Clinical manifestations of CFD span a wide continuum and include the potential for either mucocutaneous and/or deep tissue bleeding (commonly seen with afibrinogenemia and hypofibrinogenemia) or thrombotic tendencies (seen with afibrinogenemia and dysfibrinogenemia). Clinical manifestations vary from mild to catastrophic life-threatening bleeding (including intracranial hemorrhage) or thromboembolic events (including arterial ischemic stroke). Siblings with the same mutations may exhibit dissimilar phenotypic severity, particularly among individuals with afibrinogenemia.
Afibrinogenemia is often diagnosed in the newborn period following umbilical cord bleeding. Hypofibrinogenemia is associated with fewer clinical bleeding episodes and may not be diagnosed until a time of traumatic or surgical challenge. Dysfibrinogenemias are commonly diagnosed in adulthood. Although mutations have been identified in the fibrinogen gene, genotype-phenotype correlations are not easily established; this difficulty could be related to (as yet) unidentified modifier genes.24
Afibrinogenemia/Hypofibrinogenemia
General Bleeding
Afibrinogenemia is associated with a wide spectrum of bleeding symptoms ranging from recurrent intracranial and other life-threatening hemorrhage to infrequent bleeding following injury or trauma. The bleeding phenotype can vary among family members with the same genotype.
Bleeding can present in the antenatal or neonatal period, with 85% of cases presenting with umbilical cord bleeding,12 or skin, gastrointestinal, genitourinary or CNS bleeding.17,25 Musculoskeletal bleeding has been reported in 54% of patients and occurs less frequently than in severe hemophilia A and B, where greater than 90% of patients experience hemarthroses.12,17
Afribrinogenemia has been associated with unusual manifestations such as spontaneous rupture of the spleen, development of painful bone cysts,25 and intrahepatic inclusions.26 Some phenotypically mild cases may be due to diagnostic assay insensitivity, as some functional fibrinogen assays are insensitive below 50 mg/dL and a very small amount of fibrinogen is likely required to prevent severe bleeding.
Obstetric and Gynecologic Bleeding
Menometrorrhagia as well as normal menses have been reported.27 Early first trimester abortions are near universal in women with afibrinogenemia and dysfibrinogenemia unless regular fibrinogen replacement is commenced before or shortly after conception.23 Antepartum hemorrhage (usually placental abruption) is quite common in both afibrinogenemia and dysfibrinogenemia. Postpartum hemorrhage, as well as hemoperitoneum after corpus luteum rupture, has also been reported.23,27
Patients with hypofibrinogenemia have similar bleeding patterns but exhibit a milder course and may experience bleeding only after invasive procedures or major trauma. These affected individuals rarely experience spontaneous bleeding. Adverse pregnancy outcomes, which are highly associated with afibrinogenemia and dysfibrinogenemia, are notably reduced in hypofibrinogenemia.23 A case of familial hypofibrinogenemia with hepatic storage disease associated with a fibrinogen g-chain mutation has been described.28
Thromboembolic Events
Paradoxical arterial and venous thromboembolic events occurring either spontaneously or after replacement therapy are recognized with increased frequency in afibrinogenemia.23,29-31 The thrombotic phenotype usually presents following puberty, and can be controlled using regular, preventive replacement infusions of fibrinogen. Oral thrombin inhibitors may also be effective.
Coexistent thrombophilic traits were identified in some (but not all) patients with afibrinogenemia and thrombosis.30 A review of 50 CFD cases that are described in the scientific literature reported thrombosis (both related and unrelated to fibrinogen replacement) in 30% of patients overall, and in 67% of adult non-obstetric patients.23 Surgery was very frequently associated with thrombosis.23
Persons with afibrinogenemia have been reported to exhibit an increased rate of arterial events, which would be expected with enhanced platelet activation, but venous thrombi are also common.5,23 The number of embolized thrombi was 6-fold higher in fibrinogen knockout mice than in wild-type mice and led to vessel occlusion, findings that are consistent with the anti-thrombotic properties of fibrinogen.32 However, in addition to vascular occlusion by thromboemboli, vascular intramural hematomas obstructing blood flow have been detected in afibrinogenemia, and embolization of a poorly-formed, loose clot may result from a vaso-occlusive complication of defective clot formation. These paradoxical bleeding, clotting and mixed events have hampered efforts to characterize phenotypes in congenital afibrinogenemia.
Hypercoagulability in afibrinogenemia cannot be easily predicted, as afibrinogenemic patients have normal concentrations of other procoagulant proteins and consequently show normal velocity and quantity of thrombin generation. A relative excess of thrombin may be determined as an increase in circulating thrombin-antithrombin complexes (TAT), which may contribute to thromboembolic events; however elevated circulating TAT is not a consistent finding in patients with afibrinogenemia and thrombosis.31
Dysfibrinogenemia
Patients with dysfibrinogenemia exhibit an unpredictable clinical phenotype. In a compilation of 250 patients, 53% were asymptomatic, 26% experienced bleeding symptoms, and 21% had thrombotic manifestations, some of whom also had bleeding.21
Skin necrosis and arterial and venous thromboses have been described. Postpartum thrombosis, spontaneous abortions, and stillbirths are described in the ISTH database (http://site.geht.org/base-de-donnees-fibrinogene/). In the reported literature, obstetrical complications are as prevalent in dysfibrinogenemia as in afibrinogenemia, although this similar prevalence may represent reporting bias.22,23 Pregnant women with dysfibrinogenemia are at particular risk for bleeding after vaginal or cesarean delivery and regional analgesia.
Wound Healing
Impaired wound healing and wound dehiscence after surgery have been reported to occur in persons with afibrinogenemia or dysfibrinogenemia who do not receive replacement therapy, due to the formation of a non-tensile clot with inadequate deposition of restorative proteins.
Rare Coagulation Disorders Resource Room, an extension of the RBDD Registry (eu.rbdd.org), was developed in collaboration with the Indiana Hemophilia & Thrombosis Center (www.innovativehematology.org).
The Resource Room serves as a platform to promote international collaboration to increase knowledge of these very rare disorders and to improve the care of affected individuals. The international RBDD mission, under the leadership of Dr. Peyvandi, will continue to be expanded over time.
The Resource Room thanks all contributing authors of the website articles that have made this valuable information available to the global community of both individuals affected with rare coagulation disorders and their healthcare providers.
