Familial Hemophagocytic Lymphohistiocytosis Screening in Neonatal Sepsis.

OBJECTIVE: Neonatal sepsis and familial hemophagocytic lymphohistiocytosis (fHLH) have similar clinical and laboratory symptoms and the possibility of overlooking fHLH diagnosis is high in newborns with sepsis. History of consanguineous marriage and/or sibling death, hepatomegaly/splenomegaly, and hyperferritinemia (>500 ng/mL) are likely to support fHLH in newborns with sepsis. Therefore, in newborns with sepsis in whom at least 2 of these 3 criteria were detected, genetic variants was investigated for the definitive diagnosed of fHLH. According to the results of genetic examination, we investigated whether these criteria supporting fHLH could be used as a screening test in fHLH. MATERIALS AND METHODS: fHLH-associated genetic variants were investigated in 22 patients diagnosed with neonatal sepsis who fulfilled at least 2 of the following criteria (1) history of consanguineous marriage and/or sibling death, (2) hepatomegaly/splenomegaly, and (3) hyperferritinemia (>500 ng/mL). RESULTS: Heterozygous variants were determined in 6 patients (27.2%): 3 STXBP2 , 1 STX11 , 1 UNC13D , and 1 PRF1 . Polymorphisms associated with the clinical symptoms and signs of HLH were determined in 5 patients (22.7%): 4 UNC13D , 1 PRF1 . Two patients were in the heterozygous variants and polymorphism associated with the clinical symptoms and signs of HLH groups. In 12 patients, benign polymorphisms were detected in STXBP2 and UNC13D genes. No change in fHLH associated genes were found in 1 patient. CONCLUSION: Some variants and/or polymorphisms identified in our patients have been previously reported in patients with HLH. Therefore, we recommend further investigation of fHLH in patients with neonatal sepsis who fulfill at least 2 of the above 3 criteria.

Prognosis of Second Primary Malignancies in Pediatric Acute Lymphoblastic Leukemia Survivors: A Multicenter Study by the Turkish Pediatric Hematology Society.

The improved survival rates of childhood cancers raise the long-term risk of second primary malignancy (SPM) in childhood and adolescent cancer survivors. The intensity of the treatment protocol used, the use of some groups of chemotherapeutics, and radiotherapy were found to be risk factors for the development of second primary malignancies (SPMs). Forty-one patients who developed acute myelocytic leukemia or any solid organ cancer within 25 years of follow-up, after completion of pediatric acute lymphoblastic leukemia (ALL) treatment, were included in the study. The mean duration of initial ALL diagnosis to SPM was 9.3 ± 6.1 years. The 3 most common SPMs were acute myelocytic leukemia, glial tumors, and thyroid cancer. Thirteen (81%) of 16 patients exposed to cranial irradiation had cancer related to the radiation field. In total 13/41 (32%) patients died, and the 5-year overall survival rate was 70 ± 8%. Patients older than 5 years old at ALL diagnosis had significantly worse overall survival than cases younger than 5 years old. In conclusion, children and adolescents who survive ALL have an increased risk of developing SPM compared with healthy populations, and physicians following these patients should screen for SPMs at regular intervals.

Central nervous system thrombosis in pediatric acute lymphoblastic leukemia in Turkey: A multicenter study.

BACKGROUND: In patients with acute lymphoblastic leukemia (ALL), the risk of thromboembolism increases due to hemostatic changes secondary to the primary disease and due to treatment-related factors. In this multicenter study, we aimed to research the frequency of central nervous system (CNS) thrombosis occurring during treatment, hereditary and acquired risk factors, clinical and laboratory features of patients with thrombosis, treatment approaches, and thrombosis-related mortality and morbidity rates in pediatric ALL patients. PROCEDURE: Pediatric patients who developed CNS thrombosis during ALL treatment from 2010 to 2021 were analyzed retrospectively in 25 different Pediatric Hematology Oncology centers in Türkiye. The demographic characteristics of the patients, symptoms associated with thrombosis, the stage of the leukemia treatment during thrombosis, the anticoagulant therapy applied for thrombosis, and the final status of the patients recorded through electronic medical records were determined. RESULTS: Data from 70 patients with CNS thrombosis during treatment, out of 3968 pediatric patients with ALL, were reviewed. The incidence of CNS thrombosis was 1.8% (venous: 1.5 %; arterial: 0.03%). Among patients with CNS thrombosis, 47 had the event in the first 2 months. Low molecular weight heparin (LMWH) was the most commonly used treatment with a median of 6 months (min-max: 3-28 months). No treatment-related complications occurred. Chronic thrombosis findings occurred in four patients (6%). In five (7%) patients who developed cerebral vein thrombosis, neurological sequelae (epilepsy and neurological deficit) remained. One patient died related to thrombosis, and the mortality rate was 1.4%. CONCLUSION: Cerebral venous thrombosis and, less frequently, cerebral arterial thrombosis may develop in patients with ALL. The incidence of CNS thrombosis is higher during induction therapy than during other courses of treatment. Therefore, patients receiving induction therapy should be monitored carefully for clinical findings suggestive of CNS thrombosis.

