Afibrinogenemia is a very rare, inherited blood disorder in which the blood does not clot normally because of a mutation that leads to the absence of fibrinogen (also called coagulation factor I). Fibrinogen has a multitude of functions, including fibrin clot formation, platelet aggregation, and promoting wound healing at a site of injury. It facilitates the binding of platelets to form an initial clot at the site of injury, and is converted into fibrin, the major structural component of the clot. The lack of fibrinogen makes affected individuals susceptible to severe bleeding episodes, particularly during infancy and childhood.
The prevalence of afibrinogenemia is approximately one in 1,000,000, making the bleeding disorder much rarer than either type of hemophilia and difficult to diagnose.1,2
“A clinician must have a suspicion that a patient has a bleeding disorder – that is the first step to an accurate diagnosis,” said Suchitra Acharya, MD, from the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell and the Cohen Children’s Medical Center of New York. “We need to pay attention to a patient’s symptoms, delve into their bleeding history, and ask the right questions. The bleeding history is the most critical piece of information to begin to get to a diagnosis. Then, of course, you need to do the right tests.”
Rakesh P. Mehta, MD, associate professor of Clinical Medicine at Indiana University School of Medicine, agreed. “The [International Society on Thrombosis and Haemostasis] Bleeding Assessment Tool is a very useful instrument to identify patients at risk of afibrinogenemia,” he noted. “If providers were comfortable with this tool, we could find these patients and refer them to specialists sooner.”
“Most physicians are unaware of the other complications linked to afibrinogenemia, such as thromboembolic complications, splenic ruptures, bone cysts, and others,” said Philippe de Moerloose, MD, head of the hemostasis unit at University Hospital in Geneva, Switzerland.
An Autosomal, Inherited Disorder
Fibrinogen deficiencies fall into three categories: afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia or hypodysfibrinogenemia.
Hypofibrinogenemia, when fibrinogen is present in the blood but not at adequate levels for proper coagulation to occur, is a less severe form of fibrinogen deficiency. It is inherited in an autosomal dominant manner. Dysfibrinogenemia (when fibrinogen blood levels are normal) and hypodysfibrinogenemia (when fibrinogen levels are reduced) are autosomal dominant, meaning that only one parent must carry the gene to pass it to a child. The first point mutation that leads to lower fibrinogen levels was documented in 1968.3
Afibrinogenemia is the most severe fibrinogen deficiency and results from a null mutation or a severely truncated form of one of the three proteins that make up the glycoprotein fibrinogen.4 The three proteins are the Aα, Bβ, and γ chains of fibrinogen, expressed from the FGA, FBG and FGG genes, respectively. Afibrinogenemia is inherited in an autosomal recessive manner, meaning an individual must inherit two abnormal genes – a deletion, nonsense, splicing, or missense mutations in any of the three genes from each parent – to be affected.
The testing to identify whether a patient has afibrinogenemia can be conducted by a primary care provider or general hematologist but, if a patient is diagnosed, “rather than being cared for by a hematologist, [who is likely not experienced in afibrinogenemia], a referral to a hemophilia treatment center is ideal,” said Dr. Acharya, who is also the head of the bleeding disorders and thrombosis program at the Cohen Children’s Medical Center of New York. “Hemophilia treatment centers take care of these patients on a regular basis, so they are up to date on the latest advances, guidelines, and treatments that a general hematologist may not have.”
Saskia Schols, MD, PhD, a hematologist who cares for patients with bleeding disorders at the Haemophilia Treatment Center at the Radboudumc in the Netherlands, agreed. “We need more awareness by educating internists in regional hospitals and general practitioners [about this disease] so that these clinicians refer patients with an increased bleeding tendency to a hemophilia treatment center,” she said.
Typically, patients with dysﬁbrinogenemia or afibrinogenemia are identiﬁed during a clinical investigation for bleeding. “Afibrinogenemia has the potential for a mucocutaneous, deep tissue-type of bleeding and … can also present with thrombotic event,” said Dr. Acharya. “Symptoms could vary from mild to life-threatening bleeding, including a catastrophic stroke or pulmonary embolism.”
