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Congenital Dysfibrinogenemia: Fibrinogen Detroit

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Congenital Dysfibrinogenemia: Fibrinogen Detroit Congenital dysfibrinogenemia: fibrinogen detroit Eberhard F. Mammen, … , Marion I. Barnhart, Chi C. Au J Clin Invest. 1969;48(2):235-249. https://doi.org/10.1172/JCI105980. Research Article A 17 yr old female with a congenital bleeding disorder was found to suffer from dysfibrinogenemia. Whole blood and plasma coagulation times were delayed and thrombelastograms were grossly abnormal. Clottability of plasma fibrinogen by addition of thrombin was not demonstrated during the 30 min test period. Fibrinogen was revealed by turbidometric and immunologic techniques. Other coagulation factors were present in normal amounts and prothrombin activation was normal. Patient's plasma inhibited thrombin clotting times of normal plasma and purified normal fibrinogen. Fibrinolysis was not detected. The plasma fibrinogen migrated normally on paper and cellulose acetate electrophoresis, but on immunoelectrophoresis it displayed a faster mobility than normal fibrinogen. On immunodiffusion the antigenic determinants were similar to those of normal fibrinogen. The patient's fibrinogen-antifibrinogen precipitins required longer to appear and the resultant precipitin was broader and hazier than those elicited with normal fibrinogen. These findings suggest the presence of two discrete populations of fibrinogen molecules. Investigation of the family of the patient suggested that the defect has an autosomal dominant pattern of heredity. Immunologic comparisons of our patient's plasma and of her relatives with plasma of patients with “Fibrinogen Baltimore” and “Fibrinogen Cleveland” revealed certain differences in immunoelectrophoretic mobility as well as in immunodiffusion. In keeping with the nomenclatures of abnormal fibrinogens in the literature, we propose the term “Fibrinogen Detroit” for this […] Find the latest version: https://jci.me/105980/pdf Congenital Dysfibrinogenemia: Fibrinogen Detroit EBERHARD F. MAMMEN, ANANDA S. PRASAD, MARION I. BARNHART, and Cm C. Au with the technical assistance of VmIG SCHWANDT From the Departments of Physiology and Pharmacology, Pathology and Medicine, Wayne State University, School of Medicine, Detroit, Michigan 48207 and the Veterans Administration Hospital, Allen Park, Michigan 48101 A B S T R A C T A 17 yr old female with a congenital mal fibrinogen. Purified normal fibrinogen (clottability bleeding disorder was found to suffer from dysfibrino- 96.7%) and "Fibrinogen Detroit" revealed homogeneity genemia. Whole blood and plasma coagulation times when studied by ultracentrifugation and immunoelectro- were delayed and thrombelastograms were grossly ab- phoresis. Native and cleaved "Fibrinogen Detroit" had normal. Clottability of plasma fibrinogen by addition of the same sedimentation constants and molecular weights thrombin was not demonstrated during the 30 min test as the normal. In fresh samples, 3 moles of free SH period. Fibrinogen was revealed by turbidometric and groups/mole of fibrinogen were titrated in both. De- immunologic techniques. Other coagulation factors termination of the amino acid composition revealed a were present in normal amounts and prothrombin ac- decreased content of lysine, glucosamine, and galactosa- tivation was normal. Patient's plasma inhibited throm- mine in abnormal fibrinogen. Total carbohydrates, pro- bin clotting times of normal plasma and purified normal tein-bound hexoses, sialic acid, and hexosamine were fibrinogen. Fibrinolysis was not detected. decreased in the abnormal fibrinogen. The plasma fibrinogen migrated normally on paper In an investigation with Doctors Blomback a specific and cellulose acetate electrophoresis, but on immunoelec- molecular defect was revealed in the N-terminal di- trophoresis it displayed a faster mobility than normal sulfide knot of the alpha (A) chain in which the arginine fibrinogen. On immunodiffusion the antigenic determi- at the 19th position was replaced by serine. It is be- nants were similar to those of normal fibrinogen. The lieved that the substitution of a strongly basic amino patient's fibrinogen-antifibrinogen precipitins required acid with a neutral hydroxy acid may result in con- longer to appear and the resultant precipitin was broader siderable conformational changes in the N-terminal di- and hazier than those elicited with normal fibrinogen. sulfide knot of fibrinogen which might affect the "active These findings suggest the presence of two discrete site" for polymerization. The lower carbohydrate con- populations of fibrinogen molecules. tent observed in "Fibrinogen Detroit" may have been Investigation of the family of the patient suggested the result of a change in primary and tertiary structure that the defect has an autosomal dominant