Outcome of Childhood Acute Lymphoblastic Leukemia Treated Using the Thai National Protocols.

BACKGROUND: In recent decades, the prognosis for childhood leukemia has improved, especially for acute lymphoblastic leukemia (ALL). In Thailand, though, the survival rate for ALL is unimpressive. In 2006, standard national protocols for childhood leukemia treatment were implemented. We herein report the outcome of the ALL national protocols and explanations behind discrepancies in outcomes between institutions. MATERIALS AND METHODS: Between March 2006 and February 2008, 486 children with ALL from 12 institutions were enrolled in the Thai national protocols. There were 3 different protocols based on specific criteria: one each for standard risk, high risk and Burkitt's ALL. We classified participating centers into 4 groups of institutions, namely: medical schools in Bangkok, provincial medical schools, hospitals in Bangkok and provincial hospitals. We also evaluated supportive care, laboratory facilities in participating centers, socioeconomics, and patient compliance. Overall and event-free survival were determined for each group using the Kaplan Meier method. Statistical differences were determined using the log-rank test. Previous outcomes of Thai childhood ALL treatment between 2003 and 2005 served as the historic control. RESULTS: Five-year overall survival of ALL treated using the Thai national protocol was 67.2%; an improvement from the 63.7% of the 12-institute historical control (p-value=0.06). There were discrepancies in event-free survival of ALL between centers in Bangkok and up-country provinces (69.9% vs 51.2%, p-value <0.01). Socioeconomics and patient compliance were key elements in determining the outcome (65.5% vs 47.5%, 59.4% vs 42.9%) (p-value < 0.02). CONCLUSIONS: Implementation of standard national protocols for childhood leukemia in Thailand did not significantly improve the outcome of ALL. Factors leading to better outcomes included (a) improvement of treatment compliance (b) prevention of treatment abandonment and

Childhood cancer incidence and survival 2003-2005, Thailand: study from the Thai Pediatric Oncology Group.

BACKGROUND: Previous population-based incidences of childhood cancer in Thailand were achieved by extrapolating from data limited to a small number of cancer registries, not from the whole country. In addition, survival of childhood cancer patients is often described in specialized hospitals and/or institutions, but not in the general population. METHODS: All children aged 0-15 years who were newly diagnosed as having cancer were registered from 18 treatment centers during 2003-5 and classified into 12 diagnostic groups according to the International Classification of Childhood Cancer. Incidences were calculated by a standard method and survival was investigated using the ThaiPOG (Thai Pediatric Oncology Group) population-based registration data. Overall survival was calculated by the Kaplan Meier method. RESULTS: In the study period (2003-5) 2,792 newly diagnosed cases of childhood cancer were registered, with mean and median ages of 6.5 (SD=0.13) and 5.0 (0-14) years, respectively. The age-peak was between 1 and 4 years and the age-standardized rate (ASR) was 74.9 per million. Leukemia was the most common cancer (N=1421, ASR 38.1) followed by lymphoma (N=266, ASR 6.4) and neoplasms of the central nervous system (CNS, N=246, ASR 6.3). The follow-up duration totaled 101,250 months. The death rate was 1.11 per 100 person-months (95%CI: 1.02 -1.20). The 5-year overall survival was 54.9% (95%CI: 53.0%-56.9%) for all cancers. The respective, 5-year overall survival for (1) acute lymphoblastic leukemia (ALL), (2) acute non-lymphoblastic leukemia (ANLL), (3) lymphoma, (4) retinoblastoma, (5) renal tumors, (6) liver tumors, (7) germ cell tumors, (8) CNS tumors, (9) neuroblastoma, (10) soft tissue tumors and (11) bone tumors were (1) 64.5%, (2) 35.1%, (3) 59.5%, (4) 73.1%, (5) 70.4%, (6) 44.5%, (7) 70.6%, (8) 41.7%, (9) 33.6%, (10) 50.1%, and (11) 33.7%. CONCLUSIONS: The incidence of childhood cancer is lower than in western countries. Respective overall survival for ALL, lymphoma, renal tumors, liver tumors, retinoblastoma, soft tissue tumors is lower than those reported in developed countries while for CNS tumors, neuroblastoma and germ cell tumors the figures are comparable.

Late effects in survivors of childhood acute lymphoblastic leukemia: a study from Thai Pediatric Oncology Group.

