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Coexistence of chronic lymphocytic leukemia and essential thrombocythemia.

The association of chronic lymphocytic leukemia (CLL) with essential thrombocythemia (ET) is an extremely rare event and until now 3 patients with such coexistence have been reported in the literature. We report a 77-year-old white woman in whom these two disorders were diagnosed concomitantly on the basis of peripheral blood count and cytology, bone marrow cytology and histology, immunophenotyping, as well as exclusion criteria. The diagnosis of ET was also supported by spontaneous in-vitro erythroid colony growth and by evaluation of thrombopoietin (TPO) serum level. Interphase FISH analysis allowed to detect 13q14.3 deletion in 98% of lymphocytes nuclei. In contrast this aberration was not observed in the megakaryocytes. The results of PCR analysis of IgG gene rearrangement showed distinct bands characteristic for monoclonal lymphoid population in bone marrow, peripheral blood and inguinal lymph node. The patient was started on hydroxyurea 1 g/day and normalization of the platelet count was achieved. Possible etiopathogenic relationships between both disorders and differential diagnosis of ET and reactive thrombocytosis (RT) are discussed.

Aged↗

Role of blood platelets in infection and inflammation.

Blood platelets are here presented as active players in antimicrobial host defense and the induction of inflammation and tissue repair in addition to their participation in hemostasis. Megakaryopoiesis is inhibited after acute infection with viruses or bacteria. In contrast, chronic inflammation is often associated with reactive thrombocytosis. Platelets can bind and internalize pathogens and release microbicidal proteins that kill certain bacteria and fungi. By making cell-cell contacts with leukocytes and endothelial cells, platelets assist white blood cells in rolling, arrest and transmigration. On stimulation by bacteria or thrombin, platelets release the content of their alpha-granules, which include an arsenal of bioactive peptides, such as CC-chemokines and CXC-chemokines and growth factors for endothelial cells, smooth muscle cells and fibroblasts. Thus, integral to innate immunity, the tiny little platelets may become bombshells when irritated by pathogens.

Animals↗

Platelet-derived acid phosphatase isoenzyme in the serum in thrombocythemia.

Acid phosphatase is present in platelets and is released during the clotting process. In thrombocythemic conditions, this may increase serum enzymatic activity. An illustrative case in which the determination of plasma enzymatic activity suggested a platelet origin of elevated serum levels, confirmed by isoenzyme fractionation on disk polyacrylamide gel electrophoresis is presented. It is concluded that in the presence of thrombocytosis a plasma sample is preferable to a serum sample for determination of acid phosphatase activity.

Acid Phosphatase↗

Potential complications of intralesional laser photocoagulation for extensive vascular malformations.

Vascular anomalies remain a challenge for both patients and plastic surgeons. Recently, promising results have been reported using intralesional photocoagulation (ILP) to treat extensive vascular lesions. At the authors' center, they have treated more than 300 patients with vascular anomalies in different parts of the body between 1996 and 1999. They describe their operative techniques of ILP. Laser pulses of a 1,064-nm wavelength from the Nd:YAG laser were delivered to the target tissues with a 600-microm optical fiber. They report 2 patients who developed complications after a single session of ILP therapy for their extensive vascular malformations. The first patient had Klippel-Trenaunay syndrome (capillary-lymphaticovenous malformations) with widespread involvement of her buttocks and left lower limb. She had severe leukocytosis, thrombocytosis, and hyperkalemia that resolved with intravenous hydration, antibiotics, and sodium bicarbonate. In their second patient, the entire left upper limb was affected. Her total red cell count diminished by a quarter and her hemoglobin concentration dropped by more than 3 g%. This was corrected gradually with supplemental oral hematinics. Although these complications resolved uneventfully in their patients, they hope that their possible development will caution anyone who may wish to attempt this new method of therapy.

Adult↗

Gangrene of toes with normal peripheral pulses.

Ten patients with pregangrenous and gangrenous changes of the toes in the presence of normal peripheral pulses are described. In the absence of diabetes this is an uncommon condition and is only rarely reported upon in the literature. Four patients had non occlusive arteriosclerotic changes in large arteries; three suffered from thrombocytosis and one from polycythemia vera; one patient had a monoclonal gamopathy and one was exposed to cold three months before the onset of gangrene. None of these patients smoked regularly. Severe pain usually preceded the gangrene. The process did not progress proximally in any patients, and in those who underwent toe amputations the healing was uneventful. Vasodilators and low-molecular dextran were not effective. Lumbar sympathectomy was performed in three patients, also with no effect on the course of the disease. Treatment of hematological disorders gave relief in three patients. Proximal arteriosclerotic changes should be corrected if possible to eliminate a source of emboli. In two patients anti-platelet aggregation agents provided relief. Toe amputation should be conservative and performed when definite demarcation appears between necrotic and viable tissue. This condition has a benign prognosis.

