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October 2001


D-dimer and prothrombin fragment 1+2 levels after acute deep venous thrombosis
The activated enzymes of coagulation and fibrinolysis are the key players in the pathophysiology of acute deep venous thrombosis. The measurable byproducts of their activation include D-dimer fibrin degradation products formed by the action of plasmin on cross-linked fibrin; prothrombin fragment 1+2 generated by factor Xa in the cleavage of prothrombin to thrombin; fibrinopeptide A formed in the thrombin-mediated conversion of fibrinogen to fibrin; and thrombin-antithrombin complex formed by the combination of thrombin with its primary inhibitor. Among these, prothrombin fragment 1+2 reflects the degree of thrombin activation, whereas D-dimer reflects fibrinolytic activity and intravascular thrombus. The authors studied 61 patients admitted to the University of Washington Medical Center with acute DVT as confirmed by duplex ultrasonography. These patients had a median, initial thrombosis score of three and were followed up for 266 days on average. Of the patients, 92.7 percent showed initial D-dimer levels that were elevated and that were associated with the extent of the thrombus (P=.003). Prothrombin fragment 1+2 levels were increased in 94.5 percent of the patients and were lower in those with isolated calf vein thrombosis (P=.001). Forty-three percent of the patients showed recurrent thrombosis during followup. These patients had initial D-dimer and prothrombin fragment 1+2 levels that were significantly higher than those of the remaining patients. D-dimer levels of 500 ng/mL or greater had a sensitivity of 100 percent and specificity of 53.9 percent in detecting late and early recurrences of DVT. D-dimer levels of 1,000 ng/mL or greater had a sensitivity of 89.3 percent and specificity of 35.6 percent. The authors concluded that prothrombin fragment 1+2 levels are less sensitive to thrombus score than initial D-dimer levels and return to baseline more quickly, whereas increased D-dimer levels are sensitive but nonspecific markers for recurrence of DVT.

Meissner MH, Zierler BK, Bergelin RO, et al. Markers of plasma coagulation and fibrinolysis after acute deep venous thrombosis. J Vasc Surg. 2000;21:870-880.

Reprints: Mark H. Meissner, MD, Dept. of Surgery, Box 359796, Harborview Medical Center, 325 9th Ave., Seattle, WA 98195; meissner@u.washington.edu


Enzyme immunoassay testing vs. stool specimen examination for detecting Giardia lamblia
Giardiasis is the most common enteric parasitic infection in the United States, with an estimated 500,000 to 1 million cases occurring annually. The diagnostic sensitivity of conventional ovum-and-parasite examination of a single stool specimen has been reported to be quite low. Multiple O&P examinations, therefore, are often necessary and generally recommended. The commercial availability of enzyme immunosorbent assays for detecting Giardia-specific antigens in stool specimens has provided an additional tool for diagnosing giardiasis. The authors studied 206 stool samples collected from 103 patients using conventional O&P examination and the Prospect Giardia microplate assay (Alexon-Trend Inc., Ramsey, Minn.). Two stool specimens were collected from each patient within a seven-day period. Specimens meeting the following criteria were considered to be positive for G. lamblia: positive by O&P examination and positive or negative by Giardia EIA; negative by O&P examination and positive by Giardia EIA if the specimen was positive by Giardia EIA upon repeat and the other specimen in the pair was positive by O&P examination, or the other specimen in the pair was negative by O&P examination but repeatedly positive by Giardia EIA, or the other specimen in the pair was negative by Giardia EIA but the patient was clinically symptomatic and was treated for giardiasis. Of those patients determined to be infected with G. lamblia, 40 percent were symptomatic and 60 percent were asymptomatic. Fifty-four (26.2 percent) stool samples collected from 30 (29.1 percent) patients were positive for G. lamblia. Conventional O&P examination detected 88.9 percent of the positive specimens while the Giardia EIA detected 96.3 percent. Two O&P-negative specimens were initially positive but negative on repeat using the Giardia EIA, and they were considered false-positive results (specificity, 98.7 percent). Giardia EIA was determined to have a diagnotic sensitivity of 96.3 percent and specificity of 98.7 percent on paired stool samples. The sensitivity of Giardia EIA on a single stool sample was 80 percent, which is better than conventional O&P examination of a single specimen but not equivalent in sensitivity to O&P examination of two stool specimens. Conventional O&P examination of two independently collected stool specimens yielded a diagnostic sensitivity of 93.3 percent. The authors concluded that although the sensitivity of the Giardia EIA on a single stool specimen was higher than that of conventional O&P examination in symptomatic patients (83 percent and 75 percent, respectively), in asymptomatic patients (77 percent and 61 percent, respectively), and overall (80 percent and 67 percent, respectively), the examination of two stool specimens by EIA or conventional O&P examination was necessary to achieve a diagnostic sensitivity of greater than 90 percent.

