Effect of L-asparaginase administration on coagulation and platelet function in children with leukemia.

1987 ◽  
Vol 5 (5) ◽  
pp. 811-817 ◽  
Author(s):  
A C Homans ◽  
M E Rybak ◽  
R L Baglini ◽  
C Tiarks ◽  
M E Steiner ◽  
...  
Keyword(s):  
Platelet Function ◽  
Protein C ◽  
Pediatric Patients ◽  
Antithrombin Iii ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Remission Induction ◽  
Normal Range ◽  
Coagulation Abnormalities ◽  
At Iii

The use of L-asparaginase during remission induction in patients with leukemia is associated with coagulation abnormalities, which may present either as thrombosis or hemorrhage. However, because of the multiple pharmacologic and hematologic variables present in these patients, the exact contribution of L-asparaginase to these coagulation abnormalities is unclear. We studied platelet function and plasma coagulation parameters in 12 pediatric patients with acute lymphoblastic leukemia (ALL) receiving daily L-asparaginase as a single agent when in complete remission. Changes in the prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen, while statistically significant, remained within or close to the normal range during the study. Platelet function also remained normal during the study. In contrast, levels of protein C antigen decreased to a mean of 42%, a significant change from pretreatment values. Levels of antithrombin III (AT III) were likewise depressed to 15 mg/dL (34% of pretreatment value). Despite these changes in the levels of physiologic inhibitors of coagulation, this schedule of L-asparaginase administration was associated with only rare clinical thrombosis, and this study suggests that the development of this complication may be dependent on the presence of additional factors.

Sequential changes in platelet function and coagulation in leukemic children treated with L-asparaginase, prednisone, and vincristine.

1983 ◽  
Vol 1 (6) ◽  
pp. 380-385 ◽  
Author(s):  
C H Pui ◽  
C W Jackson ◽  
C Chesney ◽  
S A Lyles ◽  
W P Bowman ◽  
...  
Keyword(s):  
Platelet Function ◽  
Antithrombin Iii ◽  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Adenosine Diphosphate ◽  
Remission Induction ◽  
Induction Treatment ◽  
Aggregation Response ◽  
Thrombotic Complications

Coagulation and platelet function in 13 children with acute lymphoblastic leukemia were studied sequentially during a remission induction with L-asparaginase, prednisone, and vincristine. In the first weeks of therapy, which included four doses of L-asparaginase coagulation was characterized by significant decreases in plasma concentrations of plasminogen, antithrombin III alpha 2-macroglobulin, and fibrinogen. All measures gradually returned to normal after complication of L-asparaginase therapy. In the latter part of induction treatment, clotting times, especially partial Thromboplastin time, decreased significantly, while levels of factors V and VIII increased with recovery of platelet counts. At this time, 6 patients had an increased in vitro platelet aggregation response to adenosine diphosphate, and their partial thromboplastin times were significantly shorter than those of patients without increased aggregation. Concurrent abnormalities in coagulation and platelet function may account for the thrombotic complications that develop in some children receiving induction therapy with these agents.

Molekularbiologische Grundlagen und Diagnostik der hereditären Defekte von Antithrombin III, Protein C und Protein S

2002 ◽  
Vol 22 (02) ◽  
pp. 57-66
Author(s):  
I. Witt
Keyword(s):  
Protein C ◽  
Antithrombin Iii ◽  
Protein S ◽  
Klinische Relevanz ◽  
At Iii

