THROMBOCYTOPENIA IN PATIENTS WITH TETRALOGY OF FALLOT, A CONDITION REQUIRING IMMEDIATE ATTENTION

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1 THROMBOCYTOPENIA IN PATIENTS WITH TETRALOGY OF FALLOT, A CONDITION REQUIRING IMMEDIATE ATTENTION Teddy Ontoseno ABSTRACT Background: In Indonesia, most of the patients (95%) with Tetralogy of Fallot (TF) are still faced to disadvantageous situation, since it remains difficult for them to obtain immediate surgical corrective procedure. Delayed surgical procedure for these patients may often lead to the occurrence of fatal complications, i.e., hemostatic function disorder and cerebrovascular accident accompanied with Objective: to prove the influence of arterial oxygen saturation on the development of thrombocytopenia and to disclose correlation between arterial oxygen saturation and cut-off point and thrombocytopenia in TF patients. Methods: This was a case control study undertaken by involving 94 patients with Tetralogy of Fallot. Patients without thrombocytopenia were assigned as control group, while those with thrombocytopenia belonged to case group. Thrombocytopenia was determined as having 33, ,000 cells/mm 3 cell dynamic. Arterial oxygen saturation was below 90% in room temperature, as measured by pulse oximetri. Multiple logistic regression analysis, Kappa association analysis, and McNemar test were employed in this study. Results: From 47 patients studied, significant difference was found between age and thrombocytopenic development. Average age of thrombocytopenic group was months, and non-thrombocytopenic group was months. Oxygen saturation of <60% was found significantly influencing the development of Cut-off point of arterial oxygen saturation was 57% (Kappa and p < 0.05). Conclusions: (1) arterial oxygen saturation influences thrombocytopenic development; (2) a negative correlation of exists between arterial oxygen saturation and thrombocytopenic development; (3) cut-off point of arterial oxygen saturation is 57% with sensitivity and specificity of respectively 100% and 93.6%. Keywords: Tetralogy of Fallot, thrombocytopenia INTRODUCTION Tetralogy of Fallot (TF) is a complex abnormality of cardiac anatomic structure that develops during intrauterine life. It is one of several cyanotic congenital heart diseases most commonly found in infants or children, and the third most frequent disease among all congenital heart diseases, with the incidence rate of 10% (Therrien, 2001). The only definitive treatment for TF is surgical correction. In Indonesia, the procedure remains difficult to accomplish, since quantity and distribution of human resource and equipments to perform the operation remain inadequate. To date, cardiac corrective surgery can be undertaken only to 5% of all TF cases (Ontoseno, 1999). Lower arterial oxygen saturation often presents as the cause of fatal complications. These complications that mostly found at the first year of life are brain abscess, cerebral vascular disorder presenting as bleeding or cerebral venous disorder and cyanotic attack that may result in permanent disability and even leads to fatal outcome (Ontoseno, 1995). Division of Cardiology Department of Pediatrics Airlangga University School of Medicine Dr Soetomo Teaching Hospital, Surabaya Abnormality in blood clotting factor, such as thrombocytopenia, defects in thrombocyte and coagulative function, very likely attribute to the occurrence of bleeding and thrombosis. Thrombotic change observed is presenting as the alteration of its quantity and function, with thrombocytopenic incidence as much as 42%. However, its mechanism and predisposing factors remain unclear (Hatthaway, 1993). This study was aimed to investigate the influence of arterial oxygen saturation and hematocrite on the occurrence of thrombocytopenia in Tetralogy of Fallot patients. METHOD A case control study was undertaken to TF patients between April 2000 and January The patients, aged from 6 months to 6 years, were those admitted at Outpatient Clinic, Dr Soetomo Hospital. The diagnosis of TF was established on echocardiography. Thrombocytopenia was diagnosed if cell count was between 33,000 and 135,000/mm 3, as examined by cell dynamic. Arterial oxygen saturation was examined by means of pulse oxymetry, and it was considered as lower when it was 90% under room temperature. Sample size for case group (with thrombocytopenia) and control (without thrombocytopenia) was determined by the following formula: Folia Medica Indonesiana 49

