large VonWillebrand's Factor Multimers (ULVWF) since the early 80s 1,2,4,5,6.It was found that a specific protease labeled "ADAMTS13" is responsible for this processing physiologically and that this protease is severely deficient in most cases of familial and acquired TTP 1,7,8,and is also deficient but to a lesser extent in other conditions, in-cluding liver disease, disseminated malig-nancy, chronic inflammatory disease and pregnancy 8. For many years TTP remained an almost universally fatal disorder, with a mortality rate of 80 % within 3 months and * Lecturer in medicine and clinical hematology : Hawler medical university-colllege of medicine /Erbil-Iraq. ** Consultant internist and clinical hematologist : Medical city Baghdad Teaching hospital /Baghdad-Iraq. 1

2 Fewer than 10% survived1year. In 1977 Byrnes and Khuran discovered that plasma infusion was able to reverse the course of the disease in some patients,.(9,10), while in 1991the Canadian Apheresis Study Group conducted a controlled prospective therapeutic trial of plasma exchange ( PE ) or plasma infusion (PI), they found that PE was preferable to PI in the treatment of TTP with 78% survival at one month in the PE arm versus 49% in the PI arm 2,11. Materials and Methods: Eighteen patients with clinical diagnosis of acute acquired TTP and pregnancy / post partum related TTP who were admitted at the hematology unit of Baghdad Teaching Hospital, Medical City, during the period from November 2004 to July 2006 were included in the study. They were considered to have acute idiopathic TTP on the basis of having coomb s negative microangiopathic hemolytic anemia and thrombocytopenia in the absence of another possible explanation for these findings, while, Pregnancy and post partum related TTP was considered if the episode occurred during pregnancy or in the im-mediate post partum period Clinical-parameters associated with TTP were defined as the following: 12, Fever was defined as an explained oral temperature 38 oc. 2. Neurological dysfunction defined as any new abnormality in the neuropsychiatric exam. 3. Renal dysfunction defined as serum creatinine 1.5 mg/dl and/or blood urea 60 mg/dl. 4. Thrombocytopenia when platelets count less than 150 x109/l. 5. The presence of schistocytes and reticulocytosis was documented by blood film examined by one or more consultant hematologist (MAHA). Laboratory evaluation including renal function, Coomb s test, coagulation screen (prothrombin time & activated partial thromboplastin time) [Biomerieux France], Antinuclear antibody test, Anti ds-dna assay, Serum Lactate Dehydrogenase enzyme (LDH) assay (Randox, France), and general urine exam, were performed according to instructions of manufacturers. Primary therapy consisted of PI of 30 ml/kg body weight. PE started as soon as possible using the cell separator (Haemonetics MCS +, Haemonetics Cor-poration, USA). Ideally a special set called Therapeutic Plasma Exchange set (TPE) should be applied into the cell separator allowing a large volume of plasma ( ml ) to be withdrawn from the patient per session, in Iraq this set was not available since 2003, alternatively, sets used for platelet and red cell collection called Leukodepleted Platelets ( LDP) and ( LDP RBC) sets respectively, had been used at our unit with a modified ma-neuver allowing approximately 500ml of plasma to be separated at a single ses-sion. FFP was used as a replacement fluid. Sessions continued on daily basis, whenever possible, till response to treatment was obtained. PE given at increasing intervals, determined by practical and logistical issues. All patients who obtained response to PE had additional PE sessions tapered over the subsequent two weeks. Adjuvant treatments were given including Dexamethasone (0.2mg/kg IV, daily) Aspirin ( 100mg,oral, daily ) mainly for patients with focal neurological signs and no active bleeding and when platelets count appear to be rising. Vincristine and azathioprine were given to one patient. Brain Computerized Tomography was done to some patients with severe neurological dysfunction whenever it was possible. The following definitions and terms used according to other users (12,13) Response to treatment: was defined as the achievement of a platelet count of 150,000 for two successive days while on plasma exchange. Complete Remission ( CR ) : was defined as no requirement for PE for 30 days or more with platelet count more than Exacerbation: was defined as recurrent thrombocytopenia 2

