Dysfibrinogenemia
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It has been suggested that this article should be split into articles titled Dysfibrinogenemia and Hereditary fibrinogen Aα-Chain amyloidosis. (discuss) (March 2019) |
Dysfibrinogenemia | |
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Other names | Dysfibrinogenemia, familial[1] |
The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor,
Congenital dysfibrinogenemia is the commonest of these three disorders. Some 100 different genetic
Congenital dysfibrinogenemia is distinguished from a similar inherited disorder, congenital hypodysfibrinogenemia. Both disorders involve the circulation of dysfunctional fibrinogen but in congenital hypodysfibrinogenemia plasma fibrinogen levels are low while in congenital dysfibrinogenemia they are normal. Furthermore, the two disorders involve different gene mutations and inheritance patterns as well as somewhat different symptoms.[3][9]
Fibrinogen
Fibrinogen is a
The normal process of blood clot formation involves the coordinated operation of two separate pathways that feed into a final common pathway: 1)
- Blood clotting: fibrinogen concentration is the rate-limiting factor in blood clot formation and along with blood platelets is critical to this formation (see Coagulation).
- Platelet aggregation: fibrinogen promotes platelet aggregation by cross-linking platelet Glycoprotein IIb/IIIareceptors and thereby promotes blood clot formation through the primary hemostasis pathway.
- Blood clot lysis: The Aα fibrin chain formed from fibrinogen binds tissue plasminogen activator, an agent that breaks down blood clots to participate thereby in promoting fibrinolysis.
Based on these fibrinogen functions, a fibrinogen mutation may act either to inhibit or promote blood clot formation and/or lysis to thereby produce in individuals a
Congenital dysfibrinogenemia
Presentation
Many cases of congenital dysfibrinogenemia are asymptomatic. 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
Pathophysiology
Congenital dysfibrinogenemia is most often caused by a single
The following Table lists examples of mutations causing congenital dysfibrinogenemias. It gives: a) the mutated protein's trivial name; b) the gene mutated (i.e. FGA, FGB, or FGG), its mutation site (i.e. numbered nucleotide in the
Trivial name | Gene: site of mutation | Protein chain: site mutation | Pathophysiology | Clinical disorder | Comment |
---|---|---|---|---|---|
fibrinogen Detroit | FGA: c.114G>C/T | Aα: Arg19Ser | abnormal Polymerization | bleeding | relatively rare; first description of congenital dysfibrinogenmia[16] |
fibrinogen Metz1 | FGA: c.103C>T | Aα: Arg35Cys | delayed release of fibrinopeptide A |
bleeding | relatively common |
fibrinogen Bicetrel | FGA: c.104C>G | Aα: Arg35His | delayed release of fibrinopeptide A |
bleeding | relatively common |
fibrinogen Perth | FGA: c.1541delC | Aα: Pro495Leufs | thin clot, increased clot strength, impaired plasmin generation | bleeding and thrombosis | relatively rare |
fibrinogen Naples | FGB: c.292G>A | Bβ: Ala68thr | defective thrombin binding | thrombosis | relatively rare; homozygous |
fibrinogen BaltimoreIV | FGG: c.901C>T | λ: Arg301Cys | impaired fiber interactions | thrombosis | relatively common |
fibrinogen Vlissingen | FGG: c.1033_1038del | λ: del Asn319-Asp320 | impaired fiber interactions | thrombosis | relatively rare; nucleotides 1033-1038 and amino acids 319-320 deleted |
fibrinogen BarccelonaIV | FGG: c.902G>A | λ: Arg301His | impaired fiber interactions | thrombosis | relatively common |
Diagnosis
The diagnosis of congenital dysfibrinogenmia is made by clinical laboratory studies that find normal levels of plasma fibrinogen but significant excess in the amount of immunologically detected compared to functionally detected (i.e. able to be clotted) fibrinogen. The ratio of functionally-detected to immunologically detected fibrinogen masses in these cases is <0.7. Partial thromboplastin time, activated partial thromboplastin time, thrombin time, and reptilase time tests are usually prolonged regardless of history of bleeding or thrombosis.[11] Where available, laboratory analyses of the fibrinogen genes and peptide chains solidify the diagnosis. Initial examination of these genes or protein chains should search specifically for "hot spot" mutations, i.e. the most common mutations (see Pathophysiology section) that comprise the large bulk of mutations in the disorder.[5] In cases of dysfibrinogenemia in which acquired disease is suspected, diagnosis requires a proper diagnosis of the presence of a causable disease.[4]
Congenital dysfibrinogenmia is initially distinguished form congenital hypodysfibrinogenemia by the finding of normal immunologically-detected levels of fibrinogen in congenital dysfibrinogenemia and sub-normal levels of immunologically-detected fibrinogen in congenital hypodysfibrinogenemia. Both disorders exhibit mass ratios of functionally-detected to immunologically-detected fibrinogen that are below <0.7. Genetic and protein analyses can definitively differentiate the two disorders.[9]
Treatment
In a study of 189 individuals diagnosed with congenital dysfibrinogenemia, ~33% were asymptomatic, ~47% experienced episodic bleeding, and ~20% experienced episodic thromboses.[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]
Asymptomatic individuals
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.
