Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiology of thrombo-embolic events after therapy with asparaginase (ASP) is not fully understood. To investigate if cytotoxic drugs given in combination with asparaginase (ASP) have an additional effect on the coagulation system, a detailed analysis of coagulation factors was performed. Therefore, we investigated two combinations of the COALL-05-92-protocol, [cylophosphamide]/methotrexate/ASP ([CYC]/MTX/ASP) and high dose arabinoside/ASP (HIDAC/ASP). In 33 children with acute lymphoblastic leukaemia the following parameters were determined: plasminogen-activator-inhibitor-1, plasminogen, antiplasmin, protein C, antithrombin, modified antithrombin, prothrombin-fragments 1 + 2 and thrombinantithrombin-complex. All children had an indwelling catheter. The most distinctive result of this investigation is that plasminogen shows a deeper and longer lasting decrease in the [CYC]/MTX/ASP-combination (median 65% NHP) compared to the HIDAC/ASP-combination (median 105% NHP) (p = 0.01). The other parameters showed the characteristic changes after ASP-therapy. None of our patients developed any clinical signs of thrombosis, even though two patients showed four altered coagulation parameters on the same day. This shows, that the coexistence of indwelling catheters plus four decreased coagulation parameters does not necessarily imply the development of thrombosis. We conclude that the parameters measured in this study do not sufficiently predict the development of thrombosis.
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PMID:Coagulation and fibrinolysis in children with acute lymphoblastic leukaemia treated according to the COALL-05-92-protocol. 974 67

Recently published data suggest that the prothrombin G20210A variant, the TT677 methylenetetrahydrofolate reductase genotype, the factor V G1691A mutation, deficiencies of protein C, protein S, antithrombin, and elevated lipoprotein (a) concentrations were associated with venous thromboembolism in childhood patients treated according to the BFM protocol. To unravel the role of these prothrombotic risk factors and different treatment modalities, the present comparative study was performed in childhood leukemia patients of the same living population. Four hundred and twenty consecutively recruited leukemic children (BFM n=300; COALL n=120) were enrolled in this study with respect to the presence of prothrombotic risk factors and the occurrence of symptomatic venous thrombosis. No significant difference was found in the prevalence rates of thrombotic risk factors in the Caucasian populations studied. Symptomatic venous thromboembolism occurred in 11.6% of BFM patients compared with 2.5% in the COALL treatment group [odds ratio (OR)/95% confidence intervals (CI): 7.7/1.8-32.6; P=.005]. Including age, prothrombotic risk factors, central venous lines, treatment protocols, and anti-leukemic drugs in a logistic regression model, only the concomitant Escherichia coli asparaginase/prednisone administration in leukemic children suffering from a prothrombotic risk factor was found to increase the rate of thrombotic manifestations during leukemia treatment in patients of the same Caucasian origin (OR/95% CI: 34.5/4.39-271.42; P=.0008). Based on the data presented here, we suggest the use of prednisone and E. coli asparaginase concomitantly administered in a leukemic patient suffering from a prothrombotic risk factor to be responsible for the onset of venous thrombosis in the majority of cases.
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PMID:Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. 1167 78

The enhanced extrinsic coagulation in response to inflammation could contribute to disseminated intravascular coagulation, often manifesting cardiovascular complications. The complex mechanism remains unclear and effective management is not well established. The ability of protamine to offset bacterial endotoxin (LPS)-induced tissue factor (TF)-initiated extrinsic coagulation was demonstrated in human peripheral blood monocytes and cultured human leukaemia THP-1 monocytes, which was consistent with the inhibition of rabbit brain thromboplastin (rbTF) procoagulant activity in a cell-free in vitro model. Protamine significantly prolonged prothrombin time, further confirming the downregulation of the extrinsic pathway. However, thrombin time remained unaltered. Chromogenic assays were performed to dissect the extrinsic pathway, identifying inhibitory site(s). Protamine significantly inhibited factor VII (FVII) activation but not the dissected FX activation. The amidolytic activities of FVIIa and FXa were unaffected. The inhibited FVII activation in the presence of protamine was confirmed by the diminished FVIIa formation on Western blot analyses. Protamine preferentially inhibited TF-catalysed FVII activation, downregulating the extrinsic cascade. Protamine could be of anticoagulant significance in the management of the extrinsic hypercoagulation.
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PMID:Protamine inhibits tissue factor-initiated extrinsic coagulation. 1170 41

