EDUCATION step is a fibrinogen level assay . 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 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 afibrinogenemiaspecific 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 .
“ 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 .
“ We need more research to understand the genotype-phenotype correlation . ... Right now , there is no clear guidance .”
— Suchitra Acharya , MD
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 and more recently has served on a National Hemophilia Foundation committee 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 on 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 genotypephenotype 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 , 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 National Hemophilia Foundation and other organizations 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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Blood . 2004 ; 104 ( 5 ): 1243-1252 . 2 . Mumford AD , Ackroyd S , Alikhan R , et al . Guideline for the diagnosis and management of the rare coagulation disorders . Br J Haematol . 2014 ; 167 ( 3 ): 304-326 .
3 . Blombäck M , Blombäck B , Mammen EF , Prasad AS . Fibrinogen Detroit — a Molecular Defect in the N-terminal Disulphide Knot of Human Fibrinogen ? Nature . 1968 ; 218 ( 5137 ): 134-137 .
4 . Casini A , Undas A , Palla R , et al . Diagnosis and classification of congenital fibrinogen disorders : communication from the SSC of the ISTH . J Thromb Haemost . 2018 ; 16 ( 9 ): 1887-1890 .
5 . de Moerloose P , Neerman-Arbez M . Treatment of congenital fibrinogen disorders . Expert Opin Biol Ther . 2008:8:979-992 .
6 . Bornikova L , Peyvandi F , Allen G , et al . Fibrinogen replacement therapy for congenital fibrinogen deficiency . J Thromb Haemost . 2011 ; 9 ( 9 ): 1687-1704 .
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