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Laboratory Diagnosis and Clinical Manifestations of Patients with Dysfibrinogenemia1) Laboratoriumsdiagnostik Und Klinische Manifestation Der Dysfribrinogena¨ Mie

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Laboratory Diagnosis and Clinical Manifestations of Patients with Dysfibrinogenemia1) Laboratoriumsdiagnostik Und Klinische Manifestation Der Dysfribrinogena¨ Mie Article in press - uncorrected proof J Lab Med 2008;32(6):401–405 ᮊ 2008 by Walter de Gruyter • Berlin • New York. DOI 10.1515/JLM.2008.059 2008/59 Ha¨ mostaseologie Redaktion: C.M. Schambeck Laboratory diagnosis and clinical manifestations of patients with dysfibrinogenemia1) Laboratoriumsdiagnostik und klinische Manifestation der Dysfribrinogena¨ mie Wolfgang Miesbach* Keywords: bleeding; dysfibrinogenemia; miscarriage; thrombosis. Medical Clinic III/Institute of Transfusion Medicine, Goethe University Frankfurt, Frankfurt am Main, Zusammenfassung Germany Die angeborene Dysfibrinogena¨ mie ist eine sehr seltene Gerinnungssto¨ rung, basierend auf einem strukturellem Abstract Defekt im Fibrinogenmoleku¨ l, worunter eine Neigung zu Blutungen, Thrombosen und Aborten entstehen kann. Hereditary dysfibrinogenemia is a rare clotting disorder Wir beschreiben die Ergebnisse der Labordiagnostik und due to a structural defect in the fibrinogen molecule that die klinischen Manifestationen bei 50 Patienten mit Dys- results in a tendency for bleeding and thrombosis, as well fibrinogena¨ mie. Es wurden folgende Untersuchungen as obstetric complications. We describe the laboratory vorgenommen: Fibrinogen (Clauss), immunologisches results and clinical manifestations for 50 patients with a Fibrinogen und Hitze-Fibrinogen nach Schulz. Unter den diagnosis of dysfibrinogenemia. Various different labo- 50 Patienten mit Dysfibrinogena¨ mie (52% weiblich; ratory measurements of fibrinogen were performed on Altersmedian 52 Jahre, 9–89 Jahre) war die Fibrinogen- samples from these patients, including fibrinogen konzentration nach Clauss erniedrigt im Median mit (Clauss), heat fibrinogen precipitation according to 51 mg/dL (15–86 mg/dL; Norm 150–450 mg/dL). Die Schulz and immunological fibrinogen. Fifty patients were Bestimmungen der Fibrinogen-Antigen-Konzentrationen found with dysfibrinogenemia (52% female; median age ergaben Normalbefunde: Hitze-Fibrinogen nach Schulz, 52, range 9–89 years). The fibrinogen level according 240 mg/dL; und immunologisches Fibrinogen, 244 mg/dL. to Clauss was low, with a median of 51 mg/dL (range Die Reptilasezeit war mit 55 s verla¨ ngert (Median; Norm 15–86 mg/dL; normal range 150–450 mg/dL). Determi- -20 s). Fu¨ nfzig Prozent der Patienten hatten ein oder nation of other fibrinogen levels revealed normal results: mehrere Blutungsereignisse, meistens eine deutliche Nei- heat fibrinogen precipitation according to Schulz, gung zu Ha¨ matomen (60%) oder Nachblutung (44%). 240 mg/dL; and immunological fibrinogen, 244 mg/dL. Bei 13 Patienten ist ein thromboembolisches The median reptilase time was longer than normal, at Ereignis aufgetreten. Bei 12% der Patienten war eine 55 s (normal 20 s). Some 50% of the patients reported Neigung gleichzeitig zu Blutung und Thrombosen vor- a distinct bleeding tendency, mostly a tendency for handen. Bei 19% der weiblichen Patienten hatten einen hematoma (60%) and secondary bleeding (44%). Thir- oder mehrere Aborte. Bei Patienten mit stattgehabten teen patients had thrombotic events, of which 54% were Blutungssymptomen war die Konzentration von Fibrino- located arterially. Some 12% of the patients repor- gen nach Clauss mit 43 mg/dL im Median niedriger als ted a tendency for bleeding and for thrombosis, whereas bei Patienten ohne Blutungsproblemen (57 mg/dL). 19% had miscarriages, sometimes recurrent. We found that functional fibrinogen levels (Clauss) were generally lower in patients with bleeding manifestations (43 vs. Schlu¨ sselwo¨ rter: Abort; Blutung; Dysfibrinogena¨ mia; 57 mg/dL in other patients). Thrombose. 1)Zusammenarbeit von DGKL-Fachredaktion und GTH-Arbeits- gruppe MAISTHRO (Main-Isar-Thromboseregister). Overview *Correspondence: Wolfgang Miesbach, MD, Medical Clinic III/Institute of Transfusion Medicine, Goethe University Fibrinogen is a 340,000-Da protein that is synthesized in Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany hepatocytes. Fibrinogen is the precursor of fibrin and is Tel.: q49-69-63015051 Fax: q49-69-63016738 thus a key component in clot formation. The develop- E-Mail: [email protected] ment of the three-dimensional network in fibrin can be Article in press - uncorrected proof 402 Miesbach: Diagnosis of patients with dysfibrinogenemia divided into three steps w1x. First the fibrinogen molecule have shown that IgG antibodies directed against the is activated by thrombin, which removes two pairs of fibrinogen molecule interfere with the binding of thrombin small peptides from the Aa and Bb chains, creating two w18x and that monoclonal immunoglobulin