Hanson KL, Cartwright CP. Use of an enzyme immunoassay does not eliminate the need to analyze multiple stool specimens for sensitive detection of Giardia lamblia. J Clin Microbiol. 2001;39:474-477.

Correspondence: Charles P. Cartwright, MD, Clinical Laboratories, MC #812, Hennepin County Medical Center, 701 Park Ave., Minneapolis, MN 55415; charles.cartwright@co.hennepin.mn.us


Serum creatinine vs. creatinine clearance in peritoneal dialysis patients
Inadequate peritoneal dialysis is associated with increased morbidity and mortality. Current methods for measuring dialysis adequacy are to do a creatinine clearance and urea clearance weekly. These are proxy measures for as yet unknown toxic metabolites accumulating in uremia. Both require a 24-hr collection of peritoneal effluent and urine. This poses considerable difficulty and is an inconvenience for frail patients who have to bring the collection to the hospital for analysis. In 1976, Cockcroft and Gault developed a method of estimating creatinine clearance from a patient’s serum creatinine, age, gender, and weight. The method is relatively accurate, even at lower levels of renal function, despite the influence of the tubular secretion of creatinine. The authors undertook a study to examine whether the estimated creatinine clearance using this formula correlates with the creatinine clearance measured by the conventional method of 24-hr collection in peritoneal dialysis patients. The study was a retrospective analysis of creatinine clearance results derived from conventional 24-hr collections in 20 male and 15 female patients being treated at a hospital in Scotland. All patients were on peritoneal dialysis, and the results were systematically compared with the serum creatinine estimation of creatinine clearance using the formula from Cockcroft and Gault. The authors found a strong correlation between the two methods (r=0.82; P<0.0001). The formula, however, tended to overestimate clearances. The positive predictive value of the formula was 88 percent and the negative predictive value was 86 percent for detecting inadequate dialysis. The authors concluded that the creatinine clearance calculated using the Cockcroft and Gault formula can be used in patients on peritoneal dialysis to estimate adequacy of dialysis. This method represents a far less expensive and time-consuming alternative to 24-hr collections.

Stirling CM, Simpson K, Boulton-Jones M. Serum creatinine can predict adequacy of peritoneal dialysis—preliminary report. Clin Nephrol. 2000;54:400-403.

Reprints: C. M. Stirling, MD, Renal Unit, Dumfries and Galloway Royal Infirmary, Bankend Rd., Dumfries DGI 4AP, United Kingdom


