Taru Hays

Low-dose tissue plasminogen activator thrombolysis in children

Purpose To compare results of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing. Methods Subjects consisted of all consecutive children with objectively confirmed thrombi for whom TPA thrombolysis was clinically ordered by the authors. Initial dosing used published standard dose (0.1–0.5 mg/kg per hour). With experience, a low-dose regimen (0.01–0.06 mg/kg per hour) was given in an attempt to derive a minimal effective dose. Results Thirty-five children were treated with TPA. Either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. In contrast to the recommended adult-derived dosages of 0.1 to 0.5 mg/kg per hour, the authors found that initial doses of less than 0.01 mg/kg per hour were effective in 12 of 17 patients with acute thrombosis. Neonates required 0.06 mg/kg per hour. Route of administration (local or systemic) did not affect efficacy. Major bleeding occurred in only one extremely preterm infant. Minor bleeding, primarily oozing at intravenous sites, occurred in 27% of children during TPA infusions. Prophylactic unfractionated or low-molecular-weight heparin was infused concomitant with TPA in 42% of the children and did not increase the risk of bleeding. Conclusions TPA in very low doses appears to be safe and effective for thrombolysis of acute thromboses in most children, given appropriate patient selection.

Combined thrombolytic and anticoagulant therapy for venous thrombosis in children.

OBJECTIVES To evaluate safety, efficacy, and outcome after combination thrombolytic and anticoagulant therapy. STUDY DESIGN An open nonrandomized clinical protocol with prospective standardized monitoring and data collection. Children with a documented first episode of deep vein thrombosis were treated with urokinase 4400 U/kg load and per hour with unfractionated heparin at 10 U/kg/h. At 48 hours heparin infusions were increased to achieve a therapeutic level for 5 days. Children were given therapeutic warfarin for at least 3 months. Outcome was assessed at 48 hours and > or =1 year with history, physical examination, high-resolution imaging, and Doppler ultrasonography +/- impedance and photo plethysmography. RESULTS Thirty-two children were treated. There was 1 thrombotic death, 1 nonfatal thrombus progression, and 1 pulmonary embolism. At 48 hours half of the children showed substantial clot lysis, and on follow-up these children had complete resolution and had no symptoms. Three children with poor early clot lysis had recurrent thromboemboli, pulmonary embolism, or both, 2 had limb pain and swelling, and 2 had asymptomatic swelling. Two children had minor bleeding, whereas systemic reactions were common. CONCLUSIONS Combination therapy in children (urokinase and unfractionated heparin) was safe and efficacious. A prospective, randomized, controlled study in children is needed.

Antiphospholipid antibodies and coagulation regulatory protein abnormalities in children with pulmonary emboli.

Purpose: To evaluate the demographics, presentation, family history, and laboratory findings in children with clinically recognized pulmonary emboli. Methods: Data were collected about children with clinically recognized pulmonary emboli from 1987 to 1994 at two pediatric hematology referral centers. Results: Sixteen children, mean age 11.8 years (standard deviation 4.69 years) including 11 boys were affected. Lower extremity thromboses were present in 7/14 children evaluated. Eight of the 16 children were apparently well before development of pulmonary emboli; seven were found to have antiphospholipid antibodies. None of the 15 children tested were antithrombin III deficient. One of 14 children tested was protein C deficient. Three of 13 children tested were protein S deficient or had a free protein S antigen at the fifth percentile. One of 10 children tested had an acquired dysfibrinogenemia. Two of nine children tested had the Factor V Leiden mutation. Conclusions: Our limited data suggest at least 70% of children with pulmonary emboli referred for hematology evaluation have antiphospholipid antibodies and coagulation regulatory protein abnormalities.

Hemolytic disease of the newborn caused by a high titer anti-group B IgG from a group A mother

To the Editor: A 3-day-old infant presented with jaundice. Hewas a term infant and first child of a 29-yearold black female whose pregnancy was complicated by upper respiratory infections and premature labor. His mother brought him to the hospital from home on his third day of life concerned about jaundice. He had no fever or evidence of birth trauma. He had not stooled since birth (3 days) and was having 2–3 wet diapers each day. Family history was notable for a lack of hemoglobinopathy, spherocytosis, anemia, or neonatal jaundice. On physical examination, he had dry mucus membranes and scleral icterus. He did not have a palpable spleen or liver. His total bilirubin was 28.6 mg/dl with an indirect bilirubin of 28.0 mg/dl. His white blood-cell count was 6,100/mm, hemoglobin 12.9 GMS%, hematocrit 37%, MCV 109.9 fl, RDW 17.6%, and platelet count 382,000 mm. The reticulocyte count was 9.8%. The peripheral blood smear revealed moderate numbers of spherocytes, ovalocytes, and macrocytes. His blood group was Bþ. He had a negative direct antiglobulin test, but weak positive indirect Coombs when tested on B cells. Maternal anti-B IgG titer was >1:1,024 and her blood group was Aþ. The patient received intravenous hydration, 5 days of phototherapy, no packed red blood cell transfusion, and continued breast-feeding. Returning to Hematology clinic at 17 months of age, he had a hemoglobin of 12.3 GMS%, hematocrit 36.5%,MCV 73.6 fL, RDW 14%, reticulocyte count 1.1%, total bilirubin of 0.2 mg/dl, and a peripheral smear without spherocytes. Osmotic fragility testing on both he and his sister was normal. He had no jaundice or hepatosplenomegaly, and was growing and developing normally. Anti-B IgG from a group A mother is an infrequent cause of hemolytic disease of the newborn (HDN) [1]. This is not surprising because the development of anti-Aor B IgG from group A or B mothers is rare [2–4]. Isohemaglutinins are naturally occurring antibodies and are usually IgM, and people who develop IgG isohemaglutinins are typically group O. Since there are fewer A and B antigenic sites on a newborn’s RBCmembrane, and alternative antigenic sites in other tissues to which these antibodies could bind, anti-A or B IgG infrequently causes clinically apparent HDN [5]. After considering physiologic jaundice and the jaundice associated with poor feeding and dehydration as potential causes of our patient’s hyperbilirubinemia, we believe that our patient’s mother’s high titer anti-group B IgG is pathologic. There are no clinical or laboratory criteria available to predict the severity of ABO associated HDN. Chen et al. [6] reported thatmaternal titers of anti-A or B IgG>1:512 correlated with increased risk of HDN in group Omothers. Our patient’s mother’s titer of>1:1,024 is unique, and another similar clinical case does not exist in the literature. Our experience leads us believe that high titer anti-B IgG fromagroupAmother can causeHDNand should be considered when there is an otherwise unexplained indirect hyperbilirubinemia in a newborn.