Familial Hemophagocytic Lymphohistiocytosis With Heterozygous STX11 and Homozygous UNC13D Mutations Diagnosed in the Neonatal Period.

Patients with primary hemophagocytic lymphohistiocytosis may present with different mutations and phenotypic findings. It is usually presented as case reports because of its rare occurrence. Here, we discuss a case diagnosed with familial hemophagocytic lymphohistiocytosis 3, that presented in the neonatal period and was detected to have homozygous UNC13D and heterozygous STX11 mutations.

Central Nervous System Fungal Infections in Children With Leukemia and Undergoing Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study.

BACKGROUND: Central nervous system fungal infections (CNSFI) are seen in patients with hematologic malignancies and have high morbidity and mortality. Because of their rarity, there is limited data on CNSFI in children with no established treatment protocols or guidelines. MATERIALS AND METHODS: In this multicenter retrospective study, 51 pediatric patients with leukemia, 6 of whom had undergone bone marrow transplantation, with proven or probable CNSFI were evaluated. Fungal infections were defined as proven or probable based on European Organisation for Research and Treatment of Cancer criteria. Proven CNSFI was diagnosed by appropriate central nervous system (CNS) imaging or tissue sample findings in combination with positive microbiological results of cerebrospinal fluid. A positive culture, microscopic evidence of hyphae, a positive result of the galactomannan assays are defined as positive microbiological evidence. Probable CNSFI was defined as appropriate CNS imaging findings together with proven or probable invasive fungal infections at another focus without CNS when there is no other explanatory condition. Data was collected by using the questionnaire form (Supplemental Digital Content 1, http://links.lww.com/JPHO/A541 ). RESULTS: Seventeen patients had proven, 34 patients had probable CNSFI. Headaches and seizures were the most common clinical findings. The median time between the onset of fever and diagnosis was 5 days. The most common fungal agent identified was Aspergillus . Sixteen patients received single-agent, 35 received combination antifungal therapy. Surgery was performed in 23 patients. Twenty-two patients (43%) died, 29 of the CNSFI episodes recovered with a 20% neurological sequelae. CONCLUSION: CNSFIs should be considered in the differential diagnosis in patients with leukemia and refractory/recurrent fever, headache, neurologicalocular symptoms, and a radiologic-serological evaluation should be performed immediately. Early diagnosis and prompt management, both medical and surgical, are essential for improving clinical outcomes.

Posterior Reversible Encephalopathy Syndrome in Childhood Hematological/Oncological Diseases: Multicenter Results.

The aim of the study was to analyze the characteristics of posterior reversible encephalopathy syndrome (PRES) cases treated at 10 different institutions in our country. Fifty-eight patients diagnosed with PRES were included in this study. The data of PRES cases from 10 departments of pediatric hematology/oncology were analyzed. The mean age of the patients at the time of diagnosis of PRES was 8.95±3.66 years. Most patients (80.4%) had a primary diagnosis of acute leukemia. Patients received chemotherapy (71.4%) and/or used steroids within 14 days before the diagnosis of PRES (85.7%). Hypertension was found in 83.9% of the patients. Twenty-six patients had infections and 22 of them had febrile neutropenia. The most common electrolyte disorders were hypocalcemia, hypomagnesemia, and hypopotassemia. Six patients had tumor lysis syndrome and 4 had inappropriate antidiuretic hormone syndrome. Magnetic resonance imaging was used for diagnosis in all patients. The most commonly involved regions by magnetic resonance imaging were occipital (58%), parietal (51%), and frontal lobes (45%), respectively. Twenty-five patients required intensive care and 7 patients were intubated. In conclusion, PRES may develop during the follow-up and treatment of hematological diseases. In addition to steroid and intense combined chemotherapies, immunosuppressive agents and hypertension are also factors that may be responsible for PRES.