Factor V Leiden and habitual abortions
The incidence of habitual spontaneous abortion, defined as three or more repeated miscarriages, is in the range of 0.4 to 0.8 percent in the fertile population. Established risk factors for this condition include chromosomal aberrations, anatomical malformations, hormonal imbalance, and phospholipid antibodies. In addition, interest has more recently focused on inherited abnormalities of the coagulation system, which are apparently associated with an increased predisposition to thromboembolic complications and recurrent abortions. The mutation known as Factor V Leiden and the polymorphism known as the prothrombin variant have been studied, but their impact in habitual abortions is unclear. Increased levels of homocysteine have also been described in women having recurrent abortions, and supplementation with folic acid has improved pregnancy outcome in this group. The authors studied women experiencing habitual abortions, with particular regard to the prevalence of thrombophilic mutations. The authors’ hypothesis was that Factor V Leiden and the prothrombin variant would be over-represented in women with habitual abortions. They undertook a prospective case control evaluation of 84 women who had experienced three or more consecutive miscarriages and who were referred to the reproductive medical center at the Karolinska Institute in Stockholm, Sweden. The patients were compared with 69 control subjects. Factor V Leiden and prothrombin variant were determined by PCR. The authors found that 27.8 percent of the women who had primary habitual abortions carried the Factor V Leiden mutation, but no difference was observed in the prevalence of the prothrombin variant in this group. The authors concluded that the Factor V Leiden mutation may play a considerable role in primary recurrent abortions.

Wramsby ML, Sten-Linder M, Bremme K. Primary habitual abortions are associated with high frequency of Factor V Leiden mutation. Fertil Steril. 2000;74:987-991.

Reprints: Margaretha Wramsby, MD, Dept. of Woman & Child Health, Karolinska Institute, Box 140, 171 76 Stockholm, Sweden; margaretha.wramsby@kbh.ki.se


Prevalence of iron deficiency and cognitive impairment in
school-aged children

Iron deficiency is the most common hematologic disorder in childhood, but the cognitive effects of iron deficiency, particularly without anemia, are not well studied. The authors examined data from The National Health and Nutrition Examination Survey (NHANES) III, in which children between the ages of six and 16 years were studied. Iron status was assessed by measuring transferrin saturation, free erythrocyte protoporphyrin, and serum ferritin. Children were considered iron deficient if two of these three values were abnormal for age and gender. Hemoglobin levels were also assessed. The standardized cognitive measurements used were the Wechsler Intelligence Scale for Children-Revised and the Wide Range Achievement Test-Revised. Three percent of the 5,398 children studied had iron deficiency. Iron deficiency without anemia was more prevalent than iron deficiency with anemia. And iron deficiency was more prevalent in 12- to 16-year-old females than among six- to 11-year-old children (8.7 percent versus 1.8 percent, respectively). Iron deficiency without anemia was more prevalent in this group as well (7.2 percent). The authors found that the prevalence of iron deficiency was greater than five percent among children living below the poverty level. Average math scores were lower for the iron-deficient children without anemia compared with children with normal iron status (87.4 versus 93.7; P<0.05), as were math scores for children who had iron deficiency with anemia (86.4 versus 93.7; P<0.05). Other variables, such as age, gender, race, poverty status, caretaker status, and lead status, were also examined, but only children with iron deficiency had significantly elevated risk for scoring lower in math. The three percent of children in this study potentially represent 1.2 million school-aged children and adolescents in the United States. Depending on the findings of additional, confirmatory studies, screening programs for iron deficiency (particularly for those without anemia and for those who are at high risk) may be warranted.

Halterman JS, Kaczorowski JM, Aligne CA, et al. Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics. 2001;107:1381-1386.

Correspondence: Jill S. Halterman, MD, University of Rochester School of Medicine, 777, Strong Memorial Hospital, 601 Elmwood Ave., Rochester, NY 14642; jill_halterman@urmc.rochester.edu