g light chains polymerization sites known as A9 and B9 w2, 3x. The sec- bind to fibrinogen and interfere with all stages of poly- ond step is the formation of intermediate polymers. The merization w19x. Acquired dysfibrinogenemia may have a fibrin monomers associate in a half-staggered manner poorer prognosis than congenital dysfibrinogenemia through E and D regions and end-to-end through the D owing to possible underlying co-morbidities. A wide vari- regions of different monomer units, giving rise to longi- ety of symptoms from bleeding to thrombosis are tudinal growth of a polymer with a width of two fibrin observed in affected patients w16x. Besides some case monomers, yielding the fibrin monomer unit called pro- studies, there are only a few studies on the clinical tofibril. The third step is lateral association of these inter- manifestations in a large number of patients with mediate polymers, forming the three-dimensional fibrin dysfibrinogenemia. network w1x. The obstetric complications of dysfibrinogenemia The fibrinogen molecule is a homodimer; each half include miscarriage, mostly during the first trimester, consists of three non-identical polypeptide chains that thrombosis, bleeding and placental abruption during are termed Aa,Bb and g chains w4x. The genes for all pregnancy. There are very few studies on the impact of three chains have been localized to the long arm of chro- dysfibrinogenemia on pregnancy or on treatment mosome 4. The amino termini of the three pairs of poly- approaches. For patients with congenital dysfibrinogen- peptide chains are symmetrically arranged in a disulfide emia, effective treatment has proven extremely difficult, knot to form a central E-domain that is flanked by two since there is a broad spectrum of symptoms that are large D-domains to form a tri-nodular structure w5x. The sometimes contradictory. Our study was designed to D region is divided into several domains, including the b establish a correlation between variations in clinical and g nodules, which constitute the C-terminal parts of manifestations and laboratory test results. these chains that fold independently w6x. The C-terminal a-chain, spanning the sequence from Aa-208 to Aa-610, contains a nodule and a connecting strand w7x. The aC Patients and methods domains have several functions in the hemostatic pro- cess and act as substrates for activated factor XIII w8–12x. We investigated 50 patients from 19 families with dys- The aC domains contribute to the polymerization pro- fibrinogenemia, of whom 26 (52%) were female. The cess, accelerating it and influencing the final clot struc- median patient age was 52 years (range 9–89 years). ture w13, 14x. Amino acids Aa 572–575 are involved in Each patient was interviewed regarding history of clinical the adhesion of other proteins and structures such as manifestations. endothelial cells. Laboratory diagnosis of dysfibrinogenemia was based Congenital dysfibrinogenemia is caused by genetic on criteria established by the International Society of defects in fibrinogen, resulting in a decrease in functional Thrombosis and Hemostasis (Subcommittee on Fibrino- clotting activity despite normal circulating levels of fibrin- gen; Scientific and Standardization Committee) w20x. ogen antigen. Congenital dysfibrinogenemia may be Testing started with sensitive but non-specific screening transmitted in a homo- or heterozygous manner, and tests and then included more specific confirmatory tests. inheritance is mostly autosomal dominant or co-domi- Initially, all patients had to undergo standard screening nant. Most homozygous carriers are symptomatic, tests: thrombin time, prothrombin time, and activated whereas some heterozygous carriers are asymptomatic partial thromboplastin time. Plasma concentrations of w15x. The most common structural defects involve the fibrinogen were analyzed for all patients using several fibrinopeptides and their cleaving sites; the second most methods. In most cases, laboratory diagnosis of dysfi- common involves the g-chain polymerization region. brinogenemia can be established from a discrepancy These defects are primarily the result of DNA point muta- between fibrinogen activity and fibrinogen antigen levels tions with substitutions of single amino acids. Other dys- w23x. fibrinogenemias are caused by formation of new stop Fibrinogen activity was measured in terms of fibrin codons, and small base additions or deletions. Currently, polymerization function by the Clauss method, which a database of human fibrinogen variants includes more measures the rate of clot formation after adding a high than 430 molecular abnormalities (http://www.geht.org/ concentration of thrombin to citrated plasma. Fibrinogen databaseang/fibrinogen). Dysfibrinogenemia may also be antigen concentrations were determined by immunologic acquired secondary to liver disease, the use of certain (radial immunodiffusion) w22, 23x and precipitation (heat drugs (e.g.,
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