2 n = 4.(Z1/2α) p(1-p) W2 p = prevalence of thrombocytopenia in TF; α = 0.05; W = absolute precision level; n = minimal sample size (47) The exclusion criteria used in this study were palliative post-operative patients and patients with severe anatomic abnormality. Statistical analysis employed were multiple logistic regression test to identify the influence of arterial oxygen saturation on thrombocytopenia; correlation analysis to determine severity and presence of correlation between arterial oxygen saturation and thrombocytopenia; Kappa association analysis and McNemar test to determine cut-off point on arterial oxygen saturation and the risk of thrombocytopenic development. RESULTS From 129 patients with Tetralogy of Fallot admitted at the Outpatient Clinic, Dr Soetomo Hospital, in 9 months (from 1 April 2000 to 31 January 2001), 104 were eligible to be enrolled in this study. Table 1. Age and sex distribution of TF patients Age Male Female (months) Total % Total % Total % > > > > > > Total The table above shows that most of the patients are at the age of 60 to 72 years, in which 10 (22.73%) was male and 14 (28%) was female. Table 2. Comparison of age between thrombocytopenic and non-thrombocytopenic groups Age Thrombocytopenia Non-thrombocytopenia (months) Total % Total % Total % > > > > > > Using Mann-Whitney test, analysis on age in thrombocytopenic and non-thrombocytopenic groups revealed that the average age in thrombocytopenic group was months, while that in nonthrombocytopenic group was months, with significant difference of p = Folia Medica Indonesiana 50

3 Table 3. Comparison of sex between thrombocytopenic and non-thrombocytopenic groups Thrombocytopenia Non-thrombocytopenia Sex Total % Total % Total % Male Female Chi-Square test reveals no significant difference in sex between both groups. Table 4. Comparison of arterial oxygen saturation in categorical data between thrombocytopenic and non-thrombocytopenic groups Thrombocytopenia Non-thrombocytopenia SatO2(%) Total % Total % Total % Male Female p = 0.01 (significant) (Chi-Square test) The table shows that in all cases with thrombocytopenia arterial oxygen saturation is at the category of < 60%, while non-thrombocytopenic group mostly falls in the category %. Chi-Square test for quantitative data on arterial oxygen saturation reveals significant difference with p = 0.01 between thrombocytopenic and non-thrombocytopenic group. Table 5. ROC of arterial oxygen saturation Predictive Value SatO2 Sensitivity Specificity + (%) - (%) Kappa test McNemar test (%) (%) (S) (S) (S) (S) (S) (S) (S) (NS) (S) (NS) (S) (NS) (S) (NS) (S) (NS) (S) (NS) (S) (NS) (S) (NS) S = significant, if z > 1.96 or p < 0.05 NS = not-significant, if z < 1.96 or p > Cut-off point is considered valid if the result of Kappa Test was significant, while that of McNemar was not significant. Cut-off point of arterial oxygen saturation was 57%, with sensitivity of 100.0%, specificity was 93.6%, while the positive predictive value 94.0%, and negative predictive value 100.0% with kappa value of , which was significant (z > 1.96). Result of McNemar test was , indicating not significant (p < 0.05). Arterial oxygen saturation examination revealed an average value of % in all patients, while that in thrombocytopenic group was % and in non-thrombocytopenic group was %. The average thrombocyte count in all patients was % cells/mm 3. In thrombocytopenic group it was / Folia Medica Indonesiana 51

