William E. Hathaway

Hyperviscosity in the neonate

Clinical and blood viscosity studies were performed in a group of 18 polycythemic newborn infants. The infants had signs and symptoms such as plethora, cyanosis, respiratory distress, central nervous system manifestations, hyperbilirubinemia, thrombocytopenia, fragemented red cells, and hypoglycemia. The whole blood of these infants showed increased viscosity when compared to normal limits for healthy newborn infants. The pathogensis of the clinical manifestations associated with hyperviscosity is discussed. Studies indicate the possible importance of erythrocyte deformability in hyperviscosity of the neonate. The newborn infant is uniquely susceptible to developing hyperviscosity. Clinical manifestations associated with hyperviscosity may results in permanent sequenllae in these infants. Partial exchange transfusion results in an improvement in the whole blood viscosity which is associated with an improved clinical course.

Coagulopathy and platelet activation in Kawasaki syndrome: Identification of patients at high risk for development of coronary artery aneurysms

Prospective evaluation of platelet activation and hypercoagulability was performed in 31 patients with Kawasaki syndrome. Most patients had elevated acute-phase reactants when studied during the first 3 weeks of their illness; 17 of 25 (68%) patients had factor VIII activity greater than 150%, 18 of 24 (75%) had fibrinogen greater than 400 mg/dl, and 17 of 31 (55%) had a platelet count greater than 450,000/mm3. Antithrombin III was depressed initially in 17 of 25 (68%) patients. Depleted fibrinolytic activity, as measured by a euglobulin lysis time greater than 300 minutes, was documented in nine of 20 (45%) patients. Plasma beta-thromboglobulin (BTG) measured at 0 to 3 weeks was elevated (greater than 43 ng/ml) in seven of 24 (29%) patients. All patients with coronary artery aneurysms had elevated BTG values. The mean BTG in the group with aneurysms was 72.3 ng/ml when measured during the first 3 weeks after onset of fever, and 87.7 ng/ml at 4 to 7 weeks. The group without aneurysms had mean BTG values of 29.4 and 28.3 ng/ml at 0 to 3 and 4 to 7 weeks, respectively. The difference between the two groups was significant (P less than 0.002) for both the initial and later values. An elevated BTG during the first 3 weeks after onset of fever was highly associated with aneurysm formation in our patients (P less than 0.007). No aneurysms occurred in patients with a normal BTG value.

Homozygous protein S deficiency in an infant with purpura fulminans

Protein C, a vitamin K--dependent zymogen, and its cofactor, protein S (also vitamin K dependent), play major roles in the anticoagulant system for limiting thrombus formation.I, 2 Deficiency of either protein C or S is associated with recurrent familial thrombosis. 35 Several reports have described purpura fulminans caused by severe homozygous protein C deficiency in neonates and infants. 6, 7 However, deficiency of protein S has not been reported as a cause of neonatal purpura fulminans. We describe a 2-year-old infant with homozygous protein S deficiency who has had relapsing purpura fulminans since the age of 10 days. A brief account of this patient has been published)

The coagulopathy of childhood leukemia thrombin activation or primary fibrinolysis

Little information is available on the prevalence and etiology of the coagulopathy present in some children with acute leukemia at disease presentation. We studied 102 children with newly diagnosed acute leukemia (50 retrospective: Group A; and 52 prospective: Group B) with prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), fibrinogen (FIB), and fibrin degradation products (FDP). All patients in Group B also had assessment of thrombin activation by measurement of the crosslinked fibrin fragment, D‐dimer, and of primary fibrinolysis with the Bβ 1‐42 peptide. Additionally, ten patients from Group B had Factors II, V, VII, and × measured, and eight of these patients had measurement of tissue factor from sonicated bone marrow cells. Thirty‐two percent of Group A and 40% of Group B had totally normal coagulation studies, whereas 20% of Group A and 10% of Group B had a severe coagulopathy on disease presentation. A high percentage of both groups had elevated PT (Group A, 52%; Group B, 27%) and increased FDP (Group A, 39%; Group B, 25%). In Group B, 38% of the patients had a positive D‐dimer, whereas only 4% of this prospective group had an elevated Bβ 1‐42 peptide (P < 0.00001). Nine of ten patients with a positive D‐dimer had low levels of one or more of the extrinsic pathway factors. Three of four patients with the highest tissue factor levels were of monocytoid leukemia cell type. These data indicate that the coagulopathy associated with acute leukemia of childhood is usually mediated by thrombin activation.

The prothrombin Denver patient has two different prothrombin point mutations resulting in Glu‐300→Lys and Glu‐309→Lys substitutions

Dysprothrombinaemia is a rare, congenital cause of bleeding. Fewer than 25 families who express a functional prothrombin (factor II) defect have been reported. The original patient with prothrombin Denver had a severe haemophilia‐like bleeding disorder treated with weekly prophylactic factor replacement. Analysis of factor II activity and antigen in the patient showed a factor II activity of 5 units/dl and factor II antigen of 21 units/dl. Genomic DNA from the patient, mother and brother was obtained from peripheral blood white cells. Oligonucleotides were constructed, and prothrombin exons were amplified via polymerase chain reaction (PCR). The entire sequence of the thrombin portion of the molecule (exons VIII–XIV) and that of exons I–II and IV–VII was determined. This moderately severe dysprothrombinaemia was found to be associated with compound heterozygosity for two different Glu→Lys point mutations, at amino acid positions 300 and 309. Assays of plasma from the prothrombin Denver proband suggested that the functional defect was in the activation of zymogen to enzyme.