Chemotherapy-related fever or infection fever?

BACKGROUND: The present study investigates the reason for the onset of fever after chemotherapy (CT) for cancer with the aim of reducing unnecessary medical care. METHODS: A total of 37 consecutive cycles of CT for cancer were analyzed retrospectively from the files of patients. Fever was defined as a temperature of ≥ 38 °C lasting for 1 h. RESULTS: The study sample included 23 males and 14 females (aged 8.43 ± 5.04 [min-max]). Fever was observed in all 37 cycles of chemotherapy agent (CA), which included cytarabine (ARA-C), dacarbazine, cyclophosphamide, irinotecan, adriamycin, etoposide, ifosfamide, cisplatin, and methotrexate. Fever was recorded within the first 12 h following treatment with ARA-C (45.9%), dacarbazine (16.2%), or cyclophosphamide (8.1%). A physical examination of the patients yielded normal results, C-reactive protein (CRP) and procalcitonin (PCT) values were within the normal range, the median absolute neutrophil count (ANC) was 3200/uL (0.00-16.340/uL), and a median sedimentation (ESR) level of 10 mm/h (2-59) was determined. All fevers were accepted as having resulted from CT based on the above criteria. Paracetamol and diphenhydramine were administered and the patients' treatments were continued. CONCLUSION: Febrile episodes occurring within the first 6 h following treatment were considered to constitute an adverse drug reaction after CT for the treatment of cancer. While ARA-C fever has been previously reported on in the literature, it should be kept in mind that CT fever can be seen with different CA. Physicians should be aware of this aspect of chemotherapy-associated fever and avoid unnecessary examinations and treatments, including antibiotics.

Systemic Amyloidosis in a Patient With Familial Mediterranean Fever and Hodgkin Lymphoma: A Case Report.

Systemic amyloidosis is a clinical manifestation of the accumulation of amyloid fibrils in tissues because of persistent acute phase elevation and chronic inflammation. Its most common causes are inflammatory diseases and malignancies. Here, we present a 12-year-old girl diagnosed with systemic amyloidosis and Hodgkin lymphoma (HL) who was also previously diagnosed with familial Mediterranean fever (FMF). Despite colchicine treatment for FMF, the patient had a persistent elevation of acute phase reactants and AA-type amyloid deposits were observed in a kidney biopsy. Anakinra, an interleukin-1 antagonist, was added to the treatment. Shortly after the diagnosis of amyloidosis, mediastinal lymphadenopathy was recognized, and she was also diagnosed with HL. A chemotherapy protocol of doxorubicin, bleomycin, vinblastine, and dacarbazine was initiated. After 6 cycles of the chemotherapy and 8 months of the anakinra treatment, no recurrence or residual malignancy was observed and proteinuria was decreased. To the authors' knowledge, this is the first reported case of systemic amyloidosis in the literature associated with both FMF and HL.

Bladder Artery Embolization for Massive Hematuria Treatment in a Patient With Ataxia-Telangiectasia Acute Lymphoblastic Leukemia.

Ataxia-telangiectasia (AT) is a hereditary recessive autosomal disorder following a course of progressive cerebellar ataxia, and oculocutaneous telangiectasia. Disease-specific telangiectasias are generally localized in the oculocutaneous region, while telangiectasias located within the bladder are rarely seen in patients with AT. The patient who had been followed-up with a diagnosis of AT since the age of 3 years was later diagnosed with acute lymphoblastic leukemia at the age of 8 years. The patient developed hematuria approximately in the 29th month of treatment. The cystoscopy revealed regions of extensive hemorrhagic telangiectasis, which was interpreted as the bladder involvement of AT. The case presented here underwent several cycles of intravesical steroid and tranexamic acid treatments and intravesical cauterization procedures, but the patient was unresponsive to all medical treatment approaches. The patient was consequently evaluated by an interventional radiology unit for a selective arterial embolization. The patient's hematuria resolved after embolization. Bladder wall telangiectasia may, on rare occasions, develop in patients with AT, and can result in life-threatening hemorrhages. We also suggest that a selective arterial embolectomy can be safely carried out in pediatric patients with treatment-resistant intravesical bleeding.