4 cells/mm 3 and in non-thrombocytopenic group it was / cells/mm 3. DISCUSSION The decrease of arterial oxygen saturation or hypoxia is commonly found in Tetralogy of Fallot. However, the amount of the decrease is different and it is largely determined by the severity and progressiveness of pulmonary stenosis. The development of thrombocytopenia is likely due to prolonged hypoxia. All of these factors are responsible for the uncertain onset of Tetralogy of Fallot patients aged less than 6 months were not included in this study since iron status in such patients was still subjected to change due to the transitional period from intrauterine life into extrauterine life. Age of six months was used as the limit because collateral circulation to compensate hypoxia has not been established and thrombocytopenia is commonly found in infants at the age of less than 1 month to 3 months (Rowe, 1978). Results in this study showed that thrombocytopenic population mostly belongs to age group of moths, while respondents in non-thrombocytopenic group were mostly between 6-12 months and months (Table 5.2). Comparison of both age groups demonstrated significant difference with average age of months in thrombocytopenic group and months in control group. Above the findings correspond to the results of previous studies, in which it was found that age was related to the progressiveness of infundibulum spasm, and the increase of age is along with the increasing severity of infundibulum hypertrophy of right ventricle and the obstruction of right ventricle outflow as well as the reduction of blood count inflow to the lungs, aggravating the hypoxia. The results of this study also corresponds to the findings of Paul et al, in which thrombocytopenia was often found in patients of more than 1 year old, and those of Gross (1968), where the decrease of thrombocyte count was mostly found in patients above 3 years old. The different of these findings from those of this study was likely to be due to the different in severity of pulmonary stenosis. In patients with severe pulmonary stenosis, thrombocytopenia may manifest at earlier age compared to that in patients with lower degree of pulmonary stenosis. Relative anemia due to iron deficiency, an abnormality presenting as the decrease of erythrocyte deformability may occur, inducing rigidity in erythrocytes, resulting in incapability to pass inside blood vessels with smaller diameter, leading to uneven blood distribution and contributing to the occurrence of rolleaux and elevated blood viscosity, predisposing lysis and followed by ADP release, stimulating the enlargement of thrombocyte aggregation and, finally, resulting in thrombocytopenia (Grifgoleit, 1977). Oxygen saturation in thrombocytopenic group was mostly less than 60%, while that in nonthrombocytopenic group was between 60 and 79.9%. Quantitative data showed significant difference in arterial oxygen saturation between thrombocytopenic group and non-thrombocytopenic group as indicated by the results of Chi Square test comparing two or more independent groups with categorical data (Table 5.6). Analysis using multiple logistic Regression test reveals that oxygen saturation of < 60% significantly influence the development of Analysis of quantitative data showed that arterial oxygen saturation had significant influence on the development of These results correspond to those of previous studies that thrombocyte count was directly correlated to oxygen saturation (Gross, 1968). A study by Phomphutkul et al (1973) demonstrated that TF patients with thrombocytopenia aged more than 4 years were more hypoxic and policytemic compared to control. Using receiver operator characteristic, Kappa test and McNemar test, cut-off point of arterial oxygen saturation was found to be 57% (Kappa and p < 0.05), with sensitivity of 100% and specificity 93.6%, indicating that arterial oxygen saturation below 57% resulted in the risk of thrombocytopenic development. Arterial oxygen saturation had acceptable sensitivity and specificity. In other words, arterial oxygen saturation is reliable to be used as diagnostic tool as well as for screening test in early diagnosis of thrombocytopenia in TF patients. RECOMMENDATIONS To obtain a comprehensive understanding on the interaction of biological activity of chronic hypoxic thrombocytic components, a study should be undertaken on the involvement of thrombocyte biological activity in hypoxic poliycythemia among TF patients. 1. Further studies are warranted in order to complete the data on factors that have been discussed in Folia Medica Indonesiana 52

