2 Afibrinogenemia-Case Report Bijan Keikhaei, Ahvaz Jundishapur University of Medical Sciences Medical Sciences

3 Case Presentation A 14 Yr-old boy, was referred to the Shafa Hospital on Mehr 1392, for the Acute loss of consciousness. He was a known case of hereditary afibrinogenemia who was diagnosed at age 4 th day from umbilical cord bleeding and serum fibrinogen level <0.2 g/l. Until 1392, only incidental minor bleeding episodes occurred. He received a few fibrinogen concentrate vials in his life for mouth and gum bleeding. History of trauma was not detected. No positive family history.

Laboratory Findings Investigation findings were Hb-11gm/dl, MCV: 85Fl,MCH: 28 Pg, ESR-20mm,BUN:20 mg/dl, Cr:1 mg/dl Platelet count /cmm, PT sec (INR-1.8), APTT sec,TT:Prolonged, HBSAg: Neg,HIV Ab: Neg, HCV Ab: Neg No measurable fibrinogen

5 Physical Examination Findings at neurological examination were as follows: global motor weakness GCS: 8 Babinski reflex on the right and left

6 Case report He was admitted in the ICU ward. He had two episodes of generalized tonic colonic convulsion in the ward. Substitution therapy with fibrinogen were started immediately after neurological examination. The patient received 100 mg/kg fibrinogen( Hemocomplettan P ) every 48 hr. He also received phenytoin and Dexamethasone.

Brain CT Scan

Case Presentation While still on maintained substitution therapy, the patient condition becomes worse everyday. On day 3 th admission the patients GCS was 5. The patient blood fibrinogen level was 3 g/l with trough level 1.5 g/l. Unfortunately the patient died on the 4 th day admission.

Discussion

Terms Dysfibrinogenemia: fibrinogen with abnormal function. Hypofibrinogenemia: Reduced amount of fibrinogen in the plasma. Hypodysfibrinogenemia: inherited fibrinogens which are both functionally abnormal and reduced amounts in the plasma (<150 mg/dL) as measured by immunologic methods. Afibrinogenemia: absence of circulating fibrinogen in the plasma. Cryofibrinogenemia: Fibrinogen in the plasma (but not serum) that precipitates on exposure to low temperatures (4 C).

Structure 340 kD glycoprotein that circulates in plasma at a concentration of ~ mg/dL, with a half life of 4 days. Hexamer, consisting of three paired polypeptide chains (Aα, Bβ, γ). Synthesized in hepatocytes under the control of three different genes located on chromosome 4q. Assembly takes place in the liver, carbohydrate side chains are added to the beta and gamma chains before it is secreted into plasma. It has a trinodular structure: central E-domain (aminoterminal portions of the three polypeptides) and two D-domain (carboxyterminal portions)

Aα: Red Bβ: Blue γ: Green E-domainD-Domain

Two major forms exist, separated from each other by ion exchange chromatography: Fibrinogen 1 and 2. Fibrinogen 1: contains 2 γ chain (411 aa) Fibrinogen 2: contains one γ chain and one γ ’ chain (427 aa), has a more anionic carboxyterminal sequence. Factor XIII (protransglutaminase, fibrinoligase) binds specifically to γ ’ chain of fibrinogen 2 (factor XIII is carried by fibrinogen 2 in the plasma). Thrombin has been shown to bind to the anionic γ ’ extension of fibrin 2. Structure

Sites of important function:  Thrombin binding site  Factor XIIIa binding site,  t-PA binding site,  alpha-2 antiplasmin binding site  platelet binding site. Functions

Classification Quantitative Abnormalities Congenital Afibrinogenemia (uncommon, autosomal recessive) Hypofibrinogenemia Acquired Hypofibrinogenemia (consumptive coagulapathies, DIC) Hyperfibrinogenemia (inflammation, neoplasia) Qualitative abnormalities Congenital Dysfibrinogenemia Hypodysfibrinogenemia Acquired Liver disease Malignancies, Antifibrinogen antibodies

Inherited dysfibrinogenemia Overall, ~ 55 % are silent. ~ 25 % manifests as bleeding. ~ 20 % experience thrombosis with or without bleeding.

A rare condition, Autosomal recessive inheritance  complete lack of circulating fibrinogen Bleeding manifestation range from mild to catastrophic Excessive bleeding and early miscarriages in pregnant women Fatal umbilical cord bleeding in the neonate Inherited afibrinogenemia

High fibrinogen levels are seen : – pregnancy – oral contraceptives. – hypercoagulable state. – acute-phase reactant. Inherited afibrinogenemia

Diagnosis Initial screening tests: thrombin time (TT) and reptilase time (RT) fibrinogen activity and antigen. Afibrinogenemia: Prolonged TT, RT, virtually absent fibrinogen antigen and activity (clottable antigen). Dysfibrinogenemia: Prolonged TT, RT, normal or increased fibrinogen antigen, normal or decreased clottable fibrinogen (activity).

Treatment In February 1995, cryoprecipitate was replaced by fibrinogen concentrate. Plasma recovery of fibrinogen has been measured repeatedly: top levels were approximately 1.7 g/L and trough levels approximately 0.75 g/L.

Patients with thrombotic complications should receive anticoagulation. The optimal duration of anticoagulation is unknown (the benefit of anticoagulation should be weighed against a potentially higher risk of bleeding). Patient education concerning thrombotic risk factors (surgery, pregnancy, oral contraceptives, immobilization) Treatment

22 Discussion Congenital afibrinogenemia is a rare disorder associated with a high risk of spontaneous intracerebral bleeding. Clinical manifestations in afibrinogenemia range from minor to severe bleeding, often with long asymptomatic intervals. Bleeding may occur spontaneously as well as related to trauma.

Discussion The incidence of spontaneous intracerebral bleeding in patients with afibrinogenemia is unknown; a small number of case reports have been published. spontaneous intracerebral bleeding must be strongly suspected when an afibrinogenemic patient presents with matching clinical symptoms.

Discussion Since intracerebral hemorrhage is a life- threatening event, It is recommend that substitution therapy be installed promptly at presentation, before additional investigations are made.