In newborns, afibrinogenemia can present with umbilical cord bleeding. In the case of prolonged umbilical cord stump bleeding, afibrinogenemia and another rare bleeding disorder, factor XIII deficiency, need to be ruled out.
Afibrinogenemia can also present with joint bleeds or mucocutaneous bleeding, such as easy bruising or bleeding from mucosal lining in the nose, mouth (following a tooth extraction for example), and gastrointestinal tract. Presentation with intracranial bleeding, which could be life-threatening, is also possible, Dr. Acharya explained. Bleeding can also manifest during a medical procedure and, in women, can present as heavy periods, bleeding during a C-section or following vaginal delivery.5 Since fibrinogen is required for embryo implantation, recurrent miscarriages during the early first trimester are common among women with afibrinogenemia.
For patients with a suspected bleeding disorder, the initial diagnostic workup is a complete blood count to evaluate whether a patient has anemia from the bleeding. Next, coagulation is evaluated with a prothrombin time (PT) test, an activated partial thromboplastin time (aPTT) test, and a thrombin clotting time (TCT) test. In a patient with afibrinogenemia, the PT and aPTT will be extremely prolonged. If these tests show abnormalities, the next step is a fibrinogen functional test, such as the fibrinogen activity assay. If the result is low activity, clinicians test for fibrinogen antigen levels.6
In patients with afibrinogenemia, fibrinogen levels are below 0.1 g/L, below the detection of the assay.
“At this point, the laboratory technician usually calls me to say that they have run the assay several times and believe something is wrong with the sample because they cannot detect any fibrinogen,” said Dr. Acharya.
Diagnosis of hypofibrinogenemia requires a fibrinogen levels of less than 1.5 g/L, and, to test for dysfibrinogenemia, a fibrinogen antigen level test is conducted. “Once a reduced fibrinogen activity or antigen level is found, molecular analysis of the FGG, FBA, and FGB genes is performed,” said Dr. Schols.
“There are now several identifiable mutations in the fibrinogen gene that can be assessed to help characterize the disorder, although the absence or very low levels of fibrinogen in the blood is still the hallmark of the diagnosis,” added Dr. Mehta.
“In our center, if conventional clotting assays are not abnormal – including thrombopathy, fibrinolytic studies, bleeding times, and fibrinogen activity level – we perform whole-exome sequencing using a panel that includes 156 genes involved in thrombosis and hemostasis,” Dr. Schols told ASH Clinical News.
However, accessing the afibrinogenemia-specific genetic testing can be challenging, said Dr. Mehta. “While the initial work-up tests are available everywhere, the more specialized tests are not available in-house at many places, so the tests need to be sent out.”
A Single Treatment Option
When patients experience acute bleeding episodes, they generally receive ﬁbrinogen concentrates derived from human plasma. Fresh frozen plasma (FFP) and cryoprecipitate (frozen blood product prepared from blood plasma) are used less frequently than they once were because of the risk of viral transmission with these products, Dr. Acharya told ASH Clinical News.
Now, fibrinogen concentrates are more commonly used. The advantage of concentrates is that clinicians know the precise amount of fibrinogen in the concentrates, “which means we can normalize levels in patients when they have a bleed or if they have to go for a procedure, or during pregnancy and delivery,” Dr. Acharya said.
Fibrinogen concentrates are also the preference in the Netherlands, Dr. Schols added.
Typically, patients are monitored and given fibrinogen concentrate as needed. However, some patients will require chronic, prophylactic fibrinogen replacement therapy, such as children who have a fibrinogen activity level of less than 0.1 g/L and bleeds in the central nervous system, those who have a history of life-threatening or recurrent bleeds, or individuals who have a severe family bleeding phenotype. Pregnant women who are not on prophylaxis are started on fibrinogen replacement soon after conception, with monitoring of their levels and attempts to keep trough fibrinogen levels above 1.0 g/dL during pregnancy and above 1.5 g/dL during delivery and post-partum, according to Dr. Acharya.