Adult↗

Phase I-II trial of low-dose gemcitabine in prolonged infusion and cisplatin for advanced non-small cell lung cancer.

After monotherapy with gemcitabine in low dose in long infusion, promising results in a variety of advanced chemoresistant tumors have been reported. In a previous phase I trial on heavily pre-treated patients, maximum tolerated dose (MTD) of gemcitabine in a 6 h infusion was 250 mg/m. The objective of our phase I-II trial was to test the combination of gemcitabine in a 6-h infusion and cisplatin in the treatment of advanced non-small cell lung cancer (NSCLC). Eligible patients were chemonaive, had locally advanced or metastatic NSCLC, Eastern Oncology Cooperative Oncology Group performance status 0-2 and normal organ function. Treatment consisted of gemcitabine in a 6-h infusion on days 1 and 8, and cisplatin at 75 mg/m on day 2 of a 3-week cycle. During phase I of the trial, the dose of gemcitabine was escalated from 130 to 170, 210 and 250 mg/m. After establishing dose-limiting toxicity (DLT) and MTD of the combination, the trial continued as phase II. Altogether, 61 patients were enrolled, of whom 54 had stage IV disease. In phase I of the trial, groups of six, seven, eight and eight patients were treated at the four dose levels of gemcitabine. In phase II, the remaining 32 patients all received gemcitabine at 250 mg/m. Serious toxicity included a patient with grade 5 ventricular arrhythmia and another with grade 4 cerebrovascular ischemia; four patients had grade 3 anemia. Reversible thrombocytosis with platelets over 500 was recorded in 32 patients; 42 patients had grade 2 alopecia. In general, tolerance to this treatment was good. One patient had complete response and 27 had partial responses, for a 28 of 61 (46%) response rate. Median progression-free survival, median survival and 1-year survival were 6 months, 9.5 months and 40%, respectively. We conclude that this treatment has an acceptable, yet distinct, toxicity profile; routine thromboprophylaxis is recommended. In our population of chemonaive patients, no DLT has been encountered. Due to the remarkable response rate, further research is warranted.

Adult↗

The use of nuclear medicine procedures in the diagnosis of Budd-Chiari syndrome.

The case history of a patient with Budd-Chiari syndrome (BCS) is described. The underlaying disease proved to be essential thrombocytosis. Congential elliptocytosis was also present. The value of the conventional liver scan, percutaneous splenoportoscintigraphy and isotopic phlebography of the inferior vena cava in the diagnosis of BCS is described. It is suggested that a combination of these three noninvasive techniques be used when BCS is suspected.

Adult↗

Chronic myelocytic leukemia with near-total pulmonary microvascular obstruction by platelets.

We have described a patient with long-standing chronic granulocytic leukemia. Although most patients with this disorder eventually have a picture of acute leukemia (blast crisis), this patient had massive thrombocytosis (platelet count greater than 5.000 x 10(9)/L) without major symptoms, but he died after transfusion of 1 unit of packed red blood cells. At autopsy, he had almost total pulmonary microvascular blockage with platelets.

Adult↗

Interferon-alpha-associated bilateral simultaneous ischemic optic neuropathy.

The authors describe one patient with essential thrombocytosis and one with chronic hepatitis C infection who developed bilateral simultaneous anterior ischemic optic neuropathy within 3 months of starting treatment with interferon-alpha. One patient had several typical risk factors for conventional AION; the other did not. These cases are the fourth and fifth reported examples of this phenomenon. Interferon-alpha treatment may cause or aggravate the risk of developing anterior ischemic optic neuropathy. Vulnerable patients should be advised of this potential complication, assisted in reducing risk factors, and monitored for optic nerve and retinal vascular complications.

Adult↗

The role of the liver in the production of thrombopoietin compared with erythropoietin.