Constitutional Mismatch Repair Gene Defect Syndrome Presenting With Adenomatous Polyposis and Cafe au Lait Spots: A Case Report.

INTRODUCTION: Adenomatous polyps in the gastrointestinal system rarely occur in childhood and are accompanied by syndromes such as Familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis, Gardner and Turcot syndrome, and also mismatch repair (MMR) gene defects. In this article, we want to present a rare patient who had adenomatous polyposis and in situ carcinoma and was detected biallelic MMR gene defect. CASE: A 16-year-old female patient admitted with painless rectal bleeding, chronic abdominal pain, and anorexia for 1 year. Her physical examination was notable for multiple cafe au lait spots. The colonoscopic and histopathologic examination revealed multiple adenomatous polyps that one of them contains low-high grade dysplasia and in situ carsinoma. Genetic analysis revealed a homozygous mutation in the PMS2 gene [c.1164delT (p.H388Qfs*10) (p.His388GInfsTer10)] and she was diagnosed with constitutional MMR gene defect syndrome. Polypectomy was performed 4 times in 2 years period. Then, the patient's last colonoscopic examination revealed a large broad polyp in the rectum and multiple polyps in the other colon segments, and she underwent colectomy because of high risk of colorectal cancer. CONCLUSIONS: Adenomatous polyps are very important in childhood because of rarity. In particular, the presence of cafe au lait spots and a history of malignancy detected in relatives at an early age must be considered for CMMRD.

Structural Characteristics in the γ Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism.

Particular fibrinogen γ chain mutations occurring in the γ-module induce changes that hamper γ-γ dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen γ chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the γ chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen γ chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen γ chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (ΔΔG) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other γ-module mutations causing HHHS.

A Case of ALL Developing Posterior Reversible Encephalopathy Secondary to Hyponatremia.

Posterior reversible encephalopathy syndrome (PRES), may be due to different causes. It may develop secondary to hypertension, renal decompensation, electrolyte imbalance, and chemotherapeutic drugs. We describe a case of acute lymphoblastic leukemia in which PRES developed secondary to hyponatremia despite being normotensive during receipt of chemotherapy. Magnetic resonance imaging findings were suggestive of PRES. Partial diffusion restriction was observed in lesions in the bilateral occipitoparietal regions and the cerebellum. The patient was treated with appropriate medications with the resolution of his stroke-like symptoms. No neurological deficit was observed and clinical condition improved. The patient continued with chemotherapy. Early diagnosis and treatment of this syndrome is important in terms of preventing neurological sequelae. Cases of secondary PRES developing for several etiological reasons have been reported in induction therapy, but no pediatric cases of PRES developing secondary to hyponatremia despite being normotensive while receiving chemotherapy in acute lymphoblastic leukemia have previously been reported.

Positive correlation between insulin resistance and iron overload-induced oxidative stress in patients with fanconi anemia (FA)- and non-FA-related bone marrow failure: The results of a multicenter study.

This study investigated the relationship between DNA, protein, and lipid oxidations and insulin resistance in patients with Fanconi anemia (FA)- and non-FA-related bone marrow failure. Sixteen patients with FA, 7 non-FA-related aplastic anemia, and 10 controls were included in the study. Fasting blood glucose, simultaneous insulin, hepcidin, ferritin, 8-hydroxy deoxyguanosine (8-OHdG), protein carbonyls, malondialdehyde (MDA), and homeostatic model assessment-insulin resistance (HOMA-IR) were investigated in the patients and controls. Diepoxybutane test-positive (DEB+) patients were diagnosed with FA, whereas DEB-patients were diagnosed as non-FA. 8-OHdG levels in both FA and non-FA patients were significantly higher than those in the controls (P = .001 and P = .005, respectively). Serum ferritin levels were also higher in FA and non-FA patients than in the controls (P = .0001 and P = .005, respectively). Insulin resistance (IR) was significantly higher in FA patients than in non-FA patients and controls (P = .005 and P = .015, respectively). Significant differences were observed between 8-OHdG, ferritin, and MDA levels in patients with or without IR (P = .009, P = .001, and P = .013, respectively). Moderate and strong relations of 44% and 85% were determined between IR and ferritin levels in patients with FA or non-FA (P = .08 and P = .014, respectively). FA and non-FA patients exhibited a tendency to IR. IR was related to ferritin levels, and ferritin levels were also correlated with oxidative stress. These findings suggest that the increased rate of IR in patients with FA and non-FA may derive from increased oxidative stress, which may in turn be due to elevated serum ferritin levels.