5 previous studies in relations with the development of thrombocytopenia in TF patients. 2. Regular examination of peripheral blood and arterial oxygen saturation should be undertaken, at least once for 6 months, particularly in TF patients who will have cardiac surgery, either definitive or palliative, in order to obtain early detection of 3. Schedule and dosage of iron administration to the patients in longer period should be monitored closely, and an easy monitoring method should be established, either clinical or laboratory, by examining SI/TIBC at least once for 6 months to be able to make an early detection of the development of hyperviscosity syndrome, which may finally result in thrombocytopenia in TF patients. 4. A study on the mechanism of the decrease of erythrocyte deformability in TF patients is required, since it may stimulate erythrocyte aggregation that may lead to the formation of thrombus, an important factor in the development of REFERENCES Anderson RH, McCarthey FJ, Shinebourne EA, Tunan M, Pediatric Cardiology, Vol 2 Churchill Livingstone, London, pp Athens JW, Polycythemia: Erythrocytosis. In (G Richard Lee, ed) Wintrobe's Clinical Hematology, 9th edition. Philadelphia: Lee and Febiger, pp Baldy CM, Susunan darah dan sistem makrofagmonosit. Dalam (Carolin Wijaya, ed). Patofisiologi konsep klinis proses-proses penyakit. Edisi 4. Jakarta: Penerbit Buku Kedokteran EGC. Hlm 226. Barbara AB, Hematopoesis. In (Barbara AB, ed). Hematology principles and procedures, 3rd edition. Philadelphia: Lea & Febriger, pp Behrman ER, Kliegman RM, Tetralogy of Fallot. In (Berhman ER et al, eds). Nelson Textbook of Pediatrics, 14th edition. Philadelphia: WB Saunders Company, pp Brodsky I, Donald NG, Charles JL, Fibrinolysis in Congenital Heart Disease. Am J Clin Path 51: Corrigan JJ, Coagulation disorders. In: Miller DR, Baehner RL, eds. Blood disease of Infancy and Childhood. 6th ed. St Louis, CV Mosby Co. 878 Dennis LH, James LS, Marcel EC, Heparin treatment of haemorrhagic diasthesis in cyanotic congenital heart disease. Lancet 20: Ebert BL and Bunn HF, Regulation of the Erythropoietin Gene. Blood 94 (15): Ekert H, SV Dowling, Platelet release abnormality and reduced prothrombin levels in children with cyanotic congenital heart disease. Aus Pediatr J 13: Ekkert H, M Sheers, Preoperative and postoperative platelet function in cyanotic congenital heart disease. J Thorac Cardiovasc Surg 67: Ferencz C, Judith DR, Robert JM, Congenital heart disease prevalence at livebirth. Am J Epidemiol 121: Grigoleit HG, H Leonhart, Rheology of blood and pentoxyfilline. Pharmatherapeutica 1: Gross S, Vicki K, Jerome L, The platelet in cyanotic congenital heart disease. Pediatrics 42: Hattaway WE, Scott HG, Bleeding related to congenital heart disease and cardiac surgery. In (Hattaway WE, ed). Disorder of Hemostasis and Thrombosis, a Clinical Guide. 1st edition. New York: McGraw Hill Inc., pp Ihenacho HN, GR Breeze, DJ Fletcher, J Stuart, Consumption coagulopathy in congenital heart disease. Lancet 21: Kaplan K, Brain abscess. Med Clin North Am 68: Karr SS, Joel IB, Christopher L, Catherine AN, Judith DR, Tetralogy of Fallot, the spectrum of severity in a regional study, AJDC 146: Kidd SA, PA L Lancaster, RM McCredie, The incidence of congenital heart defects in the first year of life. J Pediatr Child Health 29: Kontras SB, Joann GB, Jo C, DM Hosier, Hyperviscosity in congenital heart disease. J Pediatr 76: Kothari SS, Mechanism of cyanotic spell in Tetralogy Fallot. The missing link? Int J Cardiol 37:1-5. Maurer HM, Carolyn MM, Joyce C, WJS Shill, Impairment in platelet aggregation in congenital heart disease. Blood 40: Meiselman HJ, EW Meriill, ER Gilliland, GA Pelletier, EW Salzman, Influence of plasma osmolarity on the rheology of human blood. Blood 45: Michael LN, Willoughby MA, Defect of platelet and capillary function. In (Michael LN, eds). Pediatric Haematology, 1st edition. Edinburgh: Churchill Livingstone. pp Folia Medica Indonesiana 53