ZusammenfassungDie enormen Fortschritte in der Molekularbiologie in den letzten Jahren ermöglichten sowohl die Aufklärung der Nukleotidsequenzen der Gene für Antithrombin III (AT III), Protein C (PROC) und Protein S (PROS) als auch die Identifizierung zahlreicher Mutationen bei hereditären Defekten dieser wichtigen Inhibitoren des plasmatischen Gerinnungssystems. Da die Gene für AT III (13,8 kb) und PROC (11,2 kb) nicht groß und relativ leicht zu analysieren sind, gibt es bereits umfangreiche »databases« der Mutationen (50, 73). Für AT III sind 79 und für PROC 160 unterschiedliche Mutationen beschrieben.Sowohl beim AT-III-Mangel als auch beim Protein-C-Mangel hat die Mutationsaufklärung neue Erkenntnisse über die Struktur-Funktions-Beziehung der Proteine gebracht. Beim Protein-C-Mangel steht die klinische Relevanz der DNA-Analyse im Vordergrund, da die Diagnostik des Protein-C-Mangels auf der Proteinebene nicht immer zuverlässig möglich ist.Das Protein-S-Gen ist für die Analytik schwer zugänglich, da es groß ist (80 kb) und außerdem ein Pseudogen existiert. Es sind schon zahlreiche Mutationen bei Patienten mit Protein-S-Mangel identifiziert worden. Eine Database ist bisher nicht publiziert. Die klinische Notwendigkeit zur Mutationsaufklärung besteht ebenso wie beim Protein-C-Mangel. Es ist zu erwarten, dass zukünftig die Identifizierung von Mutationen auch beim Protein-S-Mangel beschleunigt vorangeht.

Biological Characteristics Op Antithrombin III In An Antithrombin III Deficient Family

1981 ◽  
Author(s):  
S Kondo ◽  
T Matsuo ◽  
Y Ohoki ◽  
O Matsuo
Keyword(s):  
Antithrombin Iii ◽  
Recurrent Thrombosis ◽  
Normal Range ◽  
Japanese Family ◽  
Neutralization Activity ◽  
Normal Value ◽  
Antithrombin Activity ◽  
At Iii ◽  
Molecular Abnormality ◽  
Antifactor Xa

In the familial AT III deficiency of a Japanese family, the propositus (a-39-yr old female) and her mother had episodes of recurrent thrombosis and their AT III levels as measured immunologically and biologically were below the normal value. In the plasma of her brother, the AT III concentration as measured immunologically was half of the normal value, but his biological antithrombin activity was within the normal range. The progressive antithrombin activity and antifactor Xa activity of plasma samples in this familial AT III deficiency were within the normal range. Measurements of the rate of thrombin neutralization activity revealed that the brother’s plasma was in the normal range, but the plasma of the propositus and of her mother showed rates of thrombin neutralization activity which were somewhat below the normal value. The rate of thrombin neutralization activity per mg protein of AT III was highest in the plasma of the brother, and became slower in the mother, propositus, and pooled normal plasma in that order. In the plasma of this familial AT III deficiency, the rate of Xa neutralization activity was much slower than the normal value. It is postulated that since the antithrombin of the brother of the propositus was found to react as normal in the neutralization of thrombin, he does not have episodes of thrombosis. Such characteristic hyperfunction of antithrombin in the plasma of the brother may be due to some molecular abnormality of AT III within this hereditary deficient family.

Incidence of Aspirin ’Resistance’ as Determined Using the PFA-100 in Pediatric Patients with Arterial Ischemic Stroke.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1882-1882 ◽  
Author(s):  
Margaret L. Rand ◽  
Sylvain Lanthier ◽  
Trish Domi ◽  
Dewi Clark ◽  
Anthony K.C. Chan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Platelet Function ◽  
Pediatric Patients ◽  
Aspirin Resistance ◽  
Current Treatment ◽  
Test Time ◽  
Healthy Children ◽  
Arterial Ischemic Stroke ◽  
Normal Range ◽  
Maximum Test

