Leukostasis by hyperleukocytic childhood acute leukemia: pathophysiology, clinical presentation, and emergency care

Hyperleukocytosis (HL), defined by a peripheral white blood cell (WBC) count exceeding 100,000/mm³, is occasionally observed in childhood acute leukemia. The increased viscosity in the micro-circulation by HL and the interaction between the leukemic blasts and endometrium of blood vessels sometimes result in leukostasis. Leukostasis can incur life-threatening manifestations, such as respiratory distress, brain infarction and hemorrhage, and renal failure, needing an emergency care. Although early stage of leukostasis is difficult to detect due to nonspecific manifestations, an emergency care is mandatory because leukostasis can proceed to a fatal course. Initial management includes an aggressive fluid therapy that can reduce WBC count, and prevent other metabolic complications implicated by HL. Packed red blood cells should be judiciously transfused because it increases blood viscosity. Conversely, transfusion of platelet concentrates or fresh frozen plasma, which does not affect blood viscosity, is recommended for prevention of hemorrhage. To reduce tumor burden, leukapheresis or exchange transfusion is commonly performed. However, the efficacy is still controversial, and technical problems are present. Leukapheresis or exchange transfusion is recommended if WBC count is 200,000–300,000/mm³ or more, especially in acute myelocytic leukemia, or manifestations of leukostasis are present. In addition, early chemotherapy is the definite treatment of leukostasis.

IL-17A exacerbates diabetic retinopathy by impairing Müller cell function via Act1 signaling

Diabetic retinopathy (DR), one of the most serious complications of diabetes, has been associated with inflammatory processes. We have recently reported that interleukin (IL)-17A, a proinflammatory cytokine, is increased in the plasma of diabetic patients. Further investigation is required to clarify the role of IL-17A in DR. Ins2(Akita) (Akita) diabetic mice and high-glucose (HG)-treated primary Müller cells were used to mimic DR-like pathology. Diabetes induced retinal expression of IL-17A and IL-17 receptor A (IL-17RA) in Müller cells in contrast to ganglion cells. Further evidence demonstrated that retinal Müller cells cultured in vitro increased IL-17A and IL-17RA expression as well as IL-17A secretion in the HG condition. In both the HG-treated Müller cells and Akita mouse retina, the Act1/TRAF6/IKK/NF-κB signaling pathway was activated. IL-17A further enhanced inflammatory signaling activation, whereas Act1 knockdown or IKK inhibition blocked the downstream signaling activation by IL-17A. HG- and diabetes-induced Müller cell activation and dysfunction, as determined by increased glial fibrillary acidic protein, vascular endothelial growth factor and glutamate levels and decreased glutamine synthetase and excitatory amino acid transporter-1 expression, were exacerbated by IL-17A; however, they were alleviated by Act1 knockdown or IKK inhibition. In addition, IL-17A intravitreal injection aggravated diabetes-induced retinal vascular leukostasis, vascular leakage and ganglion cell apoptosis, whereas Act1 silencing or anti-IL-17A monoclonal antibody ameliorated the retinal vascular damage and neuronal cell apoptosis. These findings establish that IL-17A exacerbates DR-like pathology by the promotion of Müller cell functional impairment via Act1 signaling.

Pathologic rupture of the spleen in a patient with acute myelogenous leukemia and leukostasis

Rupture of the spleen can be classified as spontaneous, traumatic, or pathologic. Pathologic rupture has been reported in infectious diseases such as infectious mononucleosis, and hematologic malignancies such as acute and chronic leukemias. Splenomegaly is considered the most relevant factor that predisposes to splenic rupture. A 66-year-old man with acute myeloid leukemia evolved from an unclassified myeloproliferative neoplasm, complaining of fatigue and mild upper left abdominal pain. He was pale and presented fever and tachypnea. Laboratory analyses showed hemoglobin 8.3 g/dL, white blood cell count 278 × 109/L, platelet count 367 × 109/L, activated partial thromboplastin time (aPTT) ratio 2.10, and international normalized ratio (INR) 1.60. A blood smear showed 62% of myeloblasts. The immunophenotype of the blasts was positive for CD117, HLA-DR, CD13, CD56, CD64, CD11c and CD14. Lactate dehydrogenase was 2384 U/L and creatinine 2.4 mg/dL (normal range: 0.7-1.6 mg/dL). Two sessions of leukapheresis were performed. At the end of the second session, the patient presented hemodynamic instability that culminated in circulatory shock and death. The post-mortem examination revealed infiltration of the vessels of the lungs, heart, and liver, and massive infiltration of the spleen by leukemic blasts. Blood volume in the peritoneal cavity was 500 mL. Acute leukemia is a rare cause of splenic rupture. Male gender, old age and splenomegaly are factors associated with this condition. As the patient had leukostasis, we hypothesize that this, associated with other factors such as lung and heart leukemic infiltration, had a role in inducing splenic rupture. Finally, we do not believe that leukapheresis in itself contributed to splenic rupture, as it is essentially atraumatic...