Oral vitamin B12 treatment is effective for children with nutritional vitamin B12 deficiency.

AIM: Despite being one of common preventable deficiency disorders, vitamin B12 (vit-B12) deficiency can lead to serious health problems both in children and adult. The familiar treatment through parenteral route for vit-B12 deficiency frequently leads to poor adherence, and adequate response to treatment has lead to interest in oral supplementation. This study investigates the efficacy of oral vit-B12 treatment in children with nutritional vit-B12 deficiency. METHODS: Forty-seven children (from 1 month to 17 years) with vit-B12 levels below 200 pg/mL were allocated either of two study groups: Group 1 (1-20 months) and Group 2 (6-17 years) which were subdivided according to the duration of treatment (Group 1A&2A: 4 months; Group 1B&2B: 8 months of 1000 µg oral vit-B12, every day for a week, every other day for 2 weeks, 2 days a week for 2 weeks, then once a week). RESULTS: Vit-B12 levels among all groups were significantly restored following high oral vit-B12 doses (P = 0.013, P = 0.001), the regimen being more effective in Group1A and Group1B. Correlation analysis of serum vit-B12 levels and age at the end of treatment revealed a decreasing trend with the increasing patient age (corelation respectively -65.2%, P = 0.08; -35.4%; P = 0.25). CONCLUSION: Data from this study indicate that oral vit-B12 (1000 µg) for 4 months is effective, giving clinicians more choice, for treatment of children with nutritional vit-B12 deficiency. However, despite this high dose, lower levels were achieved in older children indicating the necessity of dosage adjustment in accordance with body weight.

The role of nitric oxide in Doxorubicin-induced cardiotoxicity: experimental study.

OBJECTIVE: We evaluated the myocardial damage in rats treated with doxorubicin (DOX) alone and in combination with nitric oxide synthase (NOS) inhibitors. MATERIALS AND METHODS: Twenty-four male Sprague Dawley rats (12 weeks old, weighing 262±18 g) were randomly assigned into 4 groups (n=6). Group I was the control group. In Group II, rats were treated with intraperitoneal (ip) injections of 3 mg/kg DOX once a week for 5 weeks. In Group III, rats received weekly ip injections of 30 mg/kg L-NAME (nonspecific NOS inhibitor) 30 min before DOX injections for 5 weeks. In Group IV, rats received weekly ip injections of 3 mg/kg L-NIL (inducible NOS inhibitor) 30 min before DOX injections for 5 weeks. Rats were weighed 2 times a week. At the end of 6 weeks, hearts were excised and then fixed for light and electron microscopy evaluation and tissue lipid peroxidation (malondialdehyde). Blood samples were also obtained for measuring plasma lipid peroxidation. RESULTS: Weight loss was observed in Group II, Group III, and Group IV. Weight loss was statistically significant in the DOX group. Findings of myocardial damage were significantly higher in animals treated with DOX only than in the control group. Histopathological findings of cardiotoxicity in rats treated with DOX in combination with L-NAME and L-NIL were not significantly different compared with the control group. The level of plasma malondialdehyde in the DOX group (9.3±3.4 µmol/L) was higher than those of all other groups. CONCLUSION: Our results showed that DOX cardiotoxicity was significantly decreased when DOX was given with NO synthase inhibitors.

The treatment of crimean-congo hemorrhagic fever with high-dose methylprednisolone, intravenous immunoglobulin, and fresh frozen plasma.

Crimean-Congo hemorrhagic fever (CCHF) is an acute tick-borne disease caused by Nairovirus, and it is sometimes characterized by reactive hemophagocytic histiocytosis (HLH). The reasons for reactive HLH are macrophage-activating syndrome and disseminated intravascular coagulation due to cytokine storm, liver dysfunction, and endothelial damage by the virus. In this study, the effectiveness of high-dose methylprednisolone (HDMP) (5 to 30 mg/kg/d), fresh frozen plasma (FFP), and intravenous immunoglobulin (IVIG) was investigated in patients with CCHF associated with reactive HLH. Twelve patients with CCHF in association with reactive HLH were included in the study. The patients were successfully treated with HDMP to suppress the macrophage activation, FFP to treat disseminated intravascular coagulation, and IVIG to treat severe thrombocytopenia. No patients received ribavirin. Fever reduced in 1.6 ± 0.8 days, WBC count increased above 4.500/µL in 4.0 ± 2.4 days, platelet count increased above 150.000/µL in 8.5 ± 2.5 days, and D-dimer level decreased under 1 mcg/dL in 5.8 ± 3.6 days. Consequently, HDMP, FFP, and IVIG may be effective in patients with CCHF associated with reactive HLH during hemorrhagic period of the disease.