Abstract A significant benefit of aspirin (ASA) has been demonstrated in the prevention of arterial thrombotic events in high-risk adult patients. Despite ASA therapy, recurrence of thromboembolic events, or treatment failure, has been reported in 10–20% of patients, and this has been termed ASA ’resistance’. This term has also been applied to the failure of ASA to affect ASA-dependent laboratory tests. As there is little information on ASA ’resistance’ in children, we examined the efficacy of ASA treatment on platelets from pediatric stroke patients using the PFA-100. Pediatric arterial ischemic stroke afflicts 2–3 children per 100,000 per year, and is associated with recurrent arterial ischemic stroke or transient ischemic attack in 20–40% of cases. Current treatment includes ASA prophylaxis (3 – 5 mg/kg/day) to inhibit platelet function and prevent recurrence, but it is not known whether this ASA dosing regimen is adequate to inhibit platelet function. Our study population consisted of 95 consecutive children with an index arterial ischemic stroke at mean age 5.9 ± 4.8 yrs (range: 0.1 – 17.0 yrs) on active ASA therapy (2.9 ± 1.2 mg/kg/day). Citrated blood samples were obtained at mean age 9.8 ± 4.8 yrs (range: 0.9 – 19 yrs), and were used to measure primary, platelet-related hemostasis in the high-shear PFA-100 system; closure times (CTs) were determined with the collagen/epinephrine cartridge that is sensitive to ASA’s inhibition of thromboxane A2 formation via platelet cyclo-oxygenase 1. The mean CT for all 95 patients was 244 ± 68.1 sec, which is greater than 163 sec, the upper limit of the normal range that we have previously determined for healthy children. The majority of patients, 75/95 (79%), had prolonged CTs (172 sec to > 300 sec), indicating inhibition of platelet function by ASA, and they were thus responsive to ASA therapy. 45 of the 75 ASA responders (63%) had CTs > 300 sec, i.e. CTs greater than the maximum test time of 300 sec, demonstrating aperture non-closure. The remaining 20/95 patients (21%) were ASA ’resistant’, as they did not respond to ASA therapy, having CTs (93 – 163 sec) within the normal range. Mean ASA dosage did not differ between ASA responders (2.8 ± 1.2 mg/kg/day) and ASA ’resistant’ patients (3.0 ± 1.4 mg/kg/day). 6 of the ASA ’resistant’ patients had their ASA dosage increased, and on repeat PFA-100 testing, 5/6 showed increased CTs > 163 sec. In conclusion, in children with arterial ischemic stroke, the majority, 79%, demonstrate inhibition of platelet function, as determined using the PFA-100, by ASA therapy at a mean dose of 2.9 mg/kg/day. The reason for the lack of inhibition of platelet function in 21% of pediatric patients, whether increased ASA dosage or alternative anti-platelet agents (e.g. clopidogrel) should be used in ASA ’resistant’ patients, and the relationship between ASA ’resistance’ and recurrence of arterial thrombotic events in children require further studies.

Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia

2006 ◽  
Vol 24 (12) ◽  
pp. 1917-1923 ◽  
Author(s):  
Sima Jeha ◽  
Paul S. Gaynon ◽  
Bassem I. Razzouk ◽  
Janet Franklin ◽  
Richard Kadota ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase Ii ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Median Number ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Heavily Pretreated

Purpose To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). Patients and Methods In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). Results The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade ≥ 3 were febrile neutropenia, anorexia, hypotension, and nausea. Conclusion Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

scholarly journals Antithrombin III Doses Rounded to Available Vial Sizes in Critically Ill Pediatric Patients

2017 ◽  
Vol 22 (1) ◽  
pp. 15-21
Author(s):  
Winifred M. Stockton ◽  
Eimeira Padilla-Tolentino ◽  
Carolyn E. Ragsdale
Keyword(s):  
Critically Ill ◽  
Low Molecular Weight Heparin ◽  
Pediatric Patients ◽  
Antithrombin Iii ◽  
Cost Savings ◽  
Pediatric Intensive Care ◽  
Acute Illness ◽  
Low Molecular Weight ◽  
Dose Administration ◽  
At Iii