The liver plays an important role in the production of haemopoietic hormones. It acts as the primary site of synthesis of erythropoietin (EPO) in the fetal stage, and it is the predominant thrombopoietin (TPO)-producing organ for life. In contrast to that of EPO and other liver proteins, the hepatic synthesis of TPO is influenced little by external signals. Hepatocytes express the TPO gene in a constitutive way, i.e. irrespective of the level of platelets in blood. Megakaryocytes and platelets remove the hormone from blood by means of their high-affinity TPO receptors. Normally, the plasma level of TPO is relatively low ( approximately 10(-12) mol/l). However, in thrombocytopenic states due to marrow failure or bleeding, the concentration of circulating TPO may increase greatly. The simple feedback regulation by TPO and its target cells is efficient in maintaining constant platelet numbers in healthy people. Persisting thrombocytopenia develops only in severe liver or marrow failure. On the other hand, an increase in circulating TPO and interleukin 6 (IL-6) may cause reactive thrombocytosis in inflammatory diseases, including cancer. The indications for recombinant human thrombopoietin (rHuTPO) therapy and its impact on transfusion medicine are still under investigation.

Animals↗

Successful treatment of essential thrombocythemia evolving into agnogenic myeloid metaplasia with interferon-alpha.

PURPOSE: Essential thrombocythemia and agnogenic myeloid metaplasia as one form of idiopathic myelofibrosis are myeloproliferative disorders and are quite rare in children. A patient with essential thrombocythemia that transformed to "adult-type" agnogenic myeloid metaplasia is described. PATIENTS AND METHODS: A routine examination of an 8-year-old girl with bronchial asthma showed thrombocytosis. Essential thrombocythemia was diagnosed 2 years later. During a 3-year follow-up without treatment, transition of the essential thrombocythemia to agnogenic myeloid metaplasia was noticed. The patient had an excellent response to interferon (IFN)-alpha therapy. CONCLUSION: This case is unique because of the availability of premorbid hematologic data and the natural progression of essential thrombocythemia to agnogenic myeloid metaplasia. Whether IFN-alpha therapy can prevent the progression of idiopathic myelofibrosis to leukemia has not yet been determined.

Child↗

Essential thrombocythemia in children.

PURPOSE: The objective of this study was to evaluate the clinical course, laboratory findings, and outcomes of children with essential thrombocythemia (ET). PATIENTS AND METHODS: The authors analyzed 36 children, ages 6 weeks to 18 years, by combining descriptions of 2 patients observed at their institution with 34 patients reported in the English medical literature. RESULTS: Fifteen patients (10 at diagnosis and 5 later on) had symptoms directly related to ET, including 9 who had severe thrombohemorrhagic phenomena. Common abnormalities included large platelets, increased marrow megakaryocytes with hyperlobulated forms, and abnormal platelet aggregation. Symptomatic patients had significantly higher platelet counts (2,419 versus 904 x 10(9)/L, P < 0.001); however, three patients with platelet counts that were only moderately elevated (600-800 x 10(9)/L) had thrombotic events. Eleven patients received various therapeutic agents. Interestingly, three patients who had one thrombotic event, and did not receive therapy, went on to have a benign clinical course. Leukemia developed in two treated patients, and they died; two others died of thrombotic complications; and myelofibrosis developed in one patient. Seventeen cases (47%) were familial. Patients with familial cases had significantly lower platelet counts, a lower incidence of hepatomegaly, and no thrombotic complications. CONCLUSIONS: This analysis of children with ET found that severe vascular complications developed in a substantial number. Platelet counts usually, but not always, correlate with the occurrence of complications. The indications for treatment and the best treatment of children with ET are currently not known, and guidelines for the management of children with ET are needed. Familial thrombocythemia is common among children with primary thrombocytosis and appears to be a different disease from ET, with a more benign course.

Adolescent↗

Tumor necrosis factor, interleukin 11, and leukemia inhibitory factor produced by Langerhans cells in Langerhans cell histiocytosis.

OBJECTIVES: : The etiology and pathophysiology of Langerhans cell histiocytosis (LCH) remain elusive. The 3-year survival in pediatric multisystem LCH is still around 80%, and children with risk organ involvement (i.e., liver, spleen, hematopoietic system, or lungs) have a less favorable outcome. To further elucidate the pathogenesis of LCH in the search for a rationale cure, the authors investigated intracellular synthesis of tumor necrosis factor (TNF), interleukin (IL)-11, and leukemia inhibitory factor (LIF) from biopsied lesions. METHODS: : Lesional cells were obtained by fine-needle aspiration biopsy from nine children with LCH. The study was accomplished by the use of an immunofluorescence staining method that allowed cytokine-producing cells to be differentiated from cytokine-binding cells. RESULTS: : All patients had histiocytes expressing TNF. Seven patients had histiocytes expressing IL-11 and six patients had histiocytes expressing LIF. The two children with the highest proportion of histiocytes displaying TNF and the three with the highest proportion of histiocytes expressing IL-11 and LIF all had risk organ involvement. Two-color staining revealed that histiocytes expressing TNF, IL-11, and LIF co-expressed CD1a molecules. CONCLUSIONS: : These observations suggest that LCH represents a cytokine-driven condition partially mediated by TNF, IL-11, and LIF. These three cytokines are all osteoclastogenic, suggesting a pathogenetic pathway for the osteolytic lesions in LCH. Furthermore, thrombocytosis in LCH may be explained by IL-11 and LIF activity.

