title: Coagulation factors and markers of activation of coagulation in homocystinuria (HOCY): a study in two siblings.
abstract: Homocystinuria due to cystathionine-beta-synthase deficiency (CBS-def-HOCY) initially often present with thromboembolic events. In most cases in which coagulation factors have been analysed, a deficiency of AT-IIIc and factor VIIc has been reported, the cause of which has not been elucidated. Activation of coagulation with consumption of coagulation factors has been postulated as the mechanism. This paper reports a longitudinal study of two patients: patient 1 with thromboembolic disease and his asymptomatic sister, patient 2. Before start of therapy in patient 1, a reduction of FVIIc, other coagulation factors, and AT-IIIc was found. Markers of activation of coagulation (F1 + 2, TAT, FM, D-dimers) were elevated only in patient 1, and only at the time of thrombotic complications. In patient 2 reduced levels of FVIIc and other coagulation proteins, and a low borderline AT-IIIc level was found. Thus, in the two patients, sustained activation of coagulation can be reasonably excluded to be the cause of low levels of coagulation proteins. Vitamin therapy with 15 mg folate and 600 mg pyridoxine per day led to almost complete normalization of amino acids in urine and plasma. Thrombosis has not recurred to date. FVIIc and the other coagulation proteins and AT-IIIc increased in parallel with the biochemical remission. Direct inhibition of the activity of AT-III and coagulation factor VIII and other factors by homocysteine was attempted in vitro but could not be shown at HC concentrations known to occur in the plasma of HOCY patients. Therefore, in these patients, deficient synthesis of coagulation factors and AT-III due to a disturbance of amino acid metabolism is still the most probable explanation for the observed low levels.
authors.affiliation: Department of Internal Medicine, Stauferklinik Schw. Gmünd (Academic University Hospital of the University of Ulm), Mutlagen, Germany.
authors.forename: H W
authors.initials: HW
authors.lastname: Schienle
authors.forename: R
authors.initials: R
authors.lastname: Seitz
authors.forename: I
authors.initials: I
authors.lastname: Rohner
authors.forename: L
authors.initials: L
authors.lastname: Lerch
authors.forename: B
authors.initials: B
authors.lastname: Krumpholz
authors.forename: G
authors.initials: G
authors.lastname: Krauss
authors.forename: B
authors.initials: B
authors.lastname: Fowler
authors.forename: R
authors.initials: R
authors.lastname: Baumgartner
authors.forename: U
authors.initials: U
authors.lastname: Willenbockel
authors.forename: R
authors.initials: R
authors.lastname: Egbring
mesh_terms: D000328:Adult; D020152:Antithrombin III Deficiency; D015415:Biomarkers / Q000097:blood*; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000172:deficiency; D005164:Factor IX / Q000378:metabolism; D005168:Factor VII Deficiency / Q000209:etiology; D005170:Factor X / Q000378:metabolism; D005172:Factor XI / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use; D006712:Homocystinuria / Q000097:blood* / Q000235:genetics; D006801:Humans; D008297:Male; D011736:Pyridoxine / Q000627:therapeutic use; D013923:Thromboembolism / Q000209:etiology
chemical_list: D015415:Biomarkers; D001779:Blood Coagulation Factors; D005164:Factor IX; D005170:Factor X; D005172:Factor XI; D005492:Folic Acid; D003541:Cystathionine beta-Synthase; D011736:Pyridoxine