Agnes J. Bishop

A syndrome of thrombosis and hemorrhage complicating l-asparaginase therapy for childhood acute lymphoblastic leukemia**

L-Asparaginase therapy for childhood acute lymphoblastic leukemia causes deficiencies of plasma hemostatic proteins, especially antithrombin, plasminogen, and fibrinogen. Severe thromboses and hemorrhages occurred in 18 children receiving vincristine, prednisone, and asparaginase therapy for ALL. Thirteen children had intracranial thrombosis or hemorrhage, four had extremity thrombosis, and one had both an intracranial hemorrhage and an extremity thrombosis. These events occur characteristically in the third and fourth weeks of therapy during or just after a three-week course of L-asparaginase. Symptoms of headache, obtundation, hemiparesis, and seizure were common for the intracranial events: local pain, swelling, and discoloration were common for the extremity thromboses. These complications have been recognized in 1 to 2% of children undergoing induction therapy which includes asparaginase.

Inherited platelet-storage pool deficiency associated with a high incidence of acute myeloid leukaemia

Summary A family with an inherited bleeding disorder extending over four generations, and multiple cases of myeloblastic and myelomonoblastic leukaemia was studied. Ten members of the family had, by history, a haemorrhagic diathesis. There were three documented cases of myeloblastic leukaemia, two documented cases of myelomonoblastic leukaemia and two more cases of leukaemia by history. In four of the cases the bleeding diathesis clearly antedated the leukaemia, in two by many years. The bleeding disorder is characterized by a long bleeding time, abnormal platelet aggregation, low platelet ADP and decreased numbers of platelet dense bodies consistent with a dense granule storage pool deficiency. The number of dense granules was decreased by immunofluorescence employing quinacrine or using an antibody to the dense granule membrane protein, granulophysin, confirming an absolute decrease in dense granule numbers rather than the presence of empty granule sacs. This congenital storage pool deficiency is associated with a high incidence of acute myeloid leukaemia in this family.

Growth hormone deficiency in patients with histiocytosis X.

Twenty-two patients with biopsy proved histiocytosis X, aged 10 months to 14 years (median 2 years) at the time of diagnosis, were observed for 6 months to 13 years (median 4 years). One patient who had received 3000 rads irradiation directly to the hypothalamic-pituitary area had clinical and biochemical evidence of growth hormone deficiency and responded to GH therapy. Thirteen patients had normal stature, normal growth velocity, and no diabetes insipidus. The GH response to insulin-induced hypoglycemia was studied in three of these 13 patients (group 1), in three children with short stature and no diabetes insipidus (group 2), and in five patients with diabetes insipidus but normal stature and growth velocity (group 3). Peak GH responses were normal (greater than 5 micrograms/L) in all patients in groups 1 and 2, but three of the five patients in group 3 had subnormal GH responses to insulin-induced hypoglycemia and to arginine, L-DOPA/propranolol, and exercise. Their growth rates continue to be normal over 6 to 14 years follow-up. Thus, although impaired GH responses were observed in four of the 12 patients tested, true growth failure occurred only in association with direct hypothalamic-pituitary irradiation. This experience and the observation that GH deficiency was diagnosed in fewer than 1% of children with histiocytosis in Canada during a 15-year period (accounting for less than 1% of all children with GH deficiency) suggest that classic GH deficiency is not a common complication of histiocytosis unless direct hypothalamic-pituitary irradiation has been given.

Increased nausea and vomiting induced by naloxone in patients receiving cancer chemotherapy.