Differentiating chemical from bacterial meningitis after neurosurgical procedures
Differentiating chemical (sterile) meningitis from bacterial meningitis following neurosurgery can be problematic. The authors retrospectively studied 70 patients who had undergone a spinal tap following a neurosurgical procedure. Those with shunts or reservoirs were excluded. Postoperative meningitis was diagnosed if the patient had more than 5 WBC/µL (>5 x 106/L) in nonbloody spinal fluid, or a WBC:RBC ratio of greater than 1:100, or positive cultures. Patients with 5 to 25 WBC/µL (5-25 x 106/L) who reported no headache, change in mental status, or fever not felt secondary to possible meningitis, and negative Gram stain results and cultures were excluded. Chemical meningitis was defined as meningitis with negative spinal fluid Gram stain, negative cultures, and patient recovery without the use of antibiotics. Bacterial meningitis was defined as positive spinal fluid cultures for a significant organism. Patients with cerebrospinal fluid pleocytosis and negative cultures but with a parameningeal focus of infection were classified as having bacterial infections. Patients with negative spinal fluid Gram stains and cultures who received antibiotics after their spinal tap were classified as "indeterminate." Spinal fluid WBC counts in patients with chemical meningitis ranged from 39 to 7,200/µL (39-7,200 x 106/L). Four of 20 patients with bacterial meningitis and no patient with chemical meningitis had a WBC count of more than 7,500 WBC/µL. Spinal fluid glucose levels were less than 40 mg/dL (or less than one-half of blood glucose levels in nondiabetics or less than one-third of blood glucose levels in diabetics) in eight of 17 patients with bacterial meningitis and six of 30 patients with chemical meningitis. (Five of six patients with chemical meningitis who had decreased CSF glucose levels had a CSF RBC count of greater than 15,000/µL.) A glucose level of less than 10 mg/dL was seen only in patients with bacterial- or indeterminate-related meningitis. The mean CSF protein was similar in all groups. Five of 20 patients with bacterial meningitis had positive Gram stains, and cultures grew mixed organisms in three cases and a single organism in 17 cases. Staphylococcus aureus was the common etiologic organism found (eight of 20 patients). Chemical meningitis is a common complication after neurosurgery. Spinal fluid findings can be similar in chemical and bacterial meningitis, however, a spinal fluid WBC count of greater than 7,500/µL and a glucose level of less than 10 mg/dL were present only in patients with bacterial meningitis.

Forgacs P, Geyer CA, Freidberg SR. Characterization of chemical meningitis after neurological surgery. Clin Infect Dis. 2001;32:179-185.

Correspondence: Pierre Forgacs, MD, Section of Infectious Diseases, Lahey Clinic Medical Center, 41 Mall Rd., Burlington, MA 01806


Growth hormone stimulation tests in children
The diagnosis of growth hormone deficiency involves assessing anthropometric variables in children: height, weight, growth velocity, and measurement of growth factor concentrations and frequent blood sampling to determine growth hormone concentrations. Growth hormone stimulation tests have become the standard of care for assessing short statured children when attempting to describe or decide on growth hormone secretory status. Such tests also are helpful in assessing the therapeutic benefit of growth hormone therapy and are used routinely by more than 80 percent of pediatric endocrinologists in the United States. The issue of what is normal response to stimuli remains elusive and depends on the assay used and the normative data established for that assay. The authors performed a study to test a novel immunofunctional growth hormone assay, making use of the dimerization of two growth hormone receptors that is accomplished by one growth hormone molecule. Results of this method were compared with those obtained using two growth hormone assays, an enzyme-linked immunosorbent assay, and an immunoradiometric assay. The comparisons were done in 19 children with short stature who were undergoing growth hormone stimulation testing at the University of Virginia Medical Center. The authors also tested 13 children with normal stature who served as controls. They used arginine and L-dopa or insulin-induced hypoglycemia as secretagogues for the test. They also measured concentrations of IGF-1, IGFBP-3, and acid labile subunit. They found a significant correlation between the peak immunofunctional growth hormone level and the ELISA growth hormone responses to stimuli, as well as between the ELISA and the immunoradiometric assay. No significant differences were noted between the short statured and normal statured children in peak or mean growth concentrations, regardless of the assay used. The IGF-1, IGFBP-3, and ALS concentrations were substantially lower in the short stature group. The authors concluded that sensitive growth hormone assays, ELISAs, and immunoradiometric assays detect a growth hormone capable of generating a biological signal comparable to the immunofunctional growth hormone assay and, furthermore, that normal growth hormone stimulation test results can be substantially lower than had been previously accepted as norms. The growth hormone-dependent growth factors may be more sensitive indicators of growth hormone sufficiency than growth hormone concentrations.

