| Congenital afibrinogenemia | |
|---|---|
| Specialty | Hematology  |
Congenital afibrinogenemia is a rare, genetically inherited blood fibrinogen disorder in which the blood does not clot normally due to the lack of fibrinogen, a blood protein necessary for coagulation. [1] This disorder is autosomal recessive, meaning that two unaffected parents can have a child with the disorder. [2] The lack of fibrinogen expresses itself with excessive and, at times, uncontrollable bleeding. [3]
As this is a disorder that is present in an individual from birth, there are no warning signs to look for. The first symptom usually seen is hemorrhage from the umbilical cord that is difficult to stop. [2]
Other symptoms include: [4]
Spontaneous bleeding of the mouth, nose, and gastrointestinal tract are common. Since blood clots can not be formed, minor injuries tend to lead to excessive bleeding or bruising. The biggest concern for individuals with afibrinogenemia is CNS hemorrhage, bleeding in the brain, which can be fatal. Many of these symptoms are chronic, and will continue to occur for the entirety of the affected individual's life.[ citation needed ]
A missense or nonsense mutation to the genes that code for the fibrinogen protein are affected. Usually the mutation leads to an early stop in the production of the protein. [3] Due to the problem being genetically based, there is no way to prevent the disease. Individuals can get genetic testing done to see if they are a carrier of the trait, and if so may choose to complete genetic counseling to better understand the disorder and help manage family planning. Parents can choose to do prenatal genetic testing for the disorder to determine if their child will have the disease. [6] The only risk factor is if both parents of a child carry the recessive allele linked to the disorder.[ citation needed ]
Individuals with the disorder have a mutation to their fibrinogen gene that prevents the formation of the protein. [3] In normal conditions, fibrinogen is converted to fibrin when it is cleaved by the enzyme thrombin in the blood. The newly formed fibrin forms a fiber-rich network that helps trap red blood cells to start the coagulation process and form a clot. [7] Since there is no fibrinogen present during afibrinogenemia, fibrin can not be formed to aid in this process.[ citation needed ]
When a problem of fibrinogen is suspected, the following tests can be ordered:
Blood fibrinogen levels of less than 0.1 g/L and prolonged bleeding test times are indicators of an individual having afibrinogenemia. [2]
A suspicion of congenital afibrinogenemia may appear on a platelet aggregation function test.
| ADP | Epinephrine | Collagen | Ristocetin | |
|---|---|---|---|---|
| P2Y receptor defect [9] (including Clopidogrel) | Decreased | Normal | Normal | Normal |
| Adrenergic receptor defect [9] | Normal | Decreased | Normal | Normal |
| Collagen receptor defect [9] | Normal | Normal | Decreased or absent | Normal |
| Normal | Normal | Normal | Decreased or absent | |
| Decreased | Decreased | Decreased | Normal or decreased | |
| Storage pool deficiency [10] | Absent second wave | Partial | ||
| Aspirin or aspirin-like disorder | Absent second wave | Absent | Normal | |
The most common treatment is fibrinogen replacement therapy, including cryoprecipitate, blood plasma, and fibrinogen concentration transfusions to help with bleeding episodes or prior to surgery. [11] Although some thrombotic complications have been reported following replacement therapy, transfusions of fibrinogen concentrate are widely considered to be the most beneficial. Fibrinogen concentrate is pure, contains a known quantity of fibrinogen, is virally inactivated, and is transfused in small amounts. [12] There is a lower chance of allergic reaction in response to transfusion. Alternatively, cryoprecipitate contains other coagulation factors, factors VIII, XIII, and von Willebrand factor. [13] There are no known cures or forms of holistic care to date. Most complications arise from the symptoms of the disorder. [5]
As there is not much data out on the life expectancy of an individual with afibrinogenemia, it is difficult to determine the average lifespan. However, the leading cause of death thus far is linked to CNS hemorrhage and postoperative bleeding. [5]
It was first described in 1920 by German doctors, Fritz Rabe and Eugene Salomon, studying a bleeding disorder presenting itself in a child from birth. [14] This disorder may also be simply called afibrinogenemia or familial afibrinogenemia. [4] About 1 in 1 million individuals are diagnosed with the disease; typically at birth. [15] Both males and females seem to be affected equally, [2] but it has a higher occurrence in regions where consanguinity is prevalent. [4]
Currently research is based in pharmacological treatments. [16] A case from 2015 was seen in which congenital afibrinogenemia was resolved in a patient after receiving a liver transplant. [17]
Haemophilia B, also spelled hemophilia B, is a blood clotting disorder causing easy bruising and bleeding due to an inherited mutation of the gene for factor IX, and resulting in a deficiency of factor IX. It is less common than factor VIII deficiency.
