The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor,
fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood cl ...
, circulates at normal levels but is dysfunctional. Congenital dysfibrinogenemia is an inherited disorder in which one of the parental genes produces an abnormal fibrinogen. This fibrinogen interferes with
normal blood clotting and/or
lysis of blood clots. The condition therefore may cause pathological
bleeding
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...
and/or
thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (t ...
.
Acquired dysfibrinogenemia is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of
liver disease
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the si ...
,
autoimmune disease, a
plasma cell dyscrasia
Plasma cell dyscrasias (also termed plasma cell disorders and plasma cell proliferative diseases) are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells ( ...
s, or certain
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s. It is associated primarily with pathological bleeding.
Hereditary fibrinogen Aα-Chain amyloidosis is a sub-category of congenital dysfibrinogenemia in which the dysfunctional fibrinogen does not cause bleeding or thrombosis but rather gradually accumulates in, and disrupts the function of, the kidney.
Congenital dysfibrinogenemia is the commonest of these three disorders. Some 100 different genetic
mutations occurring in more than 400 families have been found to cause it.
All of these mutations as well as those causing hereditary fibrinogen Aα-Chain amyloidosis exhibit partial
penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
, i.e. only some family members with one of these mutant genes develop dysfibrinogenemia-related symptoms.
While both of these congenital disorders as well as acquired dysfibrinogenemia are considered very rare, it is estimated that ~0.8% of individuals with venous thrombosis have either a congenital or acquired dysfibrinogenemia. Hence, the dysfibrinogenemia disorders may be highly under-diagnosed conditions due to isolated thrombotic events that are not appreciated as reflecting an underlying fibrinogen disorder.
Congenital dysfibrinogenemia is distinguished from a similar inherited disorder, congenital
hypodysfibrinogenemia
Hypodysfibrinogenemia, also termed congenital hypodysfibrinogenemia, is a rare hereditary fibrinogen disorder cause by mutations in one or more of the genes that encode a factor critical for blood clotting, fibrinogen. These mutations result in th ...
. 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.
Fibrinogen
Fibrinogen is a
glycoprotein made and secreted into the blood primarily by liver
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
cells.
Endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...
cells also make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood
platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...
s and their precursors, bone marrow
megakaryocytes
A megakaryocyte (''mega-'' + '' karyo-'' + '' -cyte'', "large-nucleus cell") is a large bone marrow cell with a lobated nucleus responsible for the production of blood thrombocytes (platelets), which are necessary for normal blood clotting. In hum ...
, although once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein.
The final secreted, hepatocyte-derived glycoprotein is made of two
trimers each of which is composed of three polypeptide chains,
Aα (also termed α) encoded by the ''FGA'' gene,
Bβ (also termed β) encoded by the ''FGB'' gene, and γ encoded by the ''FGG'' gene. 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. The heximer is assembled as a protein in the
endoplasmic reticulum of hepatocytes and then transferred to the Golgi where
Polysaccharides (i.e. complex sugars) and
sialic acid are added by respective
glycosylation and
sialylation Sialic acids are a class of alpha-keto acid sugars with a nine-carbon backbone.
The term "sialic acid" (from the Greek for saliva, - ''síalon'') was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this g ...
enzyme pathways thereby converting the heximer to a functional fibrinogen glycoprotein. The final circulating glycoprotein (notated as (AαBβγ)
2, (αβγ)
2, Aα
2Bβ
2γ
2, or α
2β
2γ
2) is arranged as a long flexible rod with nodules at both ends termed
D domains and central nodule termed the E domain.
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
Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another).
The forces that cause adhesion and cohesion can b ...
,
activation
Activation, in chemistry and biology, is the process whereby something is prepared or excited for a subsequent reaction.
Chemistry
In chemistry, "activation" refers to the reversible transition of a molecule into a nearly identical chemical o ...
, 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
Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
to form individual fibrin strands plus the respective
fibrinopeptides A and
B formed from this cleavage. In the final common pathway fibrin is cross-linked by activated clotting
factor XIII
Factor XIII or fibrin stabilizing factor is a zymogen found in blood of humans and some other animals. It is activated by thrombin to factor XIIIa. Factor XIIIa is an enzyme of the blood coagulation system that crosslinks fibrin. Deficiency of X ...
(termed factor XIIIa) to form mature gel-like fibrin clots. Subsequent
fibrinolysis
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other ...
pathways act to limit clot formation and dissolve clots no longer needed. Fibrinogen and its Aα fibrin chain have several functions in this process:
* 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
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
).