There are global coagulation tests and hemostatic molecular markers in the diagnosis of disseminated intravascular coagulation (DIC). In the global coagulation tests, the sensitivity of prothrombin time ratio and fibrinogen for the diagnosis of DIC is low, but their specificity is high. In platelet count and FDP, the sensitivity for the diagnosis of DIC is good, but the specificity is low. Fibrinogen may be unsuitable for the diagnosis of DIC, because it increases of the inflammatory reaction. It is possible to theoretically diagnose DIC by increased tissue factor production. It is currently considered that hemostatic molecular marker should be utilized to diagnose DIC. Thrombin-antithrombin complex and soluble fibrin are reflected to hypercoagulable state, thrombomodulin to vascular endothelial cell injuries, and plasminogen activator inhibitor-I to hypofibrinolytic state. In leukemia with DIC, hyperfibrinolysis and marked bleeding symptoms are often observed. In septicemia with DIC, hypofibrinolysis and severe organ failure often occur. Early diagnosis and treatment of DIC are important to improve the prognosis, and hemostatic molecular markers should be useful for that purpose.
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PMID:[Hemostatic abnormalities in DIC]. 1237 12

The extrinsic hypercoagulation often resulting from sepsis could contribute to disseminated intravascular coagulation and cardiovascular complications. The effective prevention and intervention remained largely complex and unclear. In a cell model of human leukemia THP-1 monocytes following bacterial endotoxin (LPS) exposure, we show the novel anticoagulant ability of polyamino acid (polyAA) to suppress the extrinsic hypercoagulation. LPS-induced monocytic tissue factor (mTF) procoagulation was readily offset by poly-L-lysine (PLK), poly-L-arginine (PLR), or poly-L-ornithine (POR) included in single-stage clotting assays. IC50 was estimated at 0.35, 0.30, or 0.58 microM for PLR, POR, or PLK, respectively, whereas, poly-L-asparatic acid (PLD) remained ineffective. In a separate approach, inclusion of cationic polyAA in human plasma significantly prolonged prothrombin time, confirming the depressed extrinsic coagulation. In chromogenic assays dissecting the extrinsic pathway, we further determined the inhibitory site(s). PLK, PLR, or POR significantly inhibited LPS-induced FVII activation, which was consistent with the diminished FVIIa formation shown on Western blotting analysis. In contrast, polyAA did not show any additional effect on either FVIIa/FXa amidolytic activities or mTF/FVIIa-catalyzed FX activation. Nor did polyAA show any effect on FVII activation directly catalyzed by FXa. Taken together, PLK, PLR, or POR preferentially inhibited mTF-dependent FVII activation, accounting for their novel anticoagulant activities. PolyAA might present the specific antagonists to arrest the extrinsic hypercoagulation following inflammation.
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PMID:Novel anticoagulant activity of polyamino acid offsets bacterial endotoxin-induced extrinsic hypercoagulation: downregulation of monocytic tissue factor-dependent FVII activation. 1450 32

Acute biphenotypic leukemia is a very rare malignancy of childhood. Hemorrhage is a frequent complication of these patients. An 18-year-old-male with acute biphenotypic leukemia developed massive gastrointestinal bleeding that was thought to be due to thrombocytopenia during chemotherapy-induced pancytopenia and did not respond to conventional therapy. Although the prothrombin time and the partial thromboplastin time were within normal limits, inspired by the success in thrombocytopenia and platelet function disorders we decided to use recombinant activated factor VII (rFVIIa) as a last resort. After using a single dose (65 microg/kg) of rFVIIa on the fifth day of bleeding, the bleeding ceased immediately. rFVIIa may be a novel therapeutic alternative in leukemia or chemotherapy-associated massive bleeding.
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PMID:Successful treatment of massive gastrointestinal hemorrhage in acute biphenotypic leukemia with recombinant factor VIIa (NovoSeven). 1506 Apr 24

The t(1;22)(p13;q13) is associated with acute megakaryoblastic leukemia (AMKL) seen mostly in young infants and known to have a poor prognosis. A 5-year-old child had prolonged prothrombin and partial thromboplastin times, low albumin, and decreased vitamin K-dependent coagulation factors and factor V activities at the time of AMKL diagnosis. All of these factors normalized following chemotherapy when remission was achieved. Cytogenetic analysis revealed a female karyotype with a balanced t(17;22)(q21;q13). Here, we present an AMKL pediatric case with a novel translocation and significant hepatocellular dysfunction that resolved with chemotherapy. The t(17;22) (q21;q13) may represent a variant of t(1;22)(p13;q13).
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PMID:Acute megakaryoblastic leukemia with t(17;22)(q21;q13) and liver dysfunction. 1547 55

