Antithrombotic therapy for venous thromboembolic disease.

Atrial fibrillation (AF), the most common sustained cardiac rhythm disturbance, is increasing in prevalence as the population ages. Although it is often associated with heart disease, AF occurs in many patients with no detectable disease. Hemodynamic impairment and thromboembolic events result in significant morbidity, mortality, and cost. Accordingly, the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) created a committee of experts to establish guidelines for management of this arrhythmia.

The committee was composed of 8 members representing the ACC and AHA, 4 representing the ESC, 1 from the North American Society of Pacing and Electrophysiology (NASPE), and a representative of the Johns Hopkins University Evidence-Based Practice Center representing the Agency for Healthcare Research and Quality’s report on Atrial Fibrillation in the Elderly. This document was reviewed by 3 official reviewers nominated by the ACC, 3 nominated by the AHA, and 3 nominated by the ESC, as well as by the ACC Clinical Electrophysiology Committee, the AHA ECG and Arrhythmia Committee, NASPE, and 25 reviewers nominated by the writing committee. The document was approved for publication by the governing bodies of the ACC, AHA, and ESC and officially endorsed by NASPE. These guidelines will be reviewed annually by the task force and will be considered current unless the task force revises or withdraws them from distribution.

The committee conducted a comprehensive review of the literature from 1980 to June 2000 relevant to AF using the following databases: PubMed/Medline, EMBASE, the Cochrane Library (including the Cochrane Database of Systematic Reviews and the Cochrane Controlled Trials Registry), and Best Evidence. Searches were limited to English language sources and to human subjects.

### A. Atrial Fibrillation

AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function. On the electrocardiogram (ECG), AF …

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ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology

Coumarin derivatives such as warfarin represent the therapy of choice for the long-term treatment and prevention of thromboembolic events. Coumarins target blood coagulation by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational gamma-carboxylation of several blood coagulation factors. Despite extensive efforts, the components of the VKOR complex have not been identified. The complex has been proposed to be involved in two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2; Online Mendelian Inheritance in Man (OMIM) 607473), and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR; OMIM 122700). Here we identify, by using linkage information from three species, the gene vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum. VKORC1 contains missense mutations in both human disorders and in a warfarin-resistant rat strain. Overexpression of wild-type VKORC1, but not VKORC1 carrying the VKCFD2 mutation, leads to a marked increase in VKOR activity, which is sensitive to warfarin inhibition.

Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2

https://www.amjmed.com/article/0002-9343(80)90181-3/pdf

Maternal and fetal sequelae of anticoagulation during pregnancy

Vitamin K epoxide reductase (VKOR) is the target of warfarin, the most widely prescribed anticoagulant for thromboembolic disorders. Although estimated to prevent twenty strokes per induced bleeding episode, warfarin is under-used because of the difficulty of controlling dosage and the fear of inducing bleeding. Although identified in 1974 (ref. 2), the enzyme has yet to be purified or its gene identified. A positional cloning approach has become possible after the mapping of warfarin resistance to rat chromosome 1 (ref. 3) and of vitamin K-dependent protein deficiencies to the syntenic region of human chromosome 16 (ref. 4). Localization of VKOR to 190 genes within human chromosome 16p12-q21 narrowed the search to 13 genes encoding candidate transmembrane proteins, and we used short interfering RNA (siRNA) pools against individual genes to test their ability to inhibit VKOR activity in human cells. Here, we report the identification of the gene for VKOR based on specific inhibition of VKOR activity by a single siRNA pool. We confirmed that MGC11276 messenger RNA encodes VKOR through its expression in insect cells and sensitivity to warfarin. The expressed enzyme is 163 amino acids long, with at least one transmembrane domain. Identification of the VKOR gene extends our understanding of blood clotting, and should facilitate development of new anticoagulant drugs.

Identification of the gene for vitamin K epoxide reductase

Prenatal exposure to oral anticoagulants during pregnancy may result in defective fetal development or life-threatening hemorrhage. Fetal exposure during the first eight weeks of pregnancy may cause abnormal development of the facial structures, hypoplastic digits, stippled epiphyses, and mental retardation. Midtrimester exposure may result in optic atrophy, faulty brain growth, and developmental retardation. Third-trimester exposure may produce fetal anticoagulation, predisposing the infant to life-threatening hemorrhage in the perinatal period. Anticoagulation with heparin sodium does not provide a clearly safe alternative, since this therapy has been associated with excessive fetal loss. (JAMA243:1549-1551, 1980)

Hazards of oral anticoagulants during pregnancy.