“The challenge with prophylactic treatment is that it requires a regular infusion, which can be inconvenient for a patient and their family,” Dr. Mehta noted. “The infusion requires intravenous access, which, for young children, can be traumatic. There is also a relatively high cost to the therapy.”
The decision of whether to begin prophylactic therapy is a difficult one. “Should we give prophylaxis already when the diagnosis is known, sometimes as soon as there is bleeding from the umbilical cord or after a circumcision [in a newborn]? Or when [the infant] is a sibling of someone diagnosed with afibrinogenemia?” asked Dr. de Moerloose. “Most of the time we wait for the first bleeding manifestation, but it is a difficult choice because you are afraid [that it might be] intracranial bleeding.”
There are currently no additional therapies in clinical trials for the disorder, although there is work on improving the Food and Drug Administration–approved fibrinogen concentrates. Gene therapy is being evaluated in other inherited bleeding disorders, but there is no such development for afibrinogenemia, likely due to the extremely small number of patients with the disease. “I do not know whether a company would support such a development,” commented Dr. de Moerloose.
Another challenge associated with fibrinogen therapy is its thrombotic risk. To protect against thrombosis in a patient on plasma-derived fibrinogen concentrate for a prolonged period, many experts recommend adding concurrent anticoagulation with small doses of either heparin or low molecular weight heparin.
Heparin is also the preferred treatment for thrombosis because there are few data on the use of the direct oral anticoagulants in this setting. “We have to pay attention when we give fibrinogen, particularly during childbirth and the postpartum period, as pregnancy itself confers a higher risk for thrombosis for a woman,” Dr. Acharya explained. “Some of these women will also require anticoagulants because we could tip the balance towards thrombosis.”
Challenges and Questions
There are many challenges associated with managing a very rare disorder such as afibrinogenemia. Dr. Acharya has been involved in the rare bleeding disorder community for almost two decades and has worked with the American Thrombosis and Hemostasis Network (ATHN) and more recently has served on a National Hemophilia Foundation committee on the State of the Science Research Summit to develop a national blueprint on rare bleeding disorders to showcase issues related to the diagnosis, testing, and treatment of afibrinogenemia. The committee is also working to make more resources readily available to clinicians who encounter this disease.
A major issue in making a timely diagnosis of afibrinogenemia is the lack of suspicion of a bleeding disorder, according to Dr. Acharya. “There is quite a lot of work that needs to be done to create awareness of this disorder.”
“Ideally, if we could screen all babies that are born for [afibrinogenemia and other rare bleeding disorders], we could identify them early,” Dr. Mehta told ASH Clinical News. “However, given the rarity of these conditions, it is not yet cost-efficient.”
The heterogeneity in clinical bleeding phenotype and limited research about the genotype-phenotype connection is another challenge, noted Dr. Schols. Like other ultra-rare genetic disorders, the natural history and clinical features of afibrinogenemia are difficult to study because few clinical centers see enough patients to conduct a comprehensive analysis.
“The phenotype likely depends on the genetic mutations of the patient, along with other genetic and non-genetic factors,” said Dr. Acharya. “Fibrinogen also has multifaceted functions and reacts with other proteins in the body differently from one individual to another – in those patients who produce it. As we understand more about the role of fibrinogen in the clotting cascade and in other functions, we are beginning to unearth some of these clinical manifestations of afibrinogenemia. Currently, though, we don’t have a good understanding of the genetics and gene modifiers, if there are any.”
There is much work to be done on behalf of patients living with afibrinogenemia and those who are still undiagnosed, Dr. Acharya acknowledged.
“My hope is that the ATHN and the National Hemophilia Foundation will continue efforts to gather resources and publish national guidelines, to establish a central lab to diagnose afibrinogenemia and other rare bleeding disorders, and to make genetic testing widely available for accurate diagnoses,” she said. “We need more research to understand the genotype-phenotype correlation in afibrinogenemia, as well. Right now, there is no clear guidance.” —By Anna Azvolinsky
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