OBJECTIVES Children have decreased levels of antithrombin III (AT III) compared to adults. These levels may be further decreased during acute illness. Administration of exogenous AT III can increase anticoagulant efficacy. The objective of this study was to evaluate AT III doses rounded to available vial sizes compared to partial vial doses in critically ill pediatric patients, including patients receiving extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). METHOD This retrospective review evaluated pediatric patients 0–18 years of age admitted to a 24-bed medical/surgical pediatric intensive care unit between June 1, 2012, and December 31, 2014, who received plasma-derived AT III. Patients received unfractionated heparin, low-molecular-weight heparin, or no anticoagulation. This review included patients who received ECMO and CRRT. RESULTS Eighty doses of AT III were administered to 24 patients (38 full vial size doses and 42 partial vial size doses). The AT III level following dose administration was ≥80% for 26 full vial doses (70%) and 16 partial vial doses (41%; p = 0.010). For patients who received multiple doses of AT III, the median time between doses was 45 hours following full vial doses, and 23 hours following partial vial doses (p = 0.011). Seven patients (29%) had documentation of new or increased bleeding. The median waste prevented from rounding doses to full vial sizes was 363 units. CONCLUSIONS After receiving AT III doses rounded to full vial sizes, patients were more likely to have a therapeutic AT III level and a longer interval between administrations. Rounding AT III doses to full vial sizes reduces waste and can result in cost savings.

AT III Barcelona: A Familial Quantitative-Qualitative AT III Deficiency

1988 ◽  
Vol 59 (01) ◽  
pp. 013-017 ◽  
Author(s):  
E Grau ◽  
J Fontcuberta ◽  
J Félez ◽  
I de Diego ◽  
R Soto ◽  
...  
Keyword(s):  
Antithrombin Iii ◽  
Normal Range ◽  
Affinity Adsorption ◽  
Crossed Immunoelectrophoresis ◽  
At Iii ◽  
Spanish Family ◽  
Slow Moving ◽  
Cofactor Activity ◽  
Ph Range ◽  
Thrombotic Tendency

SummaryA quantitative and qualitative deficiency of antithrombin III (AT III) was found in four members of a Spanish family with thrombotic tendency. In all affected members, levels of AT III antigen and activity (heparin cofactor activity) were reduced to 50% of the normal range. When crossed immunoelectrophoresis (CIE) was performed in the presence of heparin, an abnormal slow-moving peak was found. Crossed immunoelectrofocusing (CIEF) from normal and affected individuals showed that normal AT III migrated between pH 4.9–5.3 while the AT III under study was asymetrically distributed between two pH ranges: 4.9–5.3 and 4.6–4.8. Affinity adsorption of affected members’ plasma to heparin-sepharose beads revealed one population of AT III in the supernatant corresponding to the abnormal AT III, devoid of heparin cofactor activity and showing a peak between pH range: 4.6–4.8 in CIEF.Our data supports the view that a quantitative-qualitative deficiency was present in the heterozygous state in all the affected family members. Both normal and abnormal ATIII were present in plasma of the affected individuals. This abnormal ATIII was characterized by a lack of affinity for heparin. This familial ATIII deficiency was named ATIII Barcelona.

Molekularbiologische Grundlagen und Diagnostik der hereditären Defekte von Antithrombin III, Protein C und Protein S

1994 ◽  
Vol 14 (04) ◽  
pp. 199-208
Author(s):  
Irene Witt
Keyword(s):  
Protein C ◽  
Antithrombin Iii ◽  
Protein S ◽  
Klinische Relevanz ◽  
At Iii

ZusammenfassungDie enormen Fortschritte in der Molekularbiologie in den letzten Jahren ermöglichten sowohl die Aufklärung der Nukleotidsequenzen der Gene für Antithrombin III (AT III), Protein C (PROC) und Protein S (PROS) als auch die Identifizierung zahlreicher Mutationen bei hereditären Defekten dieser wichtigen Inhibitoren des plasmatischen Gerinnungssystems. Da die Gene für AT III (13,8 kb) und PROC (11,2 kb) nicht groß und relativ leicht zu analysieren sind, gibt es bereits umfangreiche »databases« der Mutationen (50, 73). Für AT III sind 79 und für RPOC 160 unterschiedliche Mutationen beschrieben.Sowohl beim AT-Ill-Mangel als auch beim Protein-C-Mangel hat die Mutationsaufklärung neue Erkenntnisse über die Struktur-Funktions-Beziehung der Proteine gebracht. Beim Protein-C-Mangel steht die klinische Relevanz der DNA- Analyse im Vordergrund, da die Diagnostik des Protein-C-Mangels auf der Proteinebene nicht immer zuverlässig möglich ist.Das Protein-S-Gen ist für die Analytik schwer zugänglich, da es groß ist (80 kb) und außerdem ein Pseudogen existiert. Es sind schon zahlreiche Mutationen bei Patienten mit Protein-S-Mangel identifiziert worden. Eine Database ist bisher nicht publiziert. Die klinische Notwendigkeit zur Mutationsaufklärung besteht ebenso wie beim Protein-C-Mangel. Es ist zu erwarten, daß zukünftig die Identifizierung von Mutationen auch beim Protein-S-Mangel beschleunigt vorangeht.