Symptomatic individuals
Individuals experiencing episodic bleeding as a result of congenital dysfibrinogenemia should be treated at a center specialized in treating
Individuals experiencing episodic thrombosis as a result of congenital dysfibrinogenemia should also be treated at a center specialized in treating
Hereditary fibrinogen Aα-Chain amyloidosis
Presentation
Individuals with hereditary fibrinogen Aα-chain
Pathophysiology
Certain mutations in the fibrinogen Aα-chain gene cause a form of
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. The disorder exhibits a highly variable penetrance among family members.[17][6] Hereditary fibrinogen Aα-Chain amyloidosis shows variable penetrance among family members, a distinctive histological appearance, proteinuria, progressive renal impairment, and markedly better survival rates than other forms of systemic renal amyloidosis.[6]
Treatment
Treatment of hereditary fibrinogen Aα-Chain amyloidosis has relied on chronic maintenance hemodialysis and, where possible, kidney transplantation. While recurrence of amyloidosis in the transplanted kidney occurs and is to be expected, transplant survival rates for this form of amyloidosis are significantly better than those for transplants in other forms of systemic renal amyloidosis. Relatively healthy individuals with hereditary fibrinogen Aα-Chain-related renal amyloidosis may be considered for kidney and liver bi-transplantation with the expectation that survival of the transplanted kidney will be prolonged by replacing the fibrinogen Aα-Chain-producing liver with a non-diseased donor liver.[6]
Acquired dysfibrinogenemia
Presentation
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. Bleeding appears to be more prominent in acquired compared to congenital dysfibrinogenemia; pathological thrombosis, while potentially occurring in these individuals as a complication of their underlying disease, is an uncommon feature of the acquired disorder.[4]
Pathophysiology
Acquired dysfibrinogenemia occurs as a known or presumed consequence of an underlying disease which directly or indirectly interferes with the clotting function of fibrinogen. Individuals with acquired dysfibrinogenemias have a greater tendency for bleeding complications than those with congenital fibrinogenemia.[4][18][19] The following Table gives some abnormalities, causes, and apparent pathophysiology along with some comments on examples of acquired dysfibrinogenemia.[3][4]
Abnormality | Cause | Pathophysiology | Comment |
---|---|---|---|
incorrect post-translational modification of fibrinogen | severe liver disease | abnormal fibrinogen sialylation |
most common cause of acquired dysfibrinogenemia |
monoclonal antibody | plasma cell dyscrasias such as multiple myeloma and MGUS |
monoclonal antibody interferes with clotting | uncommon |
polyclonal antibody |
systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis |
polyclonal antibody interferes with clotting | uncommon |
production of abnormal fibrinogen by cancer | cervical cancer of epithelium, renal cell carcinoma, others | paraneoplastic effect of cancer |
extremely rare |
Drug effect | mithramycin, isoniazid, direct thrombin inhibitors (e.g. heparin, dabigatran, bivalirudin, argatroban ) |
unclear | extremely rare case reports
|
Diagnosis
Diagnosis of acquired dysfibrinogenemia uses the same laboratory tests that are used for congenital dysfibrinogenemia plus evidence for an underlying causative disease.[4]
Treatment
Treatment of acquired dysfibrinogenemia follows the guidelines recommended for congenital dysfibrinogenemia.[4] In addition, treatment of any disease thought to be responsible for the dysfibrinogenemia might be useful. 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.[20][21]
References
- ^ "Dysfibrinogenemia". Genetic and Rare Diseases (GARD). NIH. Retrieved 19 March 2019.[permanent dead link]
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