Combined deficiency of factor V and factor VIII in a pediatric patient: a case report

Abstract

Background

Combined deficiency of factors V and VIII is a rare autosomal recessive disorder associated with an increased risk of bleeding. We present an unusual case of a 7-year-old Moroccan child with no history of consanguinity who was hospitalized owing to a hemorrhagic episode during circumcision.

Case presentation

The 7-year-old patient, a Moroccan boy from North Africa, coming from a family of five siblings, was referred for an evaluation of prolonged activated partial thromboplastin time and prothrombin time. Coagulation factor assays revealed a combined deficiency of factors V and VIII, with normal levels of other coagulation factors. This anomaly was detected in the hematology laboratory, where hemostasis tests were performed via optical methods on the Acl Top 750 analyzer. A complete blood count was conducted on the Beckman Coulter DXH 900 analyzer. Hemostasis assessments revealed an elevated activated partial thromboplastin time at 73.2 s (normal range < 36), with a patient-to-control activated partial thromboplastin time ratio of 2.58 (normal ratio < 1.2), a low prothrombin time at 18.35 s (normal prothrombin time range: 11.4–13.5), and an international normalized ratio of 1.59 (normal range: 2–3.5). Specific coagulation factor assays demonstrated a combined deficiency of factors V and VIII at 12.4% (normal range: 55–150) and 9.1% (normal range: 50–145), respectively, whereas other coagulation factor levels remained within the normal range, including the antigenic activity of von Willebrand at 71.7% (normal range: 50–150). The complete blood count showed no abnormalities, except for a small thrombocytosis. The child was managed in the pediatric hematology department, and a family investigation among the remaining siblings was initiated to search for similar cases.

Conclusion

Our study highlights a rare and often underdiagnosed genetic disorder that is often confused with a diagnosis of minor hemophilia A or congenital factor V deficiency. Differential diagnosis is crucial, particularly for von Willebrand disease. Combined deficiency of factors V and VIII should be suspected in patients with a suggestive clinical and laboratory profile, including prolonged prothrombin time and activated partial thromboplastin time along with a deficiency in coagulation factor V. Therefore, measuring factor VIII levels is highly recommended.

Background

Combined deficiency of coagulation factors V and VIII (F5 F8D) represents a rare genetic coagulopathy. This autosomal recessive condition is characterized by a simultaneous reduction in plasma levels of both factor V and factor VIII. While F5 F8D is an infrequent finding in the general population, its occurrence is notably higher in regions where consanguineous marriages are prevalent, particularly in areas surrounding the Mediterranean and Asia [1]. The historical roots of F5 F8D trace back to 1954, when it was first documented by Oeri et al., in a brother and sister in Switzerland [2]. Clinically, individuals with F5 F8D commonly manifest easy bruising, epistaxis, and various bleeding after traumatic events.

In this report, we present a case of a 7-year-old child from Morocco, North Africa, who was admitted to the hospital following a hemorrhagic episode during a circumcision procedure. This case underscores the diagnostic challenges and clinical management considerations associated with F5 F8D, emphasizing the need for increased awareness and understanding of this rare coagulopathy.

Case presentation

We report the case of a 7-year-old boy, from Morocco, North Africa, who was referred for evaluation owing to abnormal coagulation parameters and a history of prolonged hemorrhagic events during a circumcision procedure. In addition, he had a history of unexplained bruising characterized by various colors and sizes, ranging from small petechiae to larger ecchymoses, predominantly located on the arms and legs. Since childhood, the patient has exhibited gingivorrhagia and had an episode of bleeding after a dental procedure that necessitated a blood transfusion.

The patient comes from a family of five siblings, with no reported history of consanguinity between the parents, Remarkably, no similar cases of bleeding disorders were reported within the family.

The initial assessment took place in the hematology laboratory, where hemostasis tests were conducted. These tests employed optical methods on the Acl Top 750 analyzer, and a complete blood count was performed using the Beckman Coulter DXH 900 analyzer.

Hemostasis assessments revealed an elevated activated partial thromboplastin time (aPTT) at 73.2 s (normal range < 36), with a patient-to-control aPTT ratio of 2.58 (normal ratio < 1.2). They revealed a low prothrombin time (PT) at 18.35 s (normal PT range: 11.4–13.5) and an international normalized ratio (INR) of 1.59 (normal INR range: 2–3.5) (Tables 1).

Table 1 Laboratory investigation

Specific coagulation factor assays (Table 2) unveiled a combined deficiency of factors V and VIII, with levels measuring at 12.4% (normal range: 55–150) and 9.1% (normal range: 50–145), respectively, which were confirmed in a second sample. All other coagulation factor levels remained within the normal range, including the antigenic activity of von Willebrand (vWF, Ag) at 71.7% (normal range:50–150). The complete blood count did not reveal any abnormalities, except for thrombocytosis with a platelet count at 464 × 10⁹/L (normal range: 150–450). However, the other CBC parameters were within normal limits. The white blood cell count (WBC) was 7.4 × 10⁹/L (normal range 4–11) with a normal differential. The count was as follows: neutrophils: 4.0 × 10⁹/L (normal range: 1.5–8.5); lymphocytes: 3.2 × 10⁹/L (normal range: 1.5–7.0); monocytes: 0.48 × 10⁹/L (normal range: 0.2–1.5); eosinophils: 0.0 × 10⁹/L (normal range: 0.0–0.5); and basophils: 0.0 × 10⁹/L (normal range: 0.0–0.2). No peripheral blood smear nor blood typing was performed.