To evaluate the role of endogenous opiates in chemo-therapy-induced nausea and vomiting, the narcotic-antagonist naloxone was administered to six pediatric patients receiving cancer chemotherapy. Naloxone was administered by continuous intravenous (i.v.) infusion after randomized, double-blind controlled assignment at a dose of 0, 10 or 40 micrograms/kg/h for 12 h. Each patient was studied for four consecutive and identical courses of chemotherapy (eight courses for each naloxone dose or 24 courses in all). A dose-related increase in nausea (nausea score 2.5 +/- 2.24, 3.83 +/- 2.73, and 5.75 +/- 2.86/12 h, p = 0.003), vomiting (emetic events 6.0 +/- 7.50, 8.08 +/- 6.71, and 10.3 +/- 8.91/12 h, p = 0.035), and patient aversion (course preference rank 1.5 +/- 0.45, 2.83 +/- 1.17, and 3.25 +/- 0.42/4 courses, p = 0.014) was observed. The infusion of naloxone in the absence of chemotherapy was without effect. These results support a role for endogenous opiates in regulating chemotherapy-induced nausea and vomiting, and further suggest that narcotic agents may be effective antiemetics in this setting.

Improved hemophilia A carrier detection by DDAVP stimulation of factor VIII

We studied the differential increase in FVIIIc and FVIII R:Ag after the intravenous infusion of 0.30 micrograms/kg DDAVP in 20 obligate hemophilia A carriers and in 20 female controls. FVIIIc increased in carriers (59.5 +/- 23.1 to 137.5 +/- 45.9) and in controls (98.0 +/- 20.7 to 259.9 +/- 57.4) (P less than 0.001), but the magnitude of the FVIIIc increase in carriers was less than that in controls by 51.9% (P less than 0.001). FVIII R:Ag increased comparably in carriers (105.2 +/- 30.4 to 171.9 +/- 25.4) and controls (92.1 +/- 33.0 to 165.2 +/- 20.6). Using the post-DDAVP instead of the standard FVIIIc/FVIII R:Ag ratio, hemophilia carrier detection was increased from 85% (with 10% false positive and 20% false negative assignments) to 95% (with 5% false positive and 5% false negative assignments). Toxicity associated with DDAVP infusion correlated linearly with doses greater than 10.5 +/- 1.3 micrograms/m2 (P less than 0.02) and with total doses greater than 17.0 +/- 4.5 micrograms (P less than 0.02). The use of DDAVP improves carrier detection in factor VIII-deficient hemophilia.

INCREASED NAUSEA AND VOMITING INDUCED BY NALOXONE IN PATIENTS RECEIVING CANCER CHEMOTHERAPY

To evaluate the role of endogenous opiates in chemotherapy-induced nausea and vomiting, the narcotic-antagonist naloxone was administered to six pediatric patients receiving cancer chemotherapy. Naloxone was administered by continuous intravenous infusion after randomized, double-blind controlled assignment at a dose of 0, 10 or 40 ug/kg/hour for 12 hours. Each patient was studied for four consecutive and identical courses of chemotherapy (eight courses for each naloxone dose, or 24 courses in all). A dose-related increase in nausea (nausea score 2.5 ± 2.24, 3.83 ± 2.73 and 5.75 ± 2.86 per 12 hours, p=.003), vomiting (emetic events 6.0 ± 7.50, 8.08 ± 6.71 and 10.3 ± 8.91 per 12 hours, p=.035) and patient aversion (course preference rank 1.5 ± 0.45, 2.83 ± 1.17 and 3.25 ± 0.42 per four courses, p=.014) was observed. The infusion of naloxone in the absence of chemotherapy vas without effect. These results support a role for endogenous opiates in regulating chemotherapy-induced nausea and vomiting, and further, suggest that narcotic agents may lye effective anti-emetics in, this setting.

906 A FAMILY WITH AN INHERITED PLATELET STORAGE POOL DEFECT ASSOCIATED WITH A HIGH INCIDENCE OF MYELOPROLIFERATIVE DISORDERS

