[5][7] All of these mutations as well as those causing hereditary fibrinogen Aα-Chain amyloidosis exhibit partial penetrance, i.e. only some family members with one of these mutant genes develop dysfibrinogenemia-related symptoms.
All three genes are located on the long (i.e. "p") arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively) and may contain mutations that are the cause of congenital dysfibrinogenemia.
[11][12] The normal process of blood clot formation involves the coordinated operation of two separate pathways that feed into a final common pathway: 1) primary hemostasis, i.e. the adhesion, activation, and aggregation of circulating blood platelets at sites of vascular injury and 2) secondary hemostasis, i.e. cleavage of the Aα and Bβ chains of fibrinogen by thrombin to form individual fibrin strands plus the respective fibrinopeptides A and B formed from this cleavage.
Since manifestations of the disorder generally occur in early adulthood or middle-age, younger individuals with a gene mutation causing it may not have had time to develop symptoms while previously asymptomatic individuals of advanced age with such a mutation are unlikely to develop symptoms.
Bleeding episodes in most cases of this disorder are mild and commonly involve easy bruising and menorrhagia.
[9] Due to the rareness of this disorder, treatment of individuals with these presentations are based primarily on case reports, guidelines set by the United Kingdom, and expert opinions rather than controlled clinical studies.
[5] Treatment of asymptomatic congenital dysfibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as estimated based on the history of family members with the disorder and, where available, determination of the exact mutation causing the disorder plus the propensity of the particular mutation type to develop these complications.
[5] In general, individuals with this disorder require regular follow-up and multidiscipline management prior to surgery, pregnancy, and giving childbirth.
Women with the disorder appear to have an increased rate of miscarriages and all individuals with fibrinogen activity in clotting tests below 0.5 grams/liter are prone to bleeding and spontaneous abortions.
They should be instructed on antithrombotic behavioral methods fur use in high risk situations such as long car rides and air flights.
[5] Individuals with hereditary fibrinogen Aα-chain amyloidosis present with evidence ranging from asymptomatic proteinuria to progressive renal impairment and end-stage kidney disease.
The fibrinogen bearing these mutant Aα-chains is secreted into the circulation and gradually accumulates in, and causes significant injury to, the kidney.
[5][6][17] 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.
[6] Treatment of hereditary fibrinogen Aα-Chain amyloidosis has relied on chronic maintenance hemodialysis and, where possible, kidney transplantation.
[6] Acquired dysfibrinogenemia commonly present with signs, symptoms, and/or prior diagnoses of the underlying causative disease or drug intake in an individual with an otherwise unexplained bleeding tendency or episode.
[4] Acquired dysfibrinogenemia occurs as a known or presumed consequence of an underlying disease which directly or indirectly interferes with the clotting function of fibrinogen.
[4][18][19] The following Table gives some abnormalities, causes, and apparent pathophysiology along with some comments on examples of acquired dysfibrinogenemia.
For example, therapeutic plasma exchange and chemotherapy to reduce monoclonal antibody levels has been used successfully to reverse otherwise uncontrollable bleeding in cases of multiple myeloma-associated dysfibrinogenemia.