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk of long-term late effects. Therefore, systematic screenings of the late complications are essential. The objective of this study was to determine the prevalence of late effects of Thai children and adolescents after completion of ALL therapy. We performed a cross-sectional study for evaluation of the late effects in ALL survivors who came for follow-up at 10 pediatric oncology centers in Thailand. We evaluated the treatment-related late complications of children and adolescents who had finished ALL treatment for at least 2 years. Demographic data, treatment modalities, and late effects were recorded and analyzed. There were 258 survivors with a median age of 12.2 years (range 3.6-23.3 years). The median follow-up time was 7.2 years (range 2-17.5 years). Forty-seven percent (122 cases) suffered from at least one late effect. Overweight/obesity was the most common late effect. Radiation of central nervous system was a significant risk factor for overweight/obesity (OR 1.97, 95% CI 1.02-3.81) and educational problems (OR 4.3, 95% CI 1.32-14.02). Our data have demonstrated a significant prevalence of late effects after childhood ALL therapy. A long-term follow-up program for survivors of childhood cancer is therefore needed in our country.

N-terminal pro brain natriuretic peptide and cardiac function in doxorubicin administered pediatric patients.

OBJECTIVE: Assess the use of N terminal pro brain natriuretic peptide (NT-pro BNP) to early diagnose ventricular dysfunction in doxorubicin-administered children. MATERIAL AND METHOD: Fifty-five cancer patients who received accumulative dose of doxorubicin <300 mg/m2 (group 1), 49 cases with accumulative dose > or = 300 mg/m2 (group 2) and 52 cases as a control group (group 3) were included in the study. Electrocardiogram, chest roentgenogram, echocardiogram, and serum NT-pro BNP were studied. RESULTS: At age 1-10 years, there were significantly higher NT-pro BNP in group 2 than group 1 (384 +/- 291 vs. 92.2 +/- 89 pg/ml; p = 0.001), and than group 3 (79 +/- 92 pg/ml; p = 0.001). Patients with NT-pro BNP level > 1 SD of the control group were more likely to have abnormal > or = 2 echocardiographic parameters of left ventricular diastolic dysfunction than patients with NT-pro BNP < or = 1 SD (OR = 3.8, 95% CI 1.18-12.5). Patients in group 2 were more likely to have abnormal > or = 2 parameters of left ventricular diastolic dysfunction than patients in group 1 (OR = 2.8, 95% CI 1.07-7.7) and more likely to have NT-pro BNP >1 SD than group 1 (OR = 8, 95% CI 1.96-38.4). There were association of NT-pro BNP > 1 SD, accumulative dose of doxorubicin > or = 300 mg/m2, and early left ventricular diastolic dysfunction by echocardiogram. CONCLUSION: Serum NT-pro BNP > 1 SD has a high probability to diagnose early doxorubicin-induced cardiomyopathy in patient 1-10 years old.

Development of a comprehensive red blood cell enzymopathy laboratory in Thailand: the study of normal activity in eight erythroenzymes in Thais.

In order to provide a reference range for normal red blood cell enzyme activities in Thai, we analyzed data from 113 healthy non-anemic Thai people (55 males and 58 females) age 1-42 years, who all had a normal pattern of hemoglobin typing (HbA and HbA2 less than 3.5%). Hematological analysis was performed using an automated cell counter and the hemoglobin studies were carried out by low pressure liquid chromatography. Owing to a high frequency of alpha-thalassemia in Thailand, cases with an MCV < 75 fl were excluded from the study since these cases were likely to be heterozygotes for alpha0-thalassemia. Cases with reticulocytes > 2.5% were excluded from the study since reticulocytes have a higher enzyme activity than mature erythrocytes. Cases with abnormal red blood cell morphology, such as spherocytes and ovalocytes, were also excluded. These criteria were applied to select "normal" controls for our analysis. We assayed eight red blood cell enzyme activities in normal subjects: glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), pyruvate kinase (PK), hexokinase (HK), glucose phosphate isomerase (GPI), phosphofructokinase (PFK), aldolase (ALD) and phosphoglycerate kinase (PGK). The mean normal ranges (+/- SD) for G6PD, 6PGD, PK, HK, GPI, PFK, ALD and PGK were 12.7 (+/-2.2), 10.7 (+/-1.3), 18.5 (+/-4.0), 1.5 (+/-0.4), 80.5 (+/-11.8), 11.8 (+/-2.1), 4.5 (+/-1.6) and 370 (+/-43) IU/gHb, respectively. Age-dependent differences for the reference values for these enzyme activities were summarized. All red blood cell enzyme activities were highest during the early childhood period and slightly lower in the adult period. These values will be of clinically useful for future reference.

Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor?

PURPOSE: To describe a series of patients with secondary acute myelogenous leukemia (sAML) and retinoblastoma (RB). DESIGN: Retrospective observational cases series. PARTICIPANTS: Ocular and pediatric oncologists at referral centers in Europe and the Americas and the RB databases at the National Institutes of Health and the Ophthalmic Oncology Service at Memorial Sloan-Kettering Cancer Center. METHODS: Physician survey, retrospective database review, and literature search. MAIN OUTCOME MEASURES: History of RB and development of sAML, management of RB (surgery, radiotherapy, chemotherapy), age at diagnosis of RB and leukemia, French-American-British (FAB) subtype, and current status of patient (alive or dead). RESULTS: Fifteen patients with sAML were identified; 13 occurred in childhood. Mean latent period from RB to AML diagnosis was 9.8 years (median, 42 months). Nine cases were of the M2 or M5 FAB subtypes. Twelve patients (79 %) had received chemotherapy with a topoisomerase II inhibitor, 8 (43%) had received chemotherapy with an epipodophyllotoxin. Ten children died of their leukemia. CONCLUSIONS: Acute myelogenous leukemia is a rare secondary malignancy among retinoblastoma patients, many of whom were treated with primary or adjuvant chemotherapy. Additional studies are needed to assess potential risk factors contributing to sAML development in this cohort.

Hospital-based epidemiologic survey of malignancies in children infected with human immunodeficiency virus in Thailand.

To determine the incidence and spectrum of malignancies in human immunodeficiency virus-infected children, we surveyed 48 hospitals in Thailand between 1996 and 2000. There were 23 children (14 boys and 9 girls; average age at diagnosis of malignancy, 4.2 years), and the incidence rate was 0.6 per 1000 person-years. The most common malignancy was lymphoma (87.0%). The prognosis was poor.

Clinical phenotypes and molecular diagnosis in a hitherto interaction of Hb E/beta thalassemia syndrome (beta(E)/beta(-31), (A -->G)).

Molecular identification of affected alleles in the index family with rare mutation(s) and/or interaction(s) is an important prerequisite toward a proper genetic counseling. In Thailand, where more than 30% of the populations are heterozygotes for either alpha or beta thalassemia mutation(s). More than 60 different thalassemia syndromes resulting from the interactions of these heterogeneous alleles have been observed. The majority of patients in the hospital based-study are compound heterozygotes for beta thalassemia alleles and another hemoglobinopathy namely Hb E, highly prevalent in Thailand, gave rise to Hb E/beta thalassemia syndrome. The phenotypes of these syndromes vary from asymptomatic individual to a very severe phenotype mimic that of beta thalassemia major. In this report, we describe a three-year-old Thai girl presenting with mild hypochromic microcytic anemia since birth. She was born prematurely and developed anemia within the first week of life. The cause of anemia was suspected to result from prematurity and low intrauterine iron storage, however hypochromic anemia did not resolve after a three-month of iron supplement therapy. Subsequent studies indicated that the patient had Hb E/beta thalassemia disease and the molecular study revealed that the patient was a compound heterozygote for Hb E and a rare beta thalassemia mutation (beta(-31), A --> G). This hitherto genotype results in a relatively mild clinical symptom since the patient's baseline Hb values were around 9-10 g/dL with normal weight and height development during the follow-up period.

Dengue hemorrhagic fever in patients with thalassemia.