Two unrelated infants with a new disorder characterized biochemically by elevated levels of free sialic acid in urine, serum, and cell lysates have exhibited severe mental and physical impairments since the early weeks of life. Three other biochemically diagnosed cases and two possible cases from the earlier literature are reviewed to delineate this condition. Clinical features including sparse, white hair, coarse facies, hepatosplenomegaly, profound inactivity, diarrhea, and anemia permit early diagnosis of this neurovisceral storage disease.

Sialic Acid Storage Disease with Sialuria: Clinical and Biochemical Features in the Severe Infantile Type

Extract: Four patients with the clinical findings of mucolipidosis III were studied. Cultured skin fibroblast cells from three of these four patients were low in each of the five lysosomal enzyme activities measured. The ranges of the enzyme activities in these three patients were as follows: N-acetyl-β-glucosaminidase (11–19% of normal), β-galactosidase (26–33% of normal), α-fucosidase (31–55% of normal), α-mannosidase (53–62% of normal), and arylsulfatase A (16–21% of normal). In contrast, marked increases in the same enzyme activities were found in serum samples from the same patients. These include N-acetyl-β-glucosaminidase (7–16 times normal), β-galactosidase (8–11 times normal), α-fucosidase (5–10 times normal) and arylsulfatase A (14–24 times normal). Similar increases in the enzyme activities were also found in serum of patient 1; however, the changes were less dramatic. An electrophoretic analysis of one of these enzymes (N-acetyl-β-glucosaminidase) revealed an abnormal pattern in the cultured fibroblast extracts; however, the presence of a normal pattern in the serum samples suggests that this is not due to an alteration in the primary amino acid sequence. Speculation: The lysosomal enzyme activities in serum and fibroblast extracts from the mucolipidosis III patients reported here are very similar to those found previously in mucolipidosis II (I-cell) patients. This suggests that the nature of the defect may be very similar in these two distinct disorders.

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Mucolipidosis III (Pseudo-Hurler Polydystrophy): Multiple Lysosomal Enzyme Abnormalities in Serum and Cultured Fibroblast Cells

THE N-acetyl-β-D-glucosaminidase (hexosaminidase) activity in cultured human fibroblasts consists of at least three components (A, B and C)1–3. At least two of these (designated Hex A and Hex B) seem to be closely related, for (1) antiserum against Hex A reacts against Hex B, and vice versa4,5 (2) in Tay-Sachs disease only Hex A activity is deficient, accompanied by an increase in Hex B activity in certain tissues1,6, and (3) both Hex A and Hex B activities are missing in Sandhoff disease, another autosomal recessive disorder7. But in spite of several theories8–11, the precise relationship between these components remains unknown, as does the nature of the genetic and biochemical relationships between the two diseases. To investigate these questions we have fused Tay-Sachs with Sandhoff fibroblasts and obtained cultures containing heterokaryons which produce a hexosaminidase which is absent from the parent lines. It has the electrophoretic and heat lability characteristics of the Hex A found in normal fibroblasts.

Genetic complementation after fusion of Tay-Sachs and Sandhoff cells.

Sara S. Cathey,* Mariko Kudo, Stephan Tiede, Annick Raas-Rothschild, Thomas Braulke, Michael Beck, Harold A. Taylor, William M. Canfield, Jules G. Leroy, Elizabeth F. Neufeld, and Victor A. McKusick Greenwood Genetic Center, Greenwood, South Carolina Genzyme Corporation, Oklahoma City, Oklahoma Schleswig-Holstein University Hospital, Lübeck, Germany Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, Israel Department of Biochemistry, Children’s Hospital, University of Hamburg, Hamburg, Germany Children’s Hospital, University of Mainz, Mainz, Germany Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Hospital, Baltimore, Maryland

Harold A. Taylor

Papers

Hazards of oral anticoagulants during pregnancy.

Sialic Acid Storage Disease with Sialuria: Clinical and Biochemical Features in the Severe Infantile Type

Mucolipidosis III (Pseudo-Hurler Polydystrophy): Multiple Lysosomal Enzyme Abnormalities in Serum and Cultured Fibroblast Cells

Genetic complementation after fusion of Tay-Sachs and Sandhoff cells.

Molecular order in mucolipidosis II and III nomenclature