Age at Presentation
Approximately 200 patients with FV deficiency have now been described in the literature. Although most are case reports or small patient series, data are also available from registries from Iran, Italy, and North America.24,27,28 Data from the registries indicate that, unlike patients with hemophilia A and B, FV-deficient patients are more likely to have skin and mucocutaneous bleeding than hemarthroses.
Most patients with more severe FV deficiency (activity <20%) are thought to present at an early age. Most patients in the Iranian registry had bleeding symptoms before the age of 6 years. Perinatal presentation, though, was not common in that cohort; there was only one patient with umbilical stump bleeding and none with cephalohematoma.27 Although intracranial hemorrhage is relatively less common in the patient registry cohorts, at least seven reports are available in the English literature of such episodes during the perinatal period.23,30-35 It has been suggested that FV splicing mutations in particular confer a higher risk for severe phenotype, especially intracranial hemorrhage.36 Interestingly, at the other extreme, there is also one case report of a patient with <5% activity who presented at 62 years with an intracranial hemorrhage.37
The North American registry did not detail the timing of presentation, but three-quarters of the more severely affected group presented with bleeding episodes, and one-fifth were diagnosed because of family history. In contrast, most of the patients with mild disease (activity level >20%) in that registry came to attention because of either family history (44%) or preoperative screening (39%), and only 17% presented with hemorrhage.24
Variability in Presenting Symptoms
In the more severely affected subgroup (activity level <20%) of the North American registry, 44% of the bleeding episodes were in skin and mucosa, 23% in joint and muscle, 19% in the genitourinary tract, 6% in the gastrointestinal tract, and 8% in the CNS. Bleeding episodes in the mild group consisted of 62% skin and mucous membrane bleeding and 19% each with musculoskeletal and genitourinary bleeding events.24 In the Iranian cohort, 57% of patients had epistaxis and oral mucosa bleeding, 50% of the women had menorrhagia, 43% had post-procedural or postpartum bleeding, 29% had muscle hematomas, and 26% had hemarthroses. Gastrointestinal, genitourinary, and CNS bleeding episodes were each present in 6% of the patients.27
Development of Inhibitors
Acquired deficiency
Aside from mutations in the FV gene, deficiencies of FV can also arise because of acquired specific inhibitors to FV and defects that affect the storage and processing of FV. FV-specific inhibitors most often develop after exposure to preparations of bovine thrombin but have also been reported in patients who have underlying rheumatologic conditions or malignancies or who were being treated with antibiotics (for a review of acquired FV inhibitors, see Franchini M, J Thromb Thrombolysis 201122).
Congenital deficiency
Rarely, FV-deficient patients have developed inhibitors to FV after receiving normal exogenous FV, such as with FFP.6,23,24
Range of clinical symptoms by factor level
The North American Rare Bleeding Disorders Registry classified patients with FV levels less than 0.2 U mL–1 (<20% activity) as severe and those with levels greater than or equal to 0.2 U mL–1 (≥20% activity) as mild. The 18 patients with <20% activity level had a FV activity range of <1% to 5%. All 18 experienced spontaneous bleeding events, even those who first came to attention through preoperative screening or family history. Furthermore, only patients in the more severely affected group had complications (anemia, target joint development or muscular contractures, or central nervous system [CNS] events) from the bleeding episodes. In contrast, only half of the 19 mild patients (median FV activity of 35%; range, 21–55 U mL–1) bled excessively. Unfortunately, the report did not further subdivide the mild patients to correlate their bleeding episodes with FV activity.24
The Iranian registry divided its 35 FV-deficient patients into three groups: severe (FV ≤1%, n = 16), moderate (FV 2-5%, n = 13), and mild (FV 6-10%, n = 6). They found the prevalence of epistaxis (10/16 vs. 5/13 vs. 5/6), hemarthrosis (5/16 vs. 2/13 vs. 2/ 6), postprocedural bleeding (7/16 vs. 4/13 vs. 4/6), and oral mucosal bleeding (9/16 vs. 7/13 vs. 4/6) to be similar in all three groups. Of note, the two cases of CNS hemorrhage and the one case of umbilical stump bleeding occurred in severely affected individuals. Although the small number of patients precludes firm conclusions, these data suggest that all three groups are similarly likely to bleed at common sites such as mucosal surfaces but that only the more severely affected patients are at risk for bleeding in less commonly affected areas such as the CNS.27
Special Issues in Women
In the Iranian cohort, 50% of the women had menorrhagia, and 43% had postpartum bleeding. Menorrhagia was common in both the severe and moderate groups (3/4 vs. 2/6) but could not be evaluated in the mild group because there were no women of child-bearing age in that group.27 FV deficiency has been found as the underlying etiology in some cases of recurrent miscarriage.38
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.
