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Factor VII Deficiency

Hypoproconvertinemia

Factor VII (FVII) deficiency is a rare bleeding disorder that results from a genetic mutation that affects this clotting factor (hereditary). It may also develop secondary to medication use or liver disease (acquired). There is a wide spectrum of manifestations that range from mild bleeding to life-threatening hemorrhage.

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Presentation

The clinical presentation of the disease is variable [3] [11]. Patients with a mild-to-moderate disease may exhibit chronic epistaxis, gingival bleeding. Women are likely to experience menorrhagia and consequently develop iron deficiency anemia. The featured mucosal bleeding is reminiscent of platelet function disorders. Severe forms of FVII deficiency are characterized by life-threatening manifestations such as intracranial hemorrhage. Moreover, CNS hemorrhage can occur in up to 60% of cases [3] [11], especially in newborns after birth.

Hemarthrosis can also develop in patients with FVII deficiency [3] [11] although it is uncommon. This is a consistent finding in hemophilia and can lead to destruction and degeneration of joints in both diseases [12]. Other signs of bleeding include hematuria, melena, or hematochezia.

Physical exam

Bruising may be apparent on examination. Also, a limited range of joint motion is notable in patients with joint bleeding.

Very importantly, the clinician should be vigilant about signs of deep vein thrombosis (DVT) and neural deficits.

Atrial Septal Defect
  • We present a case of an atrial septal defect repair under cardiopulmonary bypass in a child with factor VII deficiency. A four-year-old girl, with the diagnosis of secundum atrial septal defect, was referred to surgery.[ncbi.nlm.nih.gov]
Poor Feeding
  • We report two cases of newborn infants (15 and 20 days old, respectively; both were full-term infants with normal vaginal deliveries) with severe factor VII (FVII) deficiencies (FVII 1%) who presented with convulsions and poor feeding.[ncbi.nlm.nih.gov]
Easy Bruising
  • The symptoms listed in order of frequency were as follows: epistaxis, petechia or ecchymose, easy bruising, and oral cavity bleeding. The genotype was determined in 8 patients.[ncbi.nlm.nih.gov]
  • Uncontrolled bleeding during menstruation, during and after surgery as well as easy bruising also occur. Treatments rely on replacement therapy using recombinant or plasma derived factor VII or prothrombin complex concentrates.[novonordisk.com]
  • Common symptoms Nosebleeds (epistaxis) Easy bruising Heavy or prolonged menstrual bleeding (menorrhagia) Bleeding in the mouth, particularly after dental surgery or tooth extraction Bleeding in the head (newborns) Heavy bleeding at circumcision Other[haemophilia.ie]
  • See Bleeding Symptoms of Rare Clotting Factor Deficiencies Common symptoms nosebleeds (epistaxis) easy bruising heavy or prolonged menstrual bleeding (menorrhagia) bleeding in the mouth, particularly after dental surgery or tooth extraction bleeding in[wfh.org]
Hemoptysis
  • Objective: To describe our findings in a 20-year-old man, who presented with hemoptysis, weight loss, and later developed a suprascapular mass.[degruyter.com]
  • Bleeding isolated to a single organ or system (eg, hematuria, hematemesis, hemoptysis) is less likely to be due to a hemostatic abnormality than to a local cause such as neoplasm or ulcer.[emedicine.medscape.com]
Hematochezia
  • Other signs of bleeding include hematuria, melena, or hematochezia. Physical exam Bruising may be apparent on examination. Also, a limited range of joint motion is notable in patients with joint bleeding.[symptoma.com]
  • Bleeding in the stomach, intestines and urogenital tract can also occur resulting in blood in the urine (hematuria) or black, tarry, bloody stools (melena or hematochezia).[rarediseases.org]
Melena
  • Other signs of bleeding include hematuria, melena, or hematochezia. Physical exam Bruising may be apparent on examination. Also, a limited range of joint motion is notable in patients with joint bleeding.[symptoma.com]
  • Bleeding in the stomach, intestines and urogenital tract can also occur resulting in blood in the urine (hematuria) or black, tarry, bloody stools (melena or hematochezia).[rarediseases.org]
Hematemesis
  • Bleeding isolated to a single organ or system (eg, hematuria, hematemesis, hemoptysis) is less likely to be due to a hemostatic abnormality than to a local cause such as neoplasm or ulcer.[emedicine.medscape.com]
Abdominal Pain
  • An 8y7m-old Chinese boy presented with half a day of right sided abdominal pain, fever, nausea, and vomiting.[ncbi.nlm.nih.gov]
Bleeding Gums
  • Mild symptoms might include: bruising and soft tissue bleeding longer bleeding time from wounds or dental extractions bleeding in joints nosebleeds bleeding gums heavy menstrual periods In more severe cases, symptoms can include: destruction of cartilage[healthline.com]
Oral Bleeding
  • The most frequent disease-presenting symptoms in hemophilia B (hematomas and oral bleeding) differed from those in FVII deficiency (epistaxis and central nervous system bleeding). Differences were confirmed by analysis of FVII-deficient women.[ncbi.nlm.nih.gov]
  • ., Klukowska, A. (2005) Management of oral bleedings with recombinant factor VIIa in children with haemophilia A and inhibitor.[scindeks.ceon.rs]
Petechiae
  • The symptoms listed in order of frequency were as follows: epistaxis, petechia or ecchymose, easy bruising, and oral cavity bleeding. The genotype was determined in 8 patients.[ncbi.nlm.nih.gov]
Joint Swelling
  • Hemarthrosis may lead to findings of joint swelling, motion limitation, and mild fever. If significant fever develops, infection should be considered. Repeated hemarthrosis leads to joint deformity complicated by muscle atrophy and contractures.[emedicine.medscape.com]
Epistaxis
  • FVIID was diagnosed for the first time in a 23-year-old pregnant woman at the 24th week of gestation due to complaint of intermittent epistaxis.[ncbi.nlm.nih.gov]
Hematuria
  • Herein, we reported a patient who had unexplained hematuria and vertigo with consanguineous parents. He has been diagnosed as having FVII deficiency based on the results of reduced FVII activity (2.0%) and antigen (12.8%).[ncbi.nlm.nih.gov]
  • […] in the gut (gastrointestinal bleeding) bleeding into joints (hemarthrosis