Biopsy, Fine-Needle↗

Measurement of thrombopoietic levels: clinical and biological relationships.

Platelet production is primarily regulated by the thrombopoietic cytokine thrombopoietin (TPO). In most cases thrombopoietin serum levels are determined by the rate of c-mpl receptor-mediated degradation after TPO uptake into platelets and megakaryocytes. The contribution of increased TPO protein synthesis by a translational mechanism was recently appreciated as the cause for hereditary thrombocythemia and will have to be elucidated in other conditions of thrombocytosis in association with increased TPO levels.

Acquired Immunodeficiency Syndrome↗

Features and prognoses of infantile patients with atopic dermatitis hospitalized for severe complications.

Although atopic dermatitis (AD) itself is regarded as a non-life threatening disease, childhood AD may be rarely accompanied by some serious complications. Six infantile AD patients who were hospitalized because of severe systemic complications, in addition to severe dermatitis on almost the entire body surface, are described. They were complicated by hypoproteinemia, hypovolemia, thrombocytosis, reduced serum immunoglobulin G, elevated serum liver enzymes and growth retardation. They had not been treated with topical corticosteroid before hospitalization. They were treated with topical corticosteroid and their eruption remarkably improved within 20 days (median) of hospitalization. Most of the abnormal clinical data including platelet numbers, serum levels of total protein, and liver enzymes had become normal at the day of discharge. After 30 +/- 4 months of follow up, their skin condition was fair with daily application of moisturizer and occasional use of topical corticosteroid, without any systemic problems. Although severe infantile AD may be accompanied by potentially life-threatening systemic complications, their prognoses concerning AD are favorable if they are treated adequately from the beginning of their infancy.

Administration, Cutaneous↗

Effects of vincristine on normal and stimulated megakaryocytopoiesis in the rat.

Vincristine was given to rats in which thrombocytopoiesis was either normal or acutely or chronically stimulated by injections of heterologous antiplatelet serum. A single dose of 0.3 mg/kg was given intravenously. The drug produced an early and a delayed megakaryocytopenia suggesting that it was toxic to differentiated megakaryocytes as well as to proliferating stem cells. The results support the hypothesis that vincristine-induced thrombocytosis may be due to homeostatic adjustments which, in turn, are activated as a result of drug-induced cytotoxicity.

Animals↗

Evidence that stimulation of megakaryocytopoiesis by low dose vincristine results from an effect on platelets.

Appropriate low dosages of vincristine stimulate megakaryocytopoiesis and produce thrombocytosis. In this study of the thrombocytotic action of vincristine, administration of a single dose of 0.1 mg/kg to rats produced an increase in megakaryocyte concentration, diameter and 24 h [3H]thymidine labelling index. Transfusion of one body equivalent of platelets from normal donors prevented stimulation of megakaryocytopoiesis by vincristine whereas platelets from vincristine-treated donors did not. These results suggest that vincristine stimulates megakaryocytopoiesis by altering the functional role of circulating platelets in the regulation of thrombopoiesis.

Animals↗

Peripheral neuropathy and plasma cell neoplasias: a report of 10 cases.

Ten patients with peripheral polyneuropathy associated with plasma cell neoplasias are reported. Progressive sensorimotor polyneuropathy was the presenting complaint in all patients. CSF protein concentration was elevated in most patients. The electrophysiological and pathological changes were consistent with a primary segmentary demyelinating disease. All patients were male and younger than the average patient with myeloma. None presented with high tumour mass or overt multiple myeloma. Six were affected with single or multiple plasmacytomas with osteolytic lesions. Unusual haematological features such as polycythaemia, thrombocytosis and lymphadenopathy were often combined with the polyneuropathy. Skin hyperpigmentation, gynaecomastia and diabetes mellitus were noted in some patients. Complete recovery of the polyneuropathy was observed in some patients after either cyclophosphamide and corticosteroid therapy or radiotherapy of localized plasmacytoma, suggesting a direct relationship between the plasmacytic proliferation and the neuropathy. The nature of the postulated factor produced by the plasma cells and responsible for nerve injury is discussed and the importance of a careful search for plasma cell proliferation in men with obscure polyneuropathies is outlined.

Adult↗