A boy, age 5, presented with easy bleeding since birth and was found to have a long bleeding time, thrombocytopenia and abnormal platelet function (absent second wave aggregation with epinephrine, decreased aggregation to collagen but a normal first wave response to ADP and normal aggregation to arachidonic acid). His bone marrow was normal. At age 6½ years this boy developed progressive anemia, thrombocytopenia and splenomegaly, and was diagnosed as having juvenile chronic myelogenous leukemia. This childs father, grandfather and two of the grandfathers sisters were found to have a similar bleeding defect with a long bleeding time, mild thrombocytopenia, abnormal aggregation pattern similar to the propositus, and deficiency of platelet ADP, serotonin and dense bodies. Thrombin-induced arachidonic acid release, conversion of arachidonic acid to thromboxane B2 and phosphorylation of platelet proteins were normal. One of the grandfathers sisters with a lifelong bleeding tendency and a platelet storage pool deficiency documented at age 38, developed myelomonocytic leukemia at age 41. Another sister and a brother of the grandfather, bleeding history uncertain, died at ages 8 and 23 of leukemia. The great grandmother and her sister both with lifelong bleeding histories had died of leukemia. The findings suggest this family has an inherited platelet storage pool deficiency associated with an increased susceptibility to the development of a myeloproliferative disorder.

CEREBROSPINAL FLUID |[lpar]|CSF|[rpar]| B2 MICROGLOBULIN |[lpar]|B2M|[rpar]|: A NON-SPECIFIC INDICATOR OF CNS LEUKEMIA, SOMNOLENCE SYNDROME, AND THERAPY-RELATED CNS INJURY

To evaluate CSF B2M as a marker of CNS leukemia, B2M was measured in the CSF (N=485) and serum (N=178) of 58 children with ALL over a 34 month period. CSF B2M and/or the CSF/serum B2M ratio were increased in patients with blast cells on cytospin, previous CNS disease in remission, overt CNS involvement, the somnolence syndrome and recent intrathecal methotrexate (p<.005). CSF B2M increased with, but not prior to, the development of overt CNS disease and peaked 3-4 weeks therafter (N=4 patients). To evaluate CSF B2M as a marker of therapy-related CNS injury, 15 patients without CNS involvement were studied serially for 20 to 80 weeks from diagnosis. CSF B2M increased following intrathecal methotrexate alone (weeks 0 to 4) from 0.58±.44 to 0.77±.54 mg/l (p<.01). Following cranial irradiation (weeks 4 to 6), CSF B2M increased further to 1.00±.73 mg/l (p<.001), and peaked after six weeks. A second peak (2.14±1.47 mg/1) was observed after 26 weeks. CSF B2M returned towards pre-therapy levels by the end of the first year. It is concluded that CSF B2M increases in response to overt but not occult CNS leukemia and to therapy-related CNS injury. The latter follows a predictable bi-modal curve following cranial irradiation and intrathecal methotrexate during the first year of treatment. Studies demonstrating production of B2M by endothelial cells in culture suggest that the source of the elevated CSF B2M seen following CNS therapy, in the absence of overt CNS leukemia, may be vascular.

A REEVALUATION OF THE BLEEDING TIME

A multivariate analysis of results of 512 individuals, (more than half less than 20 years of age) referred to the University of Manitoba Coagulation Laboratory, was performed to assess the relationship of age, sex, and various coagulation parameters to the length of the bleeding time (BT). Patient age (children had longer BTs than adults, even with other factors normal), platelet aggregation to collagen and epinephrine, platelet adhesion (ADH) and prothrombin consumption (PC) emerged as important and independent variables (p<0.01). Controlling for other variables, including von Willebrand (vW) Ag and ristocetin cofactor (RC), did not change the correlation of ADH and BT, but decreased that between PC and BT. Where vWAg, vWRC and factor VIII were all less than 120%, there was a weak negative correlation between the length of the BT and vWAg or vWRC. In contrast, where any one of these three parameters was 120% or greater, there was a weak positive correlation between vWAg or vWRC and the BT. However, the mean BT of all (8) patients with vWAg or vWRC less than 55%, normal aggregation and PC greater than 80%, was in the normal range (7.56 min). The view that vWAg level, or activity as assessed by vWRC, is, by itself, a major determinant of the length of the BT should be revised. Platelet adhesion, independent of factor level (vWAg) or activity (vWRC) appears more important.