Primary Immunodeficiencies in Children Initially Admitted with Gastrointestinal/Liver Manifestations.

Purpose: The gastrointestinal system is the most commonly affected organ, followed by the lungs, in patients with primary immunodeficiency disease (PID). Hence, it is common for children with PIDs to present with gastrointestinal symptoms. We aimed to analyze the clinical and histopathological findings of patients who were initially admitted to pediatric gastroenterology/hepatology clinics and subsequently diagnosed with PIDs to identify the clinical clues for PIDs. Methods: The demographic, laboratory, and histopathological findings, treatment modality, and outcomes of patients initially admitted to the pediatric gastroenterology/hepatology unit and subsequently diagnosed with PIDs were recorded. Results: The study included 24 patients (58.3% male; median age [range]: 29 [0.5-204] months). Common clinical presentations included chronic diarrhea (n=8), colitis (n=6), acute hepatitis (n=4), and acute liver failure (n=2). The association of autoimmune diseases, development of malignant diseases, and severe progression of viral diseases was observed in 20.8%, 8.3%, and 16.6% of the patients, respectively. Antibody deficiency was predominantly diagnosed in 29.2% of patients, combined immunodeficiency in 20.8%, immune dysregulation in 12.5%, defects in intrinsic and innate immunity in 4.2%, autoinflammatory disorders in 8.3%, and congenital defects of phagocytes in 4.2%. Five patients remained unclassified (20.8%). Conclusion: Patients with PIDs may initially experience gastrointestinal or liver problems. It is recommended that the association of autoimmune or malignant diseases or severe progression of viral diseases provide pediatric gastroenterologists some suspicion of PIDs. After screening using basic laboratory tests, genetic analysis is mandatory for a definitive diagnosis.

In vitro determination of apoptotic effect of heparin on lymphoblasts by using flow cytometric DNA analysis and measurements of caspase-9 activation and cytochrome C level.

Heparin induces apoptosis on peripheral neutrophils, mononuclear cells of the healthy controls, and on lymphoblasts of the patients with acute lymphoblastic leukemia, in vitro. We studied the caspase-9 activity and cytochrome C level as the indicators of the apoptotic effect of heparin on lymphoblasts by the intrinsic pathway of apoptosis. Twenty samples of the patients with acute lymphoblastic leukemia were included in the study. Cytochrome C level and caspase-9 activity were concomitantly determined with the percentage of apoptotic lymphoblasts when incubated in 0, 10, and 20 U/mL heparin concentrations at 0, 1, and 2 hours. The percentages of apoptosis of lymphoblasts at the first hour were higher than those at 0 and 2 hours in 10 and 20 U/mL heparin concentrations, separately (P<0.05). The mean percentage of apoptosis of lymphoblasts in 20 U/mL heparin levels was significantly higher than those in 0 and 10 U/mL heparin levels at 1 and 2 hours (P<0.05). The highest apoptotic effect of heparin on lymphoblasts was determined at the first hour in 20 U/mL heparin concentration. The mean caspase-9 activitity at the first hour was significantly higher than the values at 0 and 2 hours in 10 and 20 U/mL heparin levels, separately (P<0.05). The mean caspase-9 activity in 20 U/mL heparin concentration was significantly higher than values in 0 and 10 U/mL heparin concentrations at 1 and 2 hours (P<0.05). The highest caspase-9 activity was determined in 20 U/mL heparin levels at the first hour. The mean cytochrome C level at the first hour was significantly higher than those at 0 and 2 hours in 10 and 20 U/mL heparin concentrations, separately (P<0.05). The highest cytochrome C level was determined in 20 U/mL heparin concentration at the first hour. We claimed that heparin induces the apoptosis of lymphoblasts by the activation of the intrinsic pathway.