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 mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.
Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.
Fibrinogen 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 clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.
Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.
In medicine (hematology), bleeding diathesis is an unusual susceptibility to bleed (hemorrhage) mostly due to hypocoagulability, in turn caused by a coagulopathy. Therefore, this may result in the reduction of platelets being produced and leads to excessive bleeding. Several types of coagulopathy are distinguished, ranging from mild to lethal. Coagulopathy can be caused by thinning of the skin, such that the skin is weakened and is bruised easily and frequently without any trauma or injury to the body. Also, coagulopathy can be contributed by impaired wound healing or impaired clot formation.
Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.
Coagulopathy is a condition in which the blood's ability to coagulate is impaired. This condition can cause a tendency toward prolonged or excessive bleeding, which may occur spontaneously or following an injury or medical and dental procedures.
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 or low levels of other blood proteins. It may also be used as the replacement fluid in plasma exchange. Using ABO compatible plasma, while not required, may be recommended. Use as a volume expander is not recommended. It is given by slow injection into a vein.
Hypoprothrombinemia is a rare blood disorder in which a deficiency in immunoreactive prothrombin, produced in the liver, results in an impaired blood clotting reaction, leading to an increased physiological risk for spontaneous bleeding. This condition can be observed in the gastrointestinal system, cranial vault, and superficial integumentary system, affecting both the male and female population. Prothrombin is a critical protein that is involved in the process of hemostasis, as well as illustrating procoagulant activities. This condition is characterized as an autosomal recessive inheritance congenital coagulation disorder affecting 1 per 2,000,000 of the population, worldwide, but is also attributed as acquired.
Factor X deficiency is a bleeding disorder characterized by a lack in the production of factor X (FX), an enzyme protein that causes blood to clot in the coagulation cascade. Produced in the liver FX when activated cleaves prothrombin to generate thrombin in the intrinsic pathway of coagulation. This process is vitamin K dependent and enhanced by activated factor V.
Factor VII deficiency is a bleeding disorder characterized by a lack in the production of Factor VII (FVII) (proconvertin), a protein that causes blood to clot in the coagulation cascade. After a trauma factor VII initiates the process of coagulation in conjunction with tissue factor in the extrinsic pathway.
Factor XIII deficiency occurs exceedingly rarely, causing a severe bleeding tendency. The incidence is one in a million to one in five million people, with higher incidence in areas with consanguineous marriage such as Iran that has the highest global incidence of the disorder. Most are due to mutations in the A subunit gene. This mutation is inherited in an autosomal recessive fashion.
Purpura fulminans is an acute, often fatal, thrombotic disorder which manifests as blood spots, bruising and discolouration of the skin resulting from coagulation in small blood vessels within the skin and rapidly leads to skin necrosis and disseminated intravascular coagulation.
The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor, fibrinogen, 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 and/or thrombosis. Acquired dysfibrinogenemia is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of liver disease, autoimmune disease, a plasma cell dyscrasias, or certain cancers. 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.
Cryofibrinogenemia refers to a condition classified as a fibrinogen disorder in which a person's blood plasma is allowed to cool substantially, causing the (reversible) precipitation of a complex containing fibrinogen, fibrin, fibronectin, and, occasionally, small amounts of fibrin split products, albumin, immunoglobulins and other plasma proteins.
Factor I deficiency, also known as fibrinogen deficiency, is a rare inherited bleeding disorder related to fibrinogen function in the blood coagulation cascade. It is typically subclassified into four distinct fibrinogen disorders: afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and 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 the production and circulation at reduced levels of fibrinogen at least some of which is dysfunctional. Hypodysfibrinogenemia exhibits reduced penetrance, i.e. only some family members with the mutated gene develop symptoms.
Congenital hypofibrinogenemia is a rare disorder in which one of the three genes responsible for producing fibrinogen, a critical blood clotting factor, is unable to make a functional fibrinogen glycoprotein because of an inherited mutation. In consequence, liver cells, the normal site of fibrinogen production, make small amounts of this critical coagulation protein, blood levels of fibrinogen are low, and individuals with the disorder may develop a coagulopathy, i.e. a diathesis or propensity to experience episodes of abnormal bleeding. However, individuals with congenital hypofibrinogenemia may also have episodes of abnormal blood clot formation, i.e. thrombosis. This seemingly paradoxical propensity to develop thrombosis in a disorder causing a decrease in a critical protein for blood clotting may be due to the function of fibrin to promote the lysis or disintegration of blood clots. Lower levels of fibrin may reduce the lysis of early fibrin strand depositions and thereby allow these depositions to develop into clots.
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