Mauras N, et al. Growth hormone stimulation testing in both short and normal statured children: use of an immunofunctional assay. Pediatr Res. 2000;48:614-618.

Reprints: Nelly Mauras, MD, Nemours Children’s Clinic & Research Programs, 807 Nira St., Jacksonville, FL 32207


Use of cTnI and cTnT in selecting heart donors and as predictors of early graft failure
A study was conducted to evaluate the clinical efficacy of measuring cardiac troponin I and cardiac troponin T for the purpose of selecting heart donors and as predictors of early graft failure after heart transplantation. A total of 118 donors were retrospectively studied and divided into three groups: group I, donors with good graft function after heart transplant; group II, donors with impaired graft function after heart transplant; and group III, donors rejected for heart transplant. The groups did not differ with regard to donor age, gender, and cause of death. The mean cTnI value for group I was 0.36±0.88 µg/L; for group II was 4.45±3.28 µg/dL; and for group III was 3.02±88 µg/L. The cTnI value was significantly lower in group I than in groups II and III (P<0.0001 and P=0.018, respectively). The difference between groups II and III was also significant (P=0.023). The mean cTnT value for group I was 0.016±0.029 µg/L; for group II was 0.134±0.114 µg/L; and for group III was 0.123±0.245 µg/L. The cTnT value was significantly lower in group I when compared to groups II and III (P<0.0001 and P=0.012, respectively). No difference in cTnT value was noted between groups II and III (P=0.13). A cTnI value of greater than 1.6 µg/L as a predictor of early graft failure had a sensitivity of 73 percent and specificity of 94 percent. A cTnT value of greater than 0.1 µg/L as a predictor of early graft failure had a sensitivity of 64 percent and specificity of 98.5 percent. No significant differences were found between the groups for myoglobin, creatine kinase, CK-MB activity and mass, or CK:CK-MB ratio. The authors concluded that an increased cardiac troponin value was a predictor of early graft failure after heart transplantation. They found elevated levels of cTnT and cTnI in donors with ongoing heart dysfunction and determined that these donors should be carefully evaluated for heart transplantation.

Potapov EV, et al. Value of cardiac troponin I and T for selection of heart donors and as predictors of early graft failure. Transplantation. 2001;71:1394-1400.

Correspondence: Evgenij V. Potapov, MD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; potapov@dhzb.de


Coagulation factors and spontaneous abortion
A study was undertaken to examine the association between levels of hemostatic factors early in pregnancy and the risk of sporadic spontaneous abortion. Spontaneous abortion was defined as pregnancy loss prior to 22 weeks’ gestation. Thirty-three spontaneous abortions occured during the followup period. Ninety-nine women who remained pregnant at 22 weeks’ gestation served as the control group. Fibrinogen, factor VII antigen, activated protein C-sensitivity ratio, protein S, and plasmin-antiplasmin were measured prior to spontaneous abortion and during followup. The mean level of fibrinogen was 3.1 g/L among the cases of spontaneous abortion and 3.7 g/L among the pregnant controls (P=0.003). The mean level of factor VII antigen was 89 percent of normal among the cases of spontaneous abortion and 109 percent of normal among the controls (P=0.01). Although within the normal ranges, the reduced levels of fibrinogen and factor VII antigen in cases of spontaneous abortion remained after accounting for cocaine use and vaginal bleeding. Differences in the mean levels of plasmin-antiplasmin between spontaneous abortion cases and controls were marginally significant. Women with a fibrinogen level of less than 3.0 g/L were five times more likely to have a spontaneous abortion than women with fibrinogen levels at or above 3.0 g/L. Factor VII antigen levels below 94 percent of normal were associated with a threefold-increased risk of spontaneous abortion. These low levels were found prior to spontaneous abortion and were independent of other known risk factors.

Nelson DB, et al. Influence of hemostatic factors on spontaneous abortion. Am J Perinatol. 2001;18:195-201.

Correspondence: Deborah B. Nelson, PhD, Center for Epidemiology and Biostatistics, University of Pennsylvania, 922 Blockly Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021