Dengue hemorrhagic fever (DHF) causing by dengue viral infection is endemic in Thailand and Southeast Asian countries where thalassemias are prevalent. Thalassemic patients are also at risk to acquire dengue viral infections and to develop DHF. However, they can have different clinical manifestations and complications as well as more severity than general population requiring special awareness for proper diagnosis and management. We reported 20 thalassemic patients (10 boys and 10 girls) with DHF admitted to Department of Pediatrics, Siriraj Hospital during 1977 to 2001. Their ages ranged from 2-16 years (average 9.5 years). These cases included 5 cases of Hb H disease, 5 cases of Hb H with Hb Constant Spring (CS), 9 cases of beta-thalassemia/Hb E disease and 1 case of beta-thalassemia major. Two cases were in Grade I, 10 cases in grade II, 7 cases in Grade III and one case in grade IV severity of DHF. Though there were evidences of plasma leakage, instead of hemoconcentration, eighteen patients (90 percent) had hematocrit dropped at the range of 11-66% of the initial level. Fifteen patients (75 percent) required at least one packed red cell transfusion. Nine patients (45 percent) had mild bleeding symptoms, one of them had upper gastrointestinal hemorrhage requiring platelet concentrate transfusion. Two patients (10 percent) had serious complications including one with infection-associated hemophagocytic syndrome (IAHS) requiring intravenous immunoglobulin (IVIG) and packed red cell transfusion and the other had generalized seizure due to hyponatremia and hypotension. No mortality was observed among this group of patients. Early recognition of the DHF in thalassemic patients and appropriate packed red cell transfusion in patients with anemic symptoms is warranted to reduce morbidity and mortality in these patients.

Hematological parameters and red blood cell indices in healthy Thai children: a revision for 2005.

In order to provide a reference range for hematological parameters and red blood cells indices in Thai children, we analyzed data from 395 healthy non-anemic Thai children age from 1-16 years old, who all had normal pattern of hemoglobin typing (Hb A and Hb A2 less than 3.5%). Hematological analysis was performed using an automated cell counter and the hemoglobin studies were carried out by electrophoresis and liquid chromatography. Owing to a high frequency of a thalassemia in Thailand, cases with MCV < 75 fL has been excluded from the study since these cases were likely to be heterozygotes for alpha0 thalassemia. These criterions were applied to select so-called 'normal' controls for our analysis. Relatively mild microcytosis and hypochromia were observed, in particular in the first three years of age, suggesting an intrinsic immature nature of erythropiesis in the children. Age-dependent differences in the reference values for white blood cell (WBC) count and differential and platelet count were observed. Herein the hematological data and red blood cell indices were summarized according to ages and these will be of clinically useful for the future reference.

Evaluation of guideline for treatment of febrile neutropenia in pediatric cancer at Siriraj Hospital.

BACKGROUND: Febrile neutropenia (FN) is a common and important clinical problem in pediatric cancer. Our Institution has developed a clinical practice guideline (CPG) for treatment of FN to assist the clinicians taking care of these patients. OBJECTIVE: To evaluate characteristics of FN, sources and causative agents of infection, applicability and effectiveness of the CPG, and factors that associated with response to treatment. MATERIALS AND METHODS: The medical records of patients with FN that had completed data from September, 2003 to May, 2005 were reviewed and analysed. RESULTS: A total of 148 FN episodes in 90 patients were analysed. The predominant underlying malignancy was acute leukemia. About 50% had absolute neutrophil count (ANC) less than 100 cells/mm3 at the beginning and at reassesment on day 3 of treatment. The causes of infection with microbiological confirmation was 25%. Urinary tract infection was the predominant source of infection and gram negative bacteria was the predominant causative agent. Sixty-two percents responded to initial treatment without changing of antibiotics. Of all episodes, 91.2% were able to complete treatment according to the CPG. The mortality rate was 1.4%. ANC of less than 100 cell/mm3 on day 3 of treatment was the significant risk factor for prolonged duration of fever and unresponsiveness to low risk regimen of antibiotics. ANC of less than 100 cell/mm3 on day 3, having hematologic malignancies, and recurrent fever were associated risks for the need for antifungal agent or referral to infectious diseases specialist or death. The pretreatment ANC more than 100 cells/mm3 was a significant predictor for the responsiveness to low risk regimen without recurrent fever. CONCLUSION: Our CPG could practically be applied in FN patients and resulted in low mortality rate.

Co-inheritance of Hb Pak Num Po, a novel alpha1 gene mutation, and alpha0 thalassemia associated with transfusion-dependent Hb H disease.