Comparison of oral and parenteral vitamin K prophylaxis for prevention of late hemorrhagic disease of the newborn

4. Ascher DP, Wilson S, Fischer GW. Comparison of bacteremia and antigen detection in a neonatal group B streptococcal sepsis model [Abstract 1602]. Society for Pediatric Research. Anaheim, Calif., May 6-11, 1990. 5. Harris MC, Deuber C, Polin RA, et al. Investigation of apparent false-positive urine latex particle agglutination tests for the detection of group B streptococcal antigen. J Clin Microbiol 1989;27:2214-7. 6. Morris B, Morris R. Macromolecular uptake and transport by the small intestine of the suckling rat. In: Hemmings WA, ed. Antigen absorption by the gut. Lancaster, United Kingdom: MTP Press, 1978:23-30. 7. Roberton M, Paganelli R, Dinwiddie R, Levinsky RJ. Milk antigen absorption in the preterm and term neonate. Arch Dis Child 1982;57:369-72. 8. Vukavic T. Timing of gut closure. J Pediatr Gastroenterol Nutr 1984;3:700-3. 9. Courcal R J, Roussel-Delvallez M, Puech F, Delecour M, Martin GR. Bacteriological analysis of amniotic fluid. Biol Neonate 1982;42:166-73.

Factor VIII and renal disease.

Excerpt To the editor: Recent studies (1-3) have indicated that levels of factor VIII are increased in chronic renal disease. One study (3) in which patients were seen over a period of 4 years show...

Monitoring hypercoagulability and hypofibrinolysis following acute venous Thromboembolism in Children: Application of the CloFAL assay in a prospective inception cohort study

Although individual thrombophilia tests are frequently performed in children with venous thromboembolism (VTE), global assays provide the opportunity to fill the gap in knowledge regarding their net impact on overall coagulative (and in some cases fibrinolytic) function. We first evaluated analytic sensitivity of the Clot Formation and Lysis (CloFAL) global assay to hypercoagulability and alterations in fibrinolysis, and then characterized changes in plasma coagulative and fibrinolytic capacities over time in children with acute VTE. In plasma ex vivo and in vitro experiments, the CloFAL assay area-under-the-curve (AUC) was analytically sensitive to hypercoagulable states, and its modified fibrinolytic index (FI2) was sensitive to both hyper- and hypofibrinolytic conditions. Clinical data and plasma samples for assay were collected during follow-up of 50 children enrolled in a prospective inception cohort study of VTE from May 2006 to June 2010. Follow-up periods were designated as follows: acute (<1 month post-event), sub-acute (1-3 months), early chronic (3-12 months), and late chronic (>12 months). Since most children were sampled at fewer than three pre-defined follow-up periods, study population findings were grouped by timepoint. AUC was significantly increased, and FI(2) significantly decreased, in the acute period of VTE when compared to healthy controls, indicating hypercoagulability and hypofibrinolysis, respectively. One-third of patients were hypercoagulable, and 23% were hypofibrinolytic, in the late chronic phase. AUC and FI(2) were strongly correlated with functional fibrinogen levels. These findings indicate the utility of the CloFAL assay in monitoring plasma coagulative and fibrinolytic capacities in children with VTE. Studies of its potential role in outcome prediction are ongoing.

The prolonged thrombin time of nephrotic syndrome

Purpose Little information is available that documents the incidence and possible etiology of a prolonged thrombin time (TT) found in children with nephrotic syndrome. We speculated that this prolonged TT might best be explained by an altered fibrinogen similar to that found in the newborn. Patients and Methods We describe 20 children with nephrosis, an unexplained prolonged TT and reptilase time (RT), and an elevated fibrinogen level. Thrombin and/or plasmin effect on plasma fibrinogen was studied by analyzing for soluble monomer, D-dimer, fibrin degradation products, Bβ 1–42 peptide, and by polyacrylamide gel electrophoresis (PAGE) and agarose electrophoresis. Structural changes in the fibrinogen molecule were investigated using two- dimensional gel (2D gel) electrophoresis. Fibrinogen was purified via glycine precipitation, and the sialic acid (SA) content was determined. Results No evidence for in vivo thrombin and/or plasmin effect on fibrinogen could be detected in 13 of 20 children tested. Additionally, no fibrin/fibrinogen degradation products or soluble fibrin complexes were detected using PAGE or agarose electrophoresis in this group of patients. The Bβ isoforms of nephrosis fibrinogen were similar in isoelectric point on 2D gel electrophoresis to those of fetal fibrinogen and demonstrated a greater electronegative shift when compared with normal adult fibrinogen. Also, the SA content of nephrosis and fetal fibrinogen were greater than that measured in adult fibrinogen. Both nephrosis and fetal fibrinogen were more resistant to neuraminidase treatment than was normal adult fibrinogen. Conclusions These data support the notion that an altered fibrinogen exists in some children with nephrotic syndrome characterized by an increased TT and RT, elevated fibrinogen, and both an increased negative charge and SA content.

Lack of effectiveness of intranasal administration of human factor VIII.

Excerpt To the editor: In light of recent reports of administration of insulin and other proteins via the nasal route (1-3), we studied the intranasal administration of human factor VIII:C to sever...