3 following a response or resumption of daily PE after one day or more but less than 30 days of no PE treatment. Relapse: was defined as recurrence of TTP after remission, clinical or laboratory. Statistical Analysis :- Overall Survival ( OS ) : was calculated by the Kaplan - Meier s method from the date of PE until last contact or death. The statistical package for social sciences (SPSS version10) was used for data entry and analysis. Disease Free Survival: was calculated for those who achieve complete remission from the date of complete remission till death or relapse. Results Of the eighteen patients studied,15 ( 83.33% ) were females and 3( 16.66% ) were males. Mean age was 30 years range (16-53 yrs), the duration of symptoms ranged from 2-30 days (mean 14days). One patient died within few hours of admission, before initiation of PE. At presentation16 out of the17patient( 94.1% ) had mucocutanous bleeding, four(23.5%) Hematemesis and/ or malena, while one patient complained from vaginal bleeding. ( table 1). Anemia, reticulocytosis, and thrombocytopenia was present in 100% of our patients ( table 2). OF the 3 patients with pregnancy related TTP, two presented within seven days of delivery of their first pregnancy, while a third one got relapse in the first trimester of her first pregnancy. Four patients died during their first few sessions of PE. The 17 patients scheduled for PE had received between 8-33sessions (mean 16 sessions), including sessions done after response was obtained. Using our modified low volume PE,12 patients ( 70%) entered into CR, one (6%)patient had refractory/relapsed disease (table 3). Patients were followed for weeks (mean 64 weeks), and the overall 6 months survival was 76% (Figure1). Of those patients who entered CR, no patient had relapsed and no patient died so the disease free survival in this category of patients after a mean follow-up of 6 months was 100%. Complications related to PE were minor and mainly related to cannula site infections in three patients, however, as peripheral veins were the only vascular accesses for PE, problems in finding patent veins were of major concern and not infrequently they precluded sessions to be performed as planned. All ergic reactions ( urticaria ) to plasma infusion were common but self-limiting, parasthesia and perioral numbness related to alkalosis were only occasionally reported and selflimiting. Patients with severe neurological dysfunction, who achieved CR, had recovery of their neurological functions without residual deficit. Table 1: Clinical characteristics of enrolled 18 TTP patients at presentation. Variables Number (%) Gender Male 3(16.66%) Female 15(83.33%) Fever 11(61%) Death 5/5(100%) Survival 6/13( 46%) Pregnancy/Postpartum 3(16.6%) Neurological dysunction* Mild 5(27.7%) Severe 10(55.5%) Renal dysfunction Acute renal failure 1(5.5%) Renal insufficiency 7(38.8%) Hematuria/albuminurea 9 (50%) ANA/Anti-dsDNA +ve 3(16.6%) Pentad** 5(27.7%) *Severe neurological dysfunction include: coma, seizure, or fluctuating focal sings.mild neurological dysfunctions include headache, blurred vision, ataxia or mental status changes ** Classical Pentad of anemia, thrombocytopenia, neurological dysfunction fever and renal dysfunction. 3

4 Table 2: shows laboratory parameters at presentation. Variable Normal Value Mean Value Range PCV M:41-50% 19.8% 5-27% F:36-45% Reticulocyte% % 18.5% 4-28% Platelets count /mm Serum LDH IU/L 489 IU Total Serum bilirubin mg/dl 5.1mg/dl Indirect Bilirubin mg/dl 0.6-8mg/dl Blood Urea 20-45mg/dl 60.3mg/dl mg/dl Serum Creatinine mg/dl 1.7mg/dl mg/dl Table 3: shows the outcome of 18 enrolled patients with TTP Response Complete Response (CR) Number total18 * (%) 12 (70. 5%) Refractory/Relapse 1(5. 8%) Death during PE 4(23. 5%) Death before PE 1* Figure 1: Overall survival in 18 TTP patients enrolled in weeks Discussion The diagnosis of TTP requires a high degree of clinical suspicion, while all enrolled patients expressed a dyad of thrombocytopenia and microangiopathic hemolytic anemia only 5(27.7%) presented with the classical pentad, an observation which was also documented by other authors. 4,13. Previous studies have reported that 12-25% of TTPs are Pregnancy related (8,12). This is consistent with findings of the current study, where three of the patients (16.6%) had pregnancy related TTP, including 2 females, who had their first TTP episode during the postpartum period of their first pregnancy. while another one had her TTP prior to her pregnancy, and entered into CR using predinsolone and azathioprine with PE, and the remission was maintained for about 6 months, only to relapsed as she became pregnant(during the first trimester of her firstpregnancy). The patient had then PE reintroduced, but shortly the fetus died and she entered into a second remission even before evacuation of the conceptus. Such a Relapse in TTP upon subsequent pregnancy was reported in about a quarter of patients in a previous study 12,14.Three female patients tested positive for Anti - nuclear Antibody (ANA) and/or Anti ds- 4

