Are activated clotting times helpful in the management of anticoagulation with subcutaneous low-molecular-weight heparin?

BACKGROUND: Enoxaparin has recently been shown to be superior to unfractionated heparin in patients with unstable angina/non-ST-elevation myocardial infarction. Theoretical advantages of low-molecular-weight heparin versus unfractionated heparin include a higher ratio of anti-Xa to anti-IIa activity (3:1 for enoxaparin), a more predictable dose response that precludes the need for frequent monitoring, and the convenience of subcutaneous administration. Both activated partial thromboplastin time and activated clotting time (ACT) are used to monitor anticoagulation with heparin, and ACTs are now standard during percutaneous coronary intervention (PCI) with heparin. At doses of up to 90 mg, subcutaneous enoxaparin leads to a modest dose-related increase in activated partial thromboplastin time, but the effect on ACT is unknown. METHODS: Thrombolysis In Myocardial Infarction (TIMI) 11A was a multicenter, dose-ranging trial to evaluate the safety and tolerability of subcutaneous enoxaparin in patients with unstable angina/non-ST-elevation myocardial infarction. We obtained peak (mean 4.3 hours after enoxaparin) and trough (mean 11.5 hours after enoxaparin) anti-Xa levels and ACTs for 26 patients in the TIMI 11A trial. RESULTS: Despite doses of enoxaparin in the range of 89 +/- 19 mg every 12 hours and significant increases in anti-Xa levels even at trough, there was no change in the ACT measured by HemoTec and only a small increase with Hemachron. The correlation of peak Hemachron ACT with peak anti-Xa levels was poor (R = 0.5, P =.08). CONCLUSIONS: In contrast to heparin, ACTs are not useful for assessment of anticoagulation with subcutaneous enoxaparin and should not be relied on in patients receiving enoxaparin who require acute PCI. Studies to determine the optimal dose, safety, and efficacy of enoxaparin in patients undergoing PCI are underway.

Cerebello-oculo-renal syndromes including Arima, Senior-Löken and COACH syndromes: more than just variants of Joubert syndrome.

Cerebellar vermis hypoplasia (CVH) is part of many different malformation syndromes, especially Joubert syndrome. However, the nosology of these disorders remains uncertain. We reviewed reports of 100 children with cerebellar vermis hypoplasia, and ocular or renal involvement. Although the status of the upper brainstem was not adequately documented in most of these patients, some had hypoplasia and dysplasia of the ponto-mesencephalic isthmus and the superior portion of the cerebellar vermis, which results in a "molar tooth" sign on MRI scan. Several distinct syndromes were apparent among this group. We conclude that (a) hypoplasia of the cerebellar vermis, especially the anterior vermis, is often associated with a complex brainstem malformation; (b) the latter comprises a "molar tooth" brainstem and vermis hypoplasia-dysplasia malformation complex; (c) this complex may include the Dandy-Walker malformation, occipital cephalocele, and some abnormalities of the cerebrum as evidenced by frequent mental retardation; and (d) the "molar tooth" sign or malformation is causally heterogeneous as it occurs in several distinct malformation syndromes including Joubert syndrome, Arima syndrome, Senior-Löken syndrome, COACH syndrome, and probably familial juvenile nephronophthisis.

Clinical nosologic and genetic aspects of Joubert and related syndromes.

Joubert syndrome is an autosomal-recessive disorder characterized by cerebellar hypoplasia, hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The biochemical and genetic basis of Joubert syndrome is unknown and a specific chromosomal locus for this disorder has not been identified. Review of this disorder and related syndromes suggests that (1) hypoplasia of the cerebellar vermis in Joubert syndrome is frequently associated with a complex brain stem malformation represented as the "molar tooth sign" on magnetic resonance imaging, (2) the "molar tooth sign" could be present in association with the Dandy-Walker malformation and occipital encephalocele, (3) cerebellar hypoplasia is present in conditions related to Joubert syndrome such as Arima syndrome; Senior-Loken syndrome; cerebellar vermian hypoplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis syndrome; and juvenile nephronophthisis due to NPH1 mutations, and (4) the brainstem-vermis malformation spectrum is probably caused by at least two and probably several genetic loci. We have ascertained previously a cohort of 50 patients with a putative diagnosis of Joubert syndrome in order to evaluate the presence of associated malformations, and to initiate studies leading to the identification of genes causing Joubert and related syndromes. Among the associated malformations found in patients ascertained as having Joubert syndrome, 8% of patients had polydactyly, 4% had ocular colobomas, 2% had renal cysts, and 2% had soft-tissue tumors of the tongue. The WNT1 gene has been tested as a candidate gene for Joubert syndrome based on its expression in the developing cerebellum and an associated mutation in the swaying mouse. A search for mutations in WNT1 in a series of patients with Joubert syndrome did not detect mutations at this locus. This analysis suggested that mutations in WNT1 might not have a significant role in Joubert syndrome, and other functional candidate genes related to development of the cerebellum need to be examined. A genome-wide linkage analysis carried out in 10 Joubert syndrome pedigrees did not identify a specific chromosomal locus for this disorder. This observation, along with those from clinical studies, provides further evidence that Joubert and related syndromes are genetically heterogeneous.