* Platelet aggregation: fibrinogen promotes
platelet aggregation
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby ini ...
by cross-linking platelet
Glycoprotein IIb/IIIa
In medicine, glycoprotein IIb/IIIa (GPIIb/IIIa, also known as integrin αIIbβ3) is an integrin complex found on platelets. It is a receptor for fibrinogen and von Willebrand factor and aids platelet activation. The complex is formed via calcium ...
receptors 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
Tissue plasminogen activator (abbreviated tPA or PLAT) is a protein involved in the breakdown of blood clots. It is a serine protease () found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion ...
, an agent that breaks down blood clots to participate thereby in promoting
fibrinolysis
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other ...
.
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
diathesis to develop pathological bleeding, thrombosis, or both conditions.
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
easy bruising and
menorrhagia. Less common manifestations of bleeding may be severe or even life-threatening; these include excessive bleeding after tooth extraction, surgery,
vaginal birth
A vaginal delivery is the birth of offspring in mammals (babies in humans) through the vagina (also called the "birth canal"). It is the most common method of childbirth worldwide. It is considered the preferred method of delivery, with lower m ...
, and
miscarriage. Rarely, these individuals may suffer
hemarthrosis
Hemarthrosis is a bleeding into joint spaces. It is a common feature of hemophilia.
Causes
It usually follows injury but occurs mainly in patients with a predisposition to hemorrhage such as those being treated with warfarin (or other anticoagulan ...
or
cerebral hemorrhage. In one study of 37 individuals >50 years old afflicted with this disorder, 19% had a history of thrombosis. Thrombotic complications occur in both arteries and veins and include
transient ischemic attack
A transient ischemic attack (TIA), commonly known as a mini-stroke, is a minor stroke whose noticeable symptoms usually end in less than an hour. TIA causes the same symptoms associated with strokes, such as weakness or numbness on one side of ...
, ischemic
stroke,
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
, retinal artery thrombosis, peripheral artery thrombosis, and
deep vein thrombosis
Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...
. In one series of 33 individuals with a history of thrombosis due to congenital dysfibrinogenemia, five developed chronic
pulmonary hypertension due to ongoing
pulmonary embolism
Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream ( embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathin ...
probably stemming form deep vein thrombosis. About 26% of individuals with the disorder suffer both bleeding and thrombosis complications.
Pathophysiology
Congenital dysfibrinogenemia is most often caused by a single
autosomal dominant missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
in the ''Aα'', ''Bβ'', or ''γ'' gene; rarely, it is caused by a
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
or
compound heterozygous In medical genetics, compound heterozygosity is the condition of having two or more heterogeneous recessive alleles at a particular locus that can cause genetic disorders, genetic disease in a heterozygous state; that is, an organism is a compound h ...
missense mutation, a
deletion,
frameshift mutation,
insert mutation, or
splice site mutation in one of these genes. The most frequent sites for these mutations code for the
N-terminus of the Aα chain or the
C-terminus of the γ chain that lead to defective assembly of fibrin in early clot formation and thereby a bleeding predisposition.
Two particular missense mutations represent the majority (74% in one study of 101 individuals) of all mutations associated with dysfibrinogenemia and therefore represent prime sites to examine in the initial testing of individuals having a congenital dysfibrinogenmia bleeding disorder. These mutations alter the
codon coded for the amino acid
arginine at either the 35th position of FGA (termed Arg35; see fibrinogen Metz1 and fibrinogen Bicetre in the Table below) and or the 301st position of FGG (termed Arg301; see fibrinogen Baltimore IV in the Table below).
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
cloned
Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, ...
gene), and the names of the nucleotides (i.e.
C,
T,
A,
G) at these sites before>after the mutation; c) the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using
standard abbreviations) found in the normal-mutated circulating fibrinogen; d) the cause of the mutated fibrinogen's misfunction(s); e) the clinical consequence(s) of the mutation; and f) comments. Unless noted as a deletion (del), frame shift (fs), or homozygous mutation, all mutations are heterozygous, missense mutations.
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
The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time (aPTT or APTT), is a blood test that characterizes coagulation of the blood. A historical name for this measure is the kaolin-cephalin clotting time ( ...
,
activated partial thromboplastin time,
thrombin time
The thrombin time (TT), also known as the thrombin clotting time (TCT), is a blood test that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added. It is u ...
, and
reptilase time tests are usually prolonged regardless of history of bleeding or thrombosis.
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.
In cases of dysfibrinogenemia in which acquired disease is suspected, diagnosis requires a proper diagnosis of the presence of a causable disease.
Congenital dysfibrinogenmia is initially distinguished form congenital
hypodysfibrinogenemia
Hypodysfibrinogenemia, also termed congenital hypodysfibrinogenemia, is a rare hereditary fibrinogen disorder cause by mutations in one or more of the genes that encode a factor critical for blood clotting, fibrinogen. These mutations result in th ...
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.
Treatment
In a study of 189 individuals diagnosed with congenital dysfibrinogenemia, ~33% were asymptomatic, ~47% experienced episodic bleeding, and ~20% experienced episodic thromboses.
