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Thrombotic events in patients with afibrinogenaemia
In which clinical conditions may patients with afibrinogenaemia develop a thromboembolic event?
In the presence of a concomitant acquired or inherited thrombophilia disorder.
Under treatment with fresh frozen plasma or cryoprecipitates.
Afibrinogenaemia as such is a clinical condition that poses a thrombotic risk.
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Afibrinogenaemia is the complete absence of fibrinogen and characterised by bleeding that typically occurs in the neonatal period with umbilical cord haemorrhages. Other haemorrhages may occur in the skin, soft tissues, muscles, joints, gastrointestinal tract, or genitourinary tract. Intracranial haemorrhages occur less frequently but can be recurrent and are often fatal. [1, 2] The tendency to bleed varies widely, ranging from very few to several episodes a year. In individuals with afibrinogenaemia, clot-based coagulation tests are indeterminately prolonged and fibrinogen activity and antigen are undetectable. [3, 4]
|Laboratory parameter||Result of afibrinogenaemic patients|
|Prothrombin time (PT)||No coagulation|
|Activated partial thromboplastin time (APTT)||No coagulation|
|Thrombin time||No coagulation|
Table 1 Laboratory parameters in patients with afibrinogenaemia
Patients with afibrinogenaemia have a significantly increased risk of thromboembolic events in addition to an increased risk of bleeding. These events occur already at a young age and are often recurrent arterial or venous thromboses. In quite a few cases, the clot migrates into the pulmonary vessels, leading to the obstruction or stenosis of a pulmonary or bronchial artery. Less often seen thrombotic events include mixed forms of arterial and venous thrombosis. [4, 5, 6]
The increased thrombotic risk in fibrinogen-abstinent individuals can be explained primarily by the antithrombotic effect of fibrin, in addition to the presence of common risk factors for thrombosis, such as smoking, high blood pressure, obesity and the use of oral contraceptives [7, 8, 9]. Fibrin reduces the activation of prothrombin and also binds thrombin circulating in the blood. [10, 11] In the absence of fibrin, free thrombin remains available for platelet activation and, among other things, various growth factors are released which induce proliferation of vascular smooth muscle cells. [12, 13] Soluble fibrinogen is also able to inhibit platelet adhesion. In patients with afibrinogenaemia, the antithrombotic function of both fibrin (also called antithrombin I) and fibrinogen is absent. Furthermore, thrombus formation is maintained by other adhesive proteins, such as fibronectin or von Willebrand factor. The resulting thrombi are usually loosely packed, therefore unstable and prone to mobilisation. 
Another risk of thromboembolic events in individuals with afibrinogenaemia is the concomitant presence of acquired or inherited thrombophilia disorders. Individuals with congenital antithrombin III deficiency have a significantly increased risk of spontaneous severe arterial occlusion, such as acute coronary syndrome and stroke, venous thrombosis, and pulmonary embolism.  Similar cases have also been reported in association with concomitant protein C deficiency. [15, 16] Acquired risk factors include underlying infections or malignancy.
Fibrinogen substitution poses an additional risk to patients with afibrinogenaemia. Fresh frozen plasma (FFP) and cryoprecipitates contain fibrinogen and large amounts of other proteins such as fibronectin, VWF and factor VIII, providing a procoagulant environment. FFP also bears other transfusion-related risks such as transfusion-related acute lung injury or the undesirable infusion of microorganisms.
Fibrinogen concentrate (FC) substitution is the replacement therapy of choice in patients with afibrinogenaemia, as this has fewer risks of adverse side effects while having a higher treatment efficacy.  It has also been demonstrated that administration of FC can effectively reduce platelet adhesion and platelet aggregation even at low fibrinogen concentrations. [13, 18] Women with afibrinogenaemia have a higher probability of a successful pregnancy if they are treated early on with FC or cryoprecipitates and the amount substituted is adjusted to the fibrinogen requirement during pregnancy.
The management of patients with afibrinogenaemia can be challenging because in addition to the prevention and treatment of bleeding, the prevention and, in the worst case, treatment of thrombosis must be delivered in parallel. The treatment of thrombotic events includes the administration of anticoagulants, aggregation inhibitors and fibrinolytics. [19, 20] The treatment of bleeding episodes should ideally be performed with FC, individually adapted to age, weight and current circumstances (e.g. pregnancy), and include therapy monitoring by means of a fibrinogen activity test. [21, 22]
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