To build a risk score (RS) model of fatal intracranial hemorrhage (FICH) in patients with acute leukemia, we retrospectively assessed risk factors in 792 patients newly diagnosed with acute leukemia, 41 of whom had analyzable FICH. We found that female gender (relative risk (RR) = 5.234, P<0.001), acute promyelocytic leukemia (RR = 4.057, P = 0.003), leukocytosis (RR = 3.301, P = 0.004), thrombocytopenia (RR = 3.283, P = 0.005) and prolonged prothrombin time (RR = 3.291, P = 0.016) were significantly associated with occurrence of FICH in multivariate analysis. To calculate RS for FICH, one point was assigned for each risk factor, making the RS between 0 and 5. The RS model segregated patients into three prognostic groups: a low-risk group (LRG) for RS of 0 or 1; an intermediate-risk group (IRG) for RS of 2 or 3; and a high-risk group (HRG) for RS of 4 or 5. Expectation of FICH was well correlated with risk groups (all P-values < 0.001). Overall survival was significantly shorter in the HRG compared with the LRG. The RS model we constructed to predict the occurrence of FICH will be verified through prospective studies.
Leukemia 2006 May
PMID:Risk score model for fatal intracranial hemorrhage in acute leukemia. 1652

Hemostatic complications which can occur in the arterial or venous vasculature or in the microcirculation are the major causes of morbidity and mortality in patients with ET. In order to prevent these complications, often platelet reductive drugs are used. These agents are by themselves potentially toxic, i.e. may cause leukemia or cardiac side effects. In order to avoid these adverse effects, a better understanding of the mechanism of thrombus formation which is causative in ET is mandatory. Unfortunately, until now, no biomarkers have been identified which allow the estimation of the risk of thrombotic complications. Platelet number is not a good predictor per se since thrombotic complications can occur in some patients at low platelet numbers whereas others do not encounter a thrombosis even at very high platelet levels. On the other hand, lowering of the platelet count usually results in symptomatic improvement. In ET, morphological alterations of the megakaryocyte in the bone marrow and the circulating platelets are observed: megakaryocyte nuclei show a staghorn appearance, circulating platelets are characterized by anisocytosis and giant size. Functional studies indicate that these anatomically altered platelets function abnormally. When platelets are analyzed with a platelet function analyzer (PFA-100, which uses cartridges that measure how well a patient's platelets adhere and aggregate to form a platelet plug in the first phase of thrombus formation), in many patients with ET, closure time using collagen/ADP and collagen/epinephrine cartridges is prolonged. This seems paradoxical since these patients do not show an increased bleeding time. These results indicate that either receptors and/or consecutive signaling events are abnormal in ET platelets. Proteomic analysis of platelets of ET patients has revealed individual differences but not yet led to the identification of disease-specific proteins. Moreover, the search for alternative risk factors (factor V Leiden, prothrombin gene polymorphism, etc.) has not provided evidence for the contribution of these factors to the generation of the thrombotic risk in ET patients. In summary, despite intensive research over several decades, relatively little is known about the pathogenesis and risk factors for thrombosis in ET. I expect that this conference will contribute to the development of new strategies to identify patients at risk for hemostatic complications.
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PMID:Thrombotic complications in essential thrombocythemia (ET): clinical facts and biochemical riddles. 1656 15

Babassu is the popular name of Orbignya phalerata Mart. (Arecaceae). The mesocarp flour obtained from their fruits has been used in Brazil as medicine in the treatment of pains, constipation, obesity, leukemia, rheumatism, ulcerations, tumors, inflammations and venous diseases. The effect of the chronic oral treatment with aqueous extract of babassu mesocarp (500mg/kgday) on the number of platelets, the prothrombin time (PT), the activated partial thromboplastin time (aPTT), the nitric oxide (NO) production and the carrageenin-induced thrombosis was evaluated, using C57Bl/6 mice. The chronic oral treatment with babassu mesocarp induced an anti-thrombotic effect. There was a 88.9% reduction in the necrosis of the tail. This effect seems to be related to an increase in the ability of the macrophage to produce NO and to a slow coagulation process associated to an increase of 12.0 and 13.9% in PT and aPTT, respectively. However, the anti-thrombotic effect seems to be not related to alterations in the number of platelets. It is possible to conclude that the oral treatment with babassu mesocarp has a significant anti-thrombotic effect, which could justify the popular use of babassu mesocarp in the treatment of venous diseases. Meanwhile, this study suggests a potential use of babassu mesocarp as a prophylactic agent to avoid thrombosis events.
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PMID:Anti-thrombotic effect of chronic oral treatment with Orbignya phalerata Mart. 1714 96


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