Afibrinogenemia A Rare , Often Overlooked Bleeding Disorder
● 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 facilitates the binding of platelets to form an initial clot at the site of injury . 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 Cohen Children ’ s Medical Center in 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 can be inherited in either a dominant or recessive 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 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 for a living , 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 .
Diagnosing Afibrinogenemia
Typically , patients with dysfibrinogenemia or afibrinogenemia are identified during a clinical investigation for bleeding . “ Afibrinogenemia predominantly presents with a mucocutaneous type of bleeding and ... can also present with thrombotic event ,” said Dr . Acharya .
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 or , in women , during childbirth or miscarriage . 5
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
16 ASH Clinical News August 2021