pattern of of the protein. heredity. Immunologic comparisons of our patient's plasma and of her relatives with plasma of patients with "Fibrinogen Baltimore" and "Fibrinogen Cleve- INTRODUCTION land" revealed certain differences in immunoelectropho- A congenital disturbance in the function of fibrinogen retic mobility as well as in immunodiffusion. In keep- seems to be rare. The first patient with dysfibrinogene- ing with the nomenclatures of abnormal fibrinogens in mia was described in 1958 by Imperato and Dettori (1). the literature, we propose the term "Fibrinogen Detroit" This patient suffered from frequent hemorrhages, and for this fibrinogen. the fibrinogen was not readily converted to fibrin. In Physicochemical properties of "Fibrinogen Detroit" 1964 Menache (2) described a similar congenital fibrino- were investigated also and compared with those of nor- gen abnormality in a patient without a bleeding tend- ency. This paper was presented by Dr. Prasad at the Meeting of A third family with congenital dysfibrinogenemia was the International Society of Hematology in New York City, 2 September 1968. described in 1964 by Beck (3). Several family members Received for publication 29 April 1968 and in revised form were affected and had a mild hemorrhagic tendency. The 3 September 1968. abnormality seemed to be inherited as a dominant trait. The Journal of Clinical Investigation Volume 48 1969 235 Whole blood clotting times were normal, but friable June 1966 although she had discontinued the hormonal clots were observed. There were electrophoretic dif- therapy after two months and had failed to return to the ferences between the patient's fibrinogen and normal clinic. fibrinogen (4, 5). In view of certain differences among Family history revealed that her 35 yr old mother these patients with dysfibrinogenemia thus far described, (E.H.) also suffered from excessive menstrual bleeding Beck and coworkers (3-6) recommended the adoption and mild hemorrhages after minor injuries since early of a nomenclature similar to the one used for the descrip- childhood. She also gave a history of several episodes tion of hemoglobinopathies, and termed their abnormal of epistaxis. In spite of these bleeding tendencies, she fibrinogen "Fibrinogen Baltimore." delivered nine children without any serious complica- In 1964 von Felten, Duckert, and Frick (7) described tions. Two brothers of P. H., one 15 yr old (S. H.) and a fourth family with an abnormal fibrinogen. A recent another 14 yr old (Al. H.) gave history of frequent epi- reinvestigation of a family previously described as staxis and bleedings after minor cuts. Five other sisters "congenital hypofibrinogenemia" (8) by Beck and (D. H., An. H., K. H., C. H., and Mo. H.) and one Thomas [cited from (6)] revealed that the family suf- brother (Ma. H.) gave no history of hemorrhagic fered from dysfibrinogenemia. The pattern of heredity tendencies. seemed to be autosomal dominant (8), and the affected Physical examination revealed a well-developed and family members displayed a mild bleeding tendency. well-nourished female in no acute distress. Except for Forman, Boyer, and Ratnoff (9) described the sixth pallor, no abnormality on physical examination (in- family with an abnormal fibrinogen. The defect seemed cluding pelvic) was noted. Hemoglobin was 8.6 g/100 to lie in the aggregation of the fibrin monomers. The ml. Peripheral blood smear revealed normochromic and patient's fibrinogen was distinguishable from normal normocytic anemia. Reticulocyte count was 3.4%. To- fibrinogen and "Fibrinogen Baltimore" by immuno- tal leukocyte count and differential counts were within electrophoresis and was termed "Fibrinogen Cleveland." normal limits. Platelet count on admission was 139,000/ This report concerns a Detroit Negro family with an mm8 and subsequently it was reported to be 216,000/mm8. abnormal fibrinogen molecule, which we propose to term Serum total protein was 6.9 g/100 ml and protein elec- "Fibrinogen Detroit." Immunological and physicochem- trophoresis was unremarkable. Sickle-cell preparation ical properties of this fibrinogen also are presented in was negative. Other routine laboratory tests such as uri- this paper. nalysis, blood urea nitrogen, fasting blood sugar, and Case history. P. H., a 17 yr old Negro female, was liver function tests were noncontributory. Detailed admitted to Detroit General Hospital in June 1966 as a clotting studies are presented in Table I. referral because of anemia after excessive blood loss 500 ml of whole blood was withdrawn for isolation during menstruation. Menarche was at age 11. Menstru- and purification of fibrinogen for further studies. Im- ation was irregular, required use of 7-20 pads a day and mediately thereafter the patient received 3 U of fresh flow lasted from 7 to 12 days. whole blood and 4 g of fibrinogen'
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