Table 2 Factor assays

Following the diagnostic evaluations, the child was placed under the care of the pediatric hematology department. Furthermore, a comprehensive family investigation among the remaining siblings was initiated to explore the possibility of similar cases within the family.

Discussion

Our study sheds light on a rare and often underdiagnosed genetic disorder, frequently mistaken for mild hemophilia A or congenital factor V deficiency. This disorder represents the most common form of constitutional anomaly, involving more than one coagulation factor, linked to a unique genetic anomaly [3].

It results from mutations in two specific genes, lectin mannose binding protein 1 (LMAN1, located on chromosome 18; 18q21) or multiple coagulation factor deficiency 2 (MCFD2, located on chromosome 2; 2p21). Both of these genes encode the endoplasmic reticulum–Golgi intermediate compartment protein 53/multiple coagulation factor deficiency 2 (ERGIC-53/MCFD2) protein complex, which functions as a transport receptor, facilitating the movement of coagulation factors V and VIII from the endoplasmic reticulum to the Golgi apparatus. LMAN1 mutations account for approximately 70% of cases and exclusively consist of null mutations. MCFD2 mutations occur in approximately 30% of instances and encompass both null and missense variants [4].

In terms of differential diagnoses, factor V deficiency (parahemophilia) associated with von Willebrand disease type 1 can also present a decrease in both factor V and factor VIII levels owing to the indirect effect of von Willebrand factor on the stability of factor VIII. While the coincidental occurrence of parahemophilia and hemophilia A is a possibility, it is extremely unlikely owing to the low prevalence in the general population (1 in 1,000,000 for parahemophilia and 1 in 5,000 among males for hemophilia A) [4] Additionally, the prothrombin time (PT) is normal in patients with von Willebrand disease. The antigenic activity of von Willebrand factor (vWF, Ag) and the complete blood count (CBC) results were also normal, which ruled out a primary hemostatic disorder such as von Willebrand disease.

Molecular diagnosis plays a pivotal role in identifying specific mutations within the LMAN1 and MCFD2 genes [5] Unfortunately, owing to the lack of adequate molecular diagnosis, these mutations were not tested in our patient.

The diagnosis of this disease involves a screening correlogram and factor assay. In F5 F8D, levels of factor (F)V and FVIII typically range from 1% to 46%, with most patients falling between 5% and 30% [6] In our patient, the levels of factor V and VIII were determined to be 12.4% and 9.1%, respectively.

The simultaneous reduction in plasma levels of factor V and factor VIII results in mild-to-moderate manifestations. Bleeding symptoms vary but often resemble those of isolated factor V or VIII deficiency. Common symptoms include epistaxis, menorrhagia, easy bruising, and bleeding following trauma or surgery [6, 7]. Our patient had previously experienced prolonged bleeding following a tooth extraction.

Regarding therapeutic approaches, the management of bleeding episodes or surgical prophylaxis in F5 F8D patients depends on the severity of bleeding due to mild-to-moderate hemorrhagic symptoms. In accordance with the guidelines of the UK Hemophilia Center Doctors’ Organization for rare coagulation disorders [8], recommended treatment includes fresh frozen plasma (FFP) and providing factor V and FVIII concentrate, which compensates for the shorter half-life of plasma FVIII. In certain circumstances, desmopressin (DDAVP) can still be utilized to treat minor bleeds.

In this case, the patient was treated with fresh frozen plasma (FFP) during the acute hemorrhagic episode, with satisfactory clinical response. His bleeding stopped within hours of the transfusion. Given the relatively mild deficiency, no prophylactic treatment was initiated, and he was discharged with instructions for future FFP administration in case of surgical interventions.

Regular prophylaxis is typically unnecessary for individuals with F5 F8D, and patients are usually treated only when a bleeding episode necessitates intervention. Consideration should be given to establishing a scoring system based on PT, aPTT, FVIII, FV levels, and suggestive clinical signs to promote screening for this deficiency.

Patient follow-up

At present, the patient is being followed up by the pediatric hematology team with regular clinic visits every 6 months to monitor his coagulation status. He has not experienced any significant bleeding episodes since his initial hospitalization. The family has been educated on the nature of the disorder, and they are instructed to report any signs of bleeding immediately. Further genetic counseling has been offered to the family,

Conclusion

It is important to note that F5 F8D can be widely underdiagnosed, in part owing to the often mild nature of hemorrhagic symptoms. In addition, it may be incorrectly identified as a single coagulation factor deficiency, particularly in countries with limited resources. Thus, this disorder should be suspected in patients with a suggestive clinical and laboratory profile, including prolonged PT and aPTT along with a deficiency in coagulation factor V. Therefore, measuring factor VIII levels is highly recommended.