5 DNA, but none fulfilled the criteria for Systemic Lupus Erythematosis ( SLE ) or other autoimmune disease at the time of their TTP acute episodes and all obtained CR. 4,12,15,16. In total five patients died during this study, one died of severe bleeding and renal failure shortly after admission and before starting PE. The other four patients died within the first few days of PE, because of severe gastrointes-tinal (GIT ) bleeding in one patient, intracranial hemorrhage, Acute renal fail-ure and GIT bleeding in another. While a third one died few hours after her first PE because of sudden severe respiratory distress and a fourth died after 6 PE ses-sions when she developed severe abdominal pain with high grade fever and hematoschezia with a probable nosis of mesenteric infarction. Analysis of the pre-treatment variables in relation to outcome showed that the all the 5 died patients were febrile at presentation while 46% ( 6/13) of survival had fever at presentation,pvalue could not be obtained because of the small sample size. It was quite important to note that using our modified low volume PE, about three quarters of the patients receiv-ing such therapy attained a complete remission, and furthermore once patients attained this remission they would be disease free for at least 6 months. This observation validates the value of our approach to management and the use of low volume PE in this setting. Moreover it appears that with our approach and once patients manage to survive the first week after initiation of PE, then they are very likely to be disease free survivors. The use of low volume PE, though not the generally advocated procedure in TTP, has been observed to induce a satisfactory response in many patients with TTP in some previous studies 17,18. In Conclusion, the current study supports the fact that the classical pentad of TTP is only present in a small proportion of patients at presentation, and that low volume PE is a quite an effective procedure, inducing a satisfactory response in the majority of patients, and may serve as a suitable alternative to large volume Exchange. References 1. Moake JL. Thrombotic Microangiopathies. N. Eng J Med 2002; 347: Rock GA. Managment of Thrombotic Thrombocytopenic Purpura. Br J Hematol 2000;109: Levine SP.,Greer JP. RodgrsGM,Foerster J., Thrombotic Thrombocytopenic Purpura and other forms of Non - Immunologic Platelets Destruction : Wintrobe s Clinical Hematology; Eleventh edition Lippincott Williams & Wilkins. 2004: George JN. How I Treat Patients with Thrombotic Thrombocytopenic Purpura- Hemolytic Uremic Syndrome.Blood;2000: Furlan M., Robles R., Galbursera M., Remuzzi G, Kyrle PA, Brenner B et al. Von Willebr and factor- Cleaving Protease in Thrombotic Thrombocytopenic Purpura and the Hemolytic -Uremic Syndrome. N Eng J Med.1998;339: Veyradier A., Obert B., HoulierA., Grima JP. Specific Von Willebrand factor - CleavingProtease in Thrombotic Microangiopathies: a study of 111 cases.blood 2001;98: Moake JL.Idiopathic Thrombotic Thrombocytopenic Purpura.in ASH Year book 2004: Mannuci PM.,Canciani MT.,Forza I., et al. Changes in Health and Disease of Metalloprotease that Cleaves Von Willebrand Factor. Blood 2002; 98: ToffelmireEB, Clark WF, Cordy PE, LintonAL,Lohmann RC: Plasma exchange in thrombotic thrombocytopenic Purpura.Canad Med Ass J;1984:131: Moake JL: Moschcowitz, Multimers, and Metalloprotease.N Eng J Med:1998;339: Rock GA.,Shumak KH., Buskard NA., et al (The Canadian Apheresis Study Group). Comparison of Plasma Exchange with Plasma Infusion in the Treatment of Thrombotic Thrombocytopenic Purpura. N Eng J Med 1991; 325: Vesely SK., George JN., Lammle B., et al.adamts13 activity in TTP-HUS: Relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003;102: Thompson CE., Damon LE., Ries CA, Linker CA. Thrombotic Microangiopathies in the 1980 s : Clinical Features, Response to Treatment and the Impact of Human Immunodeficiency Virus Epidemic. Blood 1992;80 : George JN., Diagnosis of Thrombotic Thrombocytopenic Purpura in ASH year Book 2004 :

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