In a report on 474 patients with renal amyloidosis, hereditary fibrinogen Aα chain disease represented only 1.3% of all cases whereas aberrant immunoglobulin-induced renal amyloidosis (e.g. AL amyloidosis) represented 86% of the cases). Hereditary fibrinogen Aα-Chain amyloidosis is, however, the most common form of familial renal amyloidosis. Pathophysiology
Certain mutations in the fibrinogen Aα-chain gene cause a form of familial renal amyloidosis termed hereditary fibrinogen Aα-Chain amyloidosis. The disorder is due to autosomal dominant inheritance of Aα chain mutations the most common of which is hemoglobin Indianopolis, a heterzyogus missense (c.1718G>T: Arg554Leu) mutation. Other missense mutations causing this disorder are unnamed; they include 1634A>T: Glu526Val; c.1670C>A: Thr538lys; c.1676A.T:Glu540Val; and c1712C>A:Pro552His. A deletion mutation causing a frameshift viz., c.1622delT: Thr525Leu, is also a cause of the disorder. The fibrinogen bearing these mutant Aα-chains is secreted into the circulation and gradually accumulates in, and causes significant injury to, the kidney. The mutant fibrinogen does not appear to accumulate in, or injure, extra-renal tissues. Diagnosis
The diagnosis of this disorder depends on demonstrating: 1) a dysfunctional plasma fibrinogen, i.e. significantly less functionally-detected compared to immunologically-detected fibrinogen; b) presence of signs and/or symptoms of kidney disease; and c) histological evidence of often massive obliteration of renal glomeruli by amyloid as detected by Congo red staining. There also should be no evidence for systemic amyloidosis. Specialized centers use immunological and genetic studies to define the nature of the renal amyloid deposits, the presence of FGA gene mutations, and the occurrence of these mutations in family members.
During bleeding episodes, treatment with fibrinogen concentrates or in emergencies or when these concentrates are unavailable, infusions of fresh frozen plasma and/or cryoprecipitate (a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter. Tranexamic acid or fibrinogen concentrates are recommended for prophylactic treatment prior to minor surgery while fibrinogen concentrates are recommended prior to major surgery with fibrinogen concentrates usage seeking to maintain fibrinogen activity levels at >1 gram/liter. Women undergoing vaginal or Cesarean child birth should be treated at a hemophilia center with fibrinogen concentrates to maintain fibrinogen activity levels at 1.5 gram/liter. The latter individuals require careful observation for bleeding during their post-partum periods.Individuals experiencing episodic thrombosis as a result of congenital dysfibrinogenemia should also be treated at a center specialized in treating hemophilia using antithrombotic agents. They should be instructed on antithrombotic behavioral methods fur use in high risk situations such as long car rides and air flights. Venous thrombosis should be treated with low molecular weight heparin for a period that depends on personal and family history of thrombosis events. Prophylactic treatment prior to minor surgery should avoid fibrinogen supplementation and use prophylactic anticoagulation measures; prior to major surgery, fibrinogen supplementation should be used only if serious bleeding occurs; otherwise, prophylactic anticoagulation measures are recommended. Hereditary fibrinogen Aα-Chain amyloidosis
Presentation
Individuals with hereditary fibrinogen Aα-chain amyloidosis present with evidence ranging from asymptomatic proteinuria to progressive renal impairment and end-stage kidney disease. They do not evidence pathological bleeding or thrombosis and their amyloidosis is non-systemic in that it is restricted to the kidney.