Clinical Effects and Safety of Therapeutic Leukapheresis in Hyperleukocytosis / 대한수혈학회지

BACKGROUND: Therapeutic leukapheresis is the cytoreduction procedure performed before chemotherapy in patients with hyperleukocytosis for prevention of complication. However, there have been clinical concerns about bleeding tendency due to anticoagulant used during the procedure. The aim of our study was to compare the clinical characteristics and hematological parameters before and after therapeutic leukapheresis in order to evaluate its effect on bleeding tendency and to provide a guideline for treatment strategy. METHODS: The clinical data for 39 procedures of therapeutic leukapheresis performed on 17 patients with hyperleukocytosis from May 2005 to October 2013 at the National Cancer Center were reviewed retrospectively. RESULTS: The patients consisted of 11 males and six females. The mean age was 41 years old (range, 8~74). The mean number of therapeutic leukapheresis per patient was two (range, 1~4). Clinical symptoms improved in 14 patients (82%) after therapeutic leukapheresis and three patients (18%) were not yet to improve. The mean WBC count was significantly reduced by 32.6% (+/-17.4) after therapeutic leukapheresis, from 250,146/microL (+/-117,000) to 174,702/microL (+/-104,700) (P<0.001). The mean volume of single removal was 298 ml with 4.25x10(11)/L (+/-1.54) WBCs. After therapeutic leukapheresis, the mean platelet count showed a decline from 85x10(9)/L (+/-43) to 71x10(9)/L (+/-26). However, the prothrombin time (PT) and activated partial thromboplastin time (aPTT) did not show a significant increase (PT, P=0.637; aPTT, P=0.054). CONCLUSION: Therapeutic leukapheresis is demonstrated as an effective and safe treatment that can improve symptoms and reduce leukocytes in hyperleukocytosis.

Paciente con livideces en miembros inferiores y leucemia mieloide aguda / Patient with livedoid purple plates in legs, and acute myeloid leukemia

Mujer de 66 años con tres días de evolución de fiebre, máculas violáceas y dolor en miembros inferiores asociado a deterioro del estado general. Antecedente de leucemia mieloide aguda. La biopsia de piel evidenció oclusión de vasos de mediano y pequeño calibre por mielocitos atípicos. Se describen los hallazgos clínicos e histopatológicos con el fin de reconocer esta rara y progresiva condición descrita en pacientes con síndromes mieloproliferativos.

Hyperleukocytosis associated pulmonary leukostasis in acute leukaemia.

Leukostasis is a fatal complication in granulocytic leukaemia. Brain and lung are most commonly involved organs in leukostasis. In the lung, the clinical presentation simulates infections and haemorrhagic complications of acute leukaemia. Being a medical emergency, early recognition of leukostasis and initiation of therapy prevents mortality.

Therapeutic Leukapheresis for Acute Lymphoblastic Leukemia with Severe Hyperleukocytosis in a Six-Week-Old Infant (4.7 kg) / 대한소아혈액종양학회지

We report a 4.7 kg infant who received a therapeutic leukapheresis as an immediate treatment for acute lymphoblastic leukemia with severe hyperleukocytosis. By decreasing the number of circulating white blood cells, therapeutic leukapheresis helps prevent the risks of hyperviscosity and cerebrovascular and pulmonary leukostasis. In addition, it potentially reduces metabolic and renal complications associated with rapid cell lysis when applied before chemotherapy. This six-week-old female presented with vomiting for 15 days. Initial WBC count was 1,532,800/muL. After placement of 4 french two-lumen central venous catheter in both femoral vein, the CS 3000 plus was primed with 250 mL of paternal whole blood mixed with 150 mL of normal saline. After therapeutic leukapheresis, the CBC showed WBC count of 560,000/muL. Our successful experience in performing this procedure suggests that therapeutic leukapheresis be a feasible treatment even for very young infants with hyperleukocytosis.

A Case of acute respiratory distress syndrome induced by all-trans-retinoic acid / 결핵

Acute respiratory distress syndrome (ARDS) has been reported to be associated with a variety of medical and surgical conditions, including All-trans-retinoic acid (ATTA). ATRA is very efficaceous drug to acute promyelocytic leukemia (APL). This drug can induce complete remission at APL without fatal risk of disseminated intravascular coagulation. But ATRA treatment, sometimes, produces the symptoms of fever, weight gain and acute respiratory distress, renal function impairment. The causes of these symptoms are not fully proved, but supposed as the result of leukostasis and capillary leak syndrome from excessive leukocyte differentiation and cytokines release. Recently, we experienced a 24-year-old woman who complained gum bleeding for 6 days. At bone marrow biopsy, she was diagnosed as APL. 2 days after ATRA treatment, she was suffered from the symptoms of dyspnea and general ache. At laboratory examination, total leukocyte count was 50,400/mm3 PaO2 was 42.5 mmHg and chest PA revealed the findings compatible with ARDS. Treatment with low dose ara-C, corticosteroid and general supportive cares were tried. Within 3 days after treatment, the patient recovered from ADRD by evidence of arterial blood gas study and chest radiographs. She has acquired complete remission of APL with maintenance of ATRA. And so, we present this case with a review of related literatures.