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.
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.
In general, individuals with this disorder require regular follow-up and multidiscipline management prior to surgery, pregnancy, and giving
childbirth
Childbirth, also known as labour and delivery, is the ending of pregnancy where one or more babies exits the internal environment of the mother via vaginal delivery or caesarean section. In 2019, there were about 140.11 million births glob ...
. Women with the disorder appear to have an increased rate of
miscarriages
Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical ...
and all individuals with fibrinogen activity in clotting tests below 0.5 grams/liter are prone to bleeding and spontaneous abortions. Women with multiple miscarriages and individuals with excessively low fibrinogen activity levels should be considered for
prophylaxis
Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...
therapy with fibrinogen replacement during pregnancy, delivery, and/or surgery.
Symptomatic individuals
Individuals experiencing episodic bleeding as a result of congenital dysfibrinogenemia should be treated at a center specialized in treating
hemophilia. They should avoid all
medications that interfere with normal platelet function. During bleeding episodes, treatment with fibrinogen concentrates or in emergencies or when these concentrates are unavailable, infusions of
fresh frozen plasma
Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors (INR > 1.5) or low levels of other blood proteins. It may also be used as the re ...
and/or
cryoprecipitate
Cryoprecipitate, also called cryo for short, is a frozen blood product prepared from blood plasma. To create cryoprecipitate, fresh frozen plasma thawed to 1–6 °C is then centrifuged and the precipitate is collected. The precipitate is r ...
(a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter.
Tranexamic acid
Tranexamic acid (TXA) is a medication used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. It is also used for hereditary angioedema. It is taken eit ...
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
The postpartum (or postnatal) period begins after childbirth and is typically considered to end within 6 weeks as the mother's body, including hormone levels and uterus size, returns to a non-pregnant state. The terms puerperium, puerperal perio ...
periods.
Individuals experiencing episodic thrombosis as a result of congenital dysfibrinogenemia should also be treated at a center specialized in treating
hemophilia using
antithrombotic
An antithrombotic agent is a drug that reduces the formation of blood clots (thrombi).http://cancerweb.ncl.ac.uk/cgi-bin/omd?antithrombotic Antithrombotics can be used therapeutically for prevention ( primary prevention, secondary prevention) or ...
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
Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and in the treatment of myocardial in ...
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
Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom ma ...
to progressive renal impairment and
end-stage kidney disease
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
. They do not evidence pathological bleeding or thrombosis and their amyloidosis is non-systemic in that it is restricted to the kidney. 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
Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis in the US. The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein ...
) represented 86% of the cases).
Hereditary fibrinogen Aα-Chain amyloidosis is, however, the most common form of
familial renal amyloidosis
Familial renal amyloidosis is a form of amyloidosis primarily presenting in the kidney.
It is associated most commonly with congenital mutations in the fibrinogen alpha chain and classified as a dysfibrinogenemia (see Hereditary Fibrinogen Aα-C ...
.
Pathophysiology
Certain mutations in the fibrinogen Aα-chain gene cause a form of
familial renal amyloidosis
Familial renal amyloidosis is a form of amyloidosis primarily presenting in the kidney.
It is associated most commonly with congenital mutations in the fibrinogen alpha chain and classified as a dysfibrinogenemia (see Hereditary Fibrinogen Aα-C ...
termed hereditary fibrinogen Aα-Chain amyloidosis.
The disorder is due to
autosomal dominant inheritance
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
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
Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...
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
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
evidence of often massive obliteration of renal
glomeruli
''Glomerulus'' () is a common term used in anatomy to describe globular structures of entwined vessels, fibers, or neurons. ''Glomerulus'' is the diminutive of the Latin ''glomus'', meaning "ball of yarn".
''Glomerulus'' may refer to:
* the filter ...
by amyloid as detected by
Congo red
Congo red is an organic compound, the sodium salt of 3,3′-( ,1′-biphenyl4,4′-diyl)bis(4-aminonaphthalene-1-sulfonic acid). It is an azo dye. Congo red is water-soluble, yielding a red colloidal solution; its solubility is greater in organic ...
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.
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.
Treatment
Treatment of hereditary fibrinogen Aα-Chain amyloidosis has relied on chronic maintenance
hemodialysis
Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
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.
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.
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.
The following Table gives some abnormalities, causes, and apparent pathophysiology along with some comments on examples of acquired dysfibrinogenemia.
Diagnosis
Diagnosis of acquired dysfibrinogenemia uses the same laboratory tests that are used for congenital dysfibrinogenemia plus evidence for an underlying causative disease.
Treatment
Treatment of acquired dysfibrinogenemia follows the guidelines recommended for congenital dysfibrinogenemia.
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.
References
External links
{{Diseases of megakaryocytes
Coagulopathies
Autosomal dominant disorders
Rare diseases