Inherited Antithrombin III Deficiency and Thrombo-Embolism

1975 ◽  
Author(s):  
O. Egeberg
Keyword(s):  
Pulmonary Embolism ◽  
Platelet Aggregation ◽  
Venous Thrombosis ◽  
Platelet Function ◽  
Autosomal Dominant ◽  
Antithrombin Iii ◽  
Dominant Inheritance ◽  
At Iii ◽  
Coagulation Assay ◽  
Antithrombin Iii Deficiency

Thrombophilia due to inherited deficiency of blood antithrombin III (AT III, heparin cofactor, anticonvertin) in a Norwegian family was published 1965, Thromb. D. h. 13, 516 & 14, 473. Only a few families with this defect have since then been described in different countries. In another Norwegian family, two sisters, age 42 and 30, and a brother, 35, have had episodes of venous thrombosis and pulmonary embolism from the age of 24–29. Their father suffered from thrombosis and died at 67. The two sisters have blood AT III level about half of normal average, measured with a two-stage coagulation assay. Data from both families are compatible with an autosomal dominant inheritance of the plasma protein deficiency. Venous thrombosis in the families is remarkably often complicated with embolizations; this might also relate to an inadequate platelet function. Platelet aggregation time of PRP with added thrombin or ADP was found prolonged. In coumarin treatment of the patients, AT III assaying gave increased levels.

scholarly journals Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia

Blood ◽  
1994 ◽  
Vol 84 (2) ◽  
pp. 564-569 ◽  
Author(s):  
JC Barredo ◽  
TW Synold ◽  
J Laver ◽  
MV Relling ◽  
CH Pui ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Remission Induction ◽  
Synthetase Activity ◽  
Folylpolyglutamate Synthetase ◽  
Blast Cells ◽  
Acute Nonlymphoblastic Leukemia ◽  
B Lineage ◽  
Specific Control

Abstract Folylpolyglutamate synthetase (FPGS) is responsible for the metabolism of natural folates and a broad range of folate antagonists to polyglutamate derivatives. Recent studies indicated increased accumulation of methotrexate (MTX) polyglutamates (MTX-PG) in blast cells as a predictor of favorable treatment outcome in childhood acute lymphoblastic leukemia (ALL). We determined the expression of FPGS activity in blasts from children with ALL at diagnosis and after treatment with MTX as a single agent, before conventional remission induction therapy. The levels of enzyme activity in ALL blasts at diagnosis (median of 689 pmol/h/mg protein) were significantly higher (P = .003) than those found in acute nonlymphoblastic leukemia (ANLL) blasts (median of 181 pmol/h/mg protein). Comparable lineage differences in normal lymphoid versus nonlymphoid cells suggest a lineage-specific control of FPGS expression, FPGS activity increased in ALL blasts after in vivo exposure to MTX. The median increase in FPGS activity was significantly higher (P = .003) in B-lineage ALL (188%) than in T-lineage ALL (37%). Likewise, the percentage of intracellular long chain MTX-PG (Glu3–6) was significantly higher (P = .02) in B- lineage ALL (92%) than in T-lineage ALL (65%), consistent with higher FPGS activity in B-lineage blasts. This finding could explain, at least in part, the superior outcome in children with B-lineage ALL treated with antimetabolite therapy.

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