Hb H disease is generally associated with moderate to severe anemia but rarely requires regular blood transfusion. We recently studied two apparently unrelated patients with transfusion-dependent Hb H disease. Hemoglobin studies demonstrated Hb H and Hb Bart's without other detectable abnormal globin species. Extensive molecular analyses of the alpha globin genes and their regulatory sequence (HS-40) revealed that both patients are compound heterozygotes for alpha0 thalassemia (--(SEA)) and a novel point mutation, a thymidine insertion after codon 131 of the alpha1 gene. The resulting frameshift gives rise to a highly unstable alpha globin chain, which we refer to as "Hb Pak Num Po," containing an additional 34 amino acids. This unusual alpha1 globin variant clearly causes alpha thalassemia, but the unexpectedly severe phenotype suggests that this mutation may have additional effects on red cell physiology. A PCR-based (ARMS) assay was developed for rapid detection of this novel mutation, and this might be useful to study the prevalence of this novel mutation which poses potentially significant clinical consequences in populations of Southeast Asia. Detecting carriers of this mutation using the molecular diagnostic procedures described will provide the means to screen and prevent a potentially severe form of alpha thalassemia in Thailand.

Acute haemolytic crisis in a Thai patient with homozygous haemoglobin Constant Spring (Hb CS/CS): a case report.

Acute haemolysis associated with mild upper respiratory tract infection was observed in a Thai boy who presented with a rapid decline in haemoglobin (Hb) levels, haemoglobinuria and evidence of intravascular haemolysis. Several possible causes giving rise to such a condition were excluded including G6PD deficiency, which is extremely common in Thailand. Subsequent haematological and molecular analyses demonstrated that the patient was homozygous for Hb Constant Spring (Hb CS/CS), an a globin haemoglobinopathy. It has been shown previously that patients with homozygous Hb CS had mild haemolytic anaemia secondary to an accumulation of alpha(CS) chains, which are toxic to red blood cell membrane cytoskeletons. Increased body temperature might induce more precipitation of this a globin variant. This report highlights the importance of Hb CS/CS as a potential predisposing cause of acute haemolysis in children that might be aggravated by acute bacterial or viral infections. This is particularly relevant for patients of Southeast Asian descent where this abnormal haemoglobin is highly prevalent.

Homozygous hemoglobin Tak causes symptomatic secondary polycythemia in a Thai boy.

Secondary polycythemia caused by high-oxygen-affinity hemoglobin is rare in children. Most patients with this condition have asymptomatic erythrocytosis. In this article the authors describe a young boy from Thailand with plethora, hypoxemia, and aggravated respiratory distress following a chest infection. Hematological and molecular studies revealed that the boy is homozygous for Hb Tak, an extended beta-globin variant with high oxygen affinity. This report of a patient who is homozygous for high-oxygen-affinity hemoglobin highlights the clinical significance of this hemoglobin disorder, which has been previously reported in several unrelated families from Southeast Asia.

Carrier detection by DNA linkage analysis in eighty Thai hemophilia A families.

DNA linkage analysis was performed in Thai hemophilia A families to evaluate its value for carrier detection. Both intragenic and extragenic polymorphic DNA regions of the factor VIII gene, including Bcl I-RFLP in intron 18, microsatellites (CA repeats) in introns 13 and 22, and extragenic Stl4 (DXS 52) VNTR, were amplified by polymerase chain reaction (PCR) before analyses by appropriate electrophoretic procedures. A total of 80 Thai hemophilia A families (48 with a family history and 32 with a sporadic case), containing 349 DNA samples from 90 hemophilia A patients, 143 parents, and 116 relatives, were analyzed. Heterozygosities in the patients' mothers from both families with a family history and with a sporadic case were observed in 71 out of 80 families (88.75%) for all polymorphic DNA markers analyzed. The carrier status could be identified in 36 females and excluded in 44 females. This result indicates that the DNA linkage analysis can be used for carrier detection or exclusion in the majority of Thai hemophilia A families. It should also be useful for prenatal diagnosis in families at risk of hemophilia A, which is part of the prevention and control of this disease.

Malignancies in HIV-infected children at Siriraj Hospital.