Leukapheresis with high dose hydroxyurea in the management of lower leg artery obstruction in Chronic Myelogenous Leukemia / 대한내과학회지

There was no specific criteria of white cell count to determine the therapy of hyperleukocytosis in chronic myelogenous leukemia (CML). Therapeutic leukapheresis usually indicated in acute myelogenous leukemia with over 100,000/mm3 of white blood cell, leukocyte infiltration and leukostasis with over 100,000/mm3 of white blood cell, and hairy cell leukemia with no response to drug and splenectomy. Leukapheresis can reverse the hyperleukocytic syndrome rapidly, be used immediately without having to wait for the result of allopurinol to reduce the risk of uric acid nephropathy and decrease the tumor cell mass so as to minimize the extent of cytolysis- induced hyperuricemia, hyperkalemia and hyperphosphatemia. We report a case of 56-year-old man presented right lower leg pain, gait disturbance who was diagnosed CML 4 years before. He showed right popliteal artery obstruction in doppler sonogram and immediatly started leukapheresis. After two therapeutic leukapheresis, symptoms were improved and popliteal blood flow was improved by follow-up doppler sonogram. As a result, we consider that leukapheresis without use of anticoagulant or thrombolytic agents is effective therapy in CML associated leukocytosis and vascular obstruction.

Evaluation of therapeutic leukapheresis in hyperleukocytic leukemias / 대한수혈학회지

BACKGROUND: Leukemia with hyperleukocytosis is risk factor for early mortality and morbidity. Therepeutic leukapheresis has been recognized as the choice of treatment modality to prevent leukostatic complications by selective removal of abnormal leukocytes. METHODS: We analyzed the clinical and laboratory data in total of 44 therapeutic leukapheresis performed at Samsung Medical Center in 31 patients (15 males, 16 females) with hyperleukocytic leukemias from March 1, 1995 to August 31, 1998. The change of laboratory findings related to therapeutic leukapheresis as well as the correlation between preprocedural and postprocedural hematologic parameters, the degree of leukoreduction and clinical efficacy were evaluated. RESULTS: The age distribution was from 6 months to 77 years with the 35 years of mean age. The most common diagnosis of patients who were performed therapeutic leukapheresis was acute myeloblastic leukemia (15/32, 46.9%) followed by acute lymphoblastic leukemia (9/32, 28.1%), and major leukostatic symptoms were dyspnea and headache. The mean leukocyte count before leukapheresis were 167,400/microliter and the mean leukoreduction per procedure was 50,080/microliter (30.3%). The changes of hemoglobin and platelet count were not significant. The efficacies of therapeutic leukapheresis were 66.7% in acute myeloblastic leukemia, 44.4% in acute lymphoblastic leukemia and 37.5% in other leukemia patients. Patients with low initial leukocyte count and blast count or low final leukocyte count showed higher clinical improvement rate than patients without those parameters. CONCLUSION: The present study for therapeutic leukaphresis indicate that it is relatively safe and can be used to relieve leukostatic symptoms and improve clinical status in leukemic patients.

Clinicohematologic Observations of Acute Leukemias with Hyperleukocytosis / 대한내과학회지

OBJECTIVES: It is well known that Acute Leukemic patients with Hyperleukocytosis (ALH, leukocyte count>or=100,000/micro L) have poor prognosis. This is indebted in fatal complications arising from cerebral and pulmonary leukostasis. To investigate the factors influence on the prognosis of these patients, we have analyzed age, sex, laboratory findings and complications and their relationship to remission rate. METHODS: Retrospective evaluation was done from January 1985 to March 1994 on fifty-four patients with ALH. We excluded secondary leukemias transformed from chronic myelogeneous leukemia, relapsed acute leukemia and myelodysplastic syndrome in this study. The prognostic factors associated with early death were also evaluated. RESULTS: 1) Hyperuricemia and incidence of central nervous system and respiratory symptoms were higher in acute myelogeneous leukemia (AML) with hyperleu-kocytosis than in acute lymphocytic leukemia (ALL), 2) Twenty-two of fifty-four patients had complete remission by remission induction chemotherapy. Remission rate was 41%, median duration of remission was 26 weeks and 1 year survival rate was 11%. 3) There were no differences in remission rate between male and female and higher WBC group (WBC>or=200,000/micro L) and lower WBC group (WBC 100,000~200,000/micro L). 4) The group with better performance status (ECOG score1-2), younger (age below 40) and higher hemoglobin level (Hb>or=10g/dL) had higher remission rate. The group of AML and with hepatomegaly had lower remission rate than the group of ALL and without hepatomegly. 5) Early death rate of AML was higher than that of All. Infection was the most common cause of early death in both AML and ALL. 6) Early death rate between the two groups managed with and without leukapheresis was not different. CONCLUSIONS: This result reveals that acute leukemia with hyperleukocytosis is grave disease, especially the patients with poor performance status (ECOG score: 3-4), older age above 40 and severe anemia (Hb<10g/dL) have poor prognosis, The group of AML and with hepatomegaly showed worse prognosis than the group of ALL and without hepatomegaly.