Giemsa-11 technique. Applications in the chromosomal characterization of hematologic specimens

SummaryUse of the Giemsa-11 procedure for the localization of heterochromatic regions of human chromosomes and for differentiation of primate and rodent chromosomes has been somewhat limited since its discovery in 1972. An adaptation of this technique to the cytogenetic characterization of hematologic specimens has aided in the interpretation of translocations, deletions, and inversions involving human chromosome 9. The chromosomal analyses of 10% of over 100 patients, principally leukemic, were aided through the use of this auxiliary procedure. The diseases of these patients are given and portions of karyotypes are presented to show clarification of abnormalities made possible through the use of the Giemsa-11 technique.

Hemolysis due to branch pulmonary stenosis after the arterial switch procedure.

An infant with d-transposition of the great arteries underwent arterial switch operation using the modified Jatene technique. Severe bilateral branch pulmonary artery stenosis and mechanical hemolysis subsequently developed. The hemolysis resolved after surgical repair of the stenotic arteries. Probable causes are discussed.

634 SPONTANEOUS REMISSION OF ACQUIRED VON WILLEBRAND'S DISEASE (VWD) FOLLOWING RESECTION OF WILM'S TUMOR

This report concerns a child with a Wilms tumor and laboratory evidence of vWD. The vWD was characterized by a prolonged PTT, low factor VIII (VIIIc), low ristocetin cofactor activity (VIIIr), low factor VIII antigen (VIIIag) and a prolonged bleeding time. In addition, she had low von Willebrands disease antigen II (vWagII) that has been shown by Montgomery and Zimmerman (Am Soc Hematol Plenary Session, Dec 1977) to be decreased in patients with classical vWD.The following studies were obtained:Since this child underwent an earlier uneventful tonsillectomy and both parents and a sibling have normal VIIIc, VIIIr, VIIIag and vWagII, this is felt to represent a spontaneous remission of an acquired vWD without VIIIc or VIIIr inhibitors. This picture of vWD with an VIIIag that is decreased more than the VIIIc and VIIIr has not previously been reported. Since VIIIag and vWagII are physically and immunologically distinct, the finding of decreased VIIIag and vWagII in this case of acquired vWD,as previously found in hereditary classical vWD, suggests that both are under similar genetic and/or synthetic control.

Premature chromosome condensation as a predictive indicator of relapse in children and adolescents with acute leukemia: initial observations.

Premature chromosome condensation has been used to determine a proliferative potential index (PPI) in a study of children in leukemia remission at varying times during the disease. Values 35% and greater were considered predictive of relapse. Such values preceded relapse with a mean of 5 months in acute lymphoblastic leukemia (ALL) patients who had previously relapsed and in myeloid leukemia patients. ALL patients followed from diagnosis and children off therapy had fluctuating and false predictive PPI values preceding long courses of continued remission. This study suggests that the PPI as a predictive indicator for relapse may be useful for patients with ALL who have previously relapsed and for patients with myeloid leukemias. Future exploration to further evaluate this mechanism of prediction is to be attempted by investigating the ability to obtain similar and more detailed information through the use of peripheral blood rather than bone marrow samples.

Methodology of premature chromosome condensation and its potential for relapse prediction in acute leukemia of children and adolescents

Premature chromosome condensation has been examined as a method for measuring the proliferative potential of bone marrow cells derived from children with acute leukemia with the intention of finding a predictor of relapse. A proliferative potential index (PPI) has been determined for patients with active disease at diagnosis and relapse, as well as at onset of remission and at extramedullary relapse. A modification of the technique established by Hittelman is described, which can be easily performed by the leukemia cytogeneticist. A PPI of 35% or greater is usually obtained for patients at diagnosis or in relapse. At the onset of remission, the PPI declines to values significantly below 35% and during extramedullary relapse the value of the PPI is near normal (12%). The method for the determination of the PPI is given in detail.

Results of systemic urokinase (UK) and heparin treatment for extensive venous thrombosis in children. |[dagger]| 667

Background: Extensive venous thromboses and resultant complications including post-phlebitic syndrome (PPS) are recognized in children with increasing frequency; optimal therapy has not been determined. We studied systemic UK and heparin therapy in children with documented extensive venous thrombosis.