BACKGROUND: Some malignancies such as Kaposi's sarcoma, non-Hodgkin's lymphoma (NHL) are one of the acquired immunodeficiency syndrome (AIDS)-defining illnesses. With the improving survival of patients with AIDS due to better prevention and treatment of infectious complications, there may well be an increase in AIDS-related malignancies. OBJECTIVE: To study malignancies in human immunodeficiency virus (HIV)-infected children in view of demographic data, HIV disease status, characters of malignancies, and treatment outcome. METHOD: Retrospective study was performed in HIV-infected children with malignancies at Siriraj Hospital from January 1995 to October 2001. RESULTS: During the 6 year and 10 month period, there were 7 HIV-infected children (2 boys, 5 girls) with malignancies. Mean age at diagnosis of malignancies was 3 years 7 months (2 years 6 months-5 years). Hepatomegaly and lymphadenopathy were the most common presenting symptoms. All patients had NHL stage III or IV. Burkitt's lymphoma was the predominant type. Six patients were treated with appropriate chemotherapy and one patient also received antiretroviral therapy. Only one patient with large cell lymphoma stage IV who received both antiretroviral and chemotherapy has survived to date. Five patients died during chemotherapy treatment and one patient died before receiving chemotherapy. Causes of death of these patients were infections. One of them with Burkitt's lymphoma stage III also had central nervous system (CNS) relapse at the time of death. Mean survival time after diagnosis with malignancies was 11 months (15 days-3 years 1 month). CONCLUSION: NHL is the most common malignancy in HIV-infected children at Siriraj Hospital. Age at presentation of NHL in these children is younger than their non-HIV counterpart. Outcome of treatment is poor. Adjustment protocol for treatment of malignancy in HIV-infected children combined with antiretroviral therapy for controlling HIV infection should be studied further.

Secondary hemophagocytic lymphohistiocytosis in children: an analysis of etiology and outcome.

UNLABELLED: Fifty-two pediatric patients were diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) at the Department of Pediatrics, Siriraj Hospital between 1989 and 1998. Of these, 15 were infection-associated (IAHS), 25 were malignancy-associated (MAHS) and 12 were idiopathic HLH. Causative organisms for IAHS were Salmonella (3), Staphylococcus (2), enterobactor (2), dengue virus (3), malaria (2) and one each of Ebstein Barr virus (EBV), Serratia marcesens and Penicillium maneffei. Unlike those reported in adults and in the Western literature, 47 of 52 children in the present series were immunocompetent hosts. In addition, the proportion of MAHS was higher than expected (48.1%). Twenty-two of 25 MAHS presented with hemophagocytic syndrome and were subsequently found to have malignant diseases. Sixty per cent of MAHS (15 cases) were associated with non-Hodgkin's lymphoma (NHL), mainly T-cell. Other malignancies included acute leukemias (7) MDS (1), Langerhans cell histiocytosis (1) and histiocytic sarcoma (1). Treatment approaches were specific therapy for individuals with known causes. Supportive treatment with blood components transfusions, steroid, intravenous immunoglobulins (IVIG), and chemotherapeutic agents, mainly vinblastine and etoposides, were used in indicated cases. Of the 52 cases, 15 (28.8%) had a fatal outcome during the acute phase, and other 4 died of their subsequent malignant diseases. There was a statistically significant association between poorer prognosis and patients' age < 3 years (p= 0.004) or MAHS (p=0.005). CONCLUSION: Secondary HLH is not uncommon in Thai children who are immunocompetent. Malignancies, particulary NHL, are highly suspicious especially for cases not responsive to conventional therapy. Poor prognostic factors are age less than 3 years and MAHS.

Thrombotic complications during induction chemotherapy of acute childhood lymphoblastic leukemia.

The incidence of thrombosis during induction chemotherapy of acute childhood lymphoblastic leukemia (ALL) patients was 6 found to be in 105 (5.7%). There were 4 cerebral infarctions, 1 superior vena cava (SVC) obstruction and 1 deep vein thrombosis. Among these, 2 of them died. A prospective study was further conducted of the change in coagulation and anticoagulation factors during 6 weeks of induction chemotherapy. It was found that the activated partial thromboplastin time (aPTT) was within normal range in all cases throughout 6 weeks, while prothrombin time (PT) and thrombin time (TT) were slightly prolonged, especially during the first 3 weeks of this phase. The natural anticoagulant panels which included protein C (PC), protein S (PS) and antithrombin III (AT III) and also fibrinogen level, were lower during the first 3 weeks and reached its nadir during the second and third week. The lower level of natural anticoagulants might be an important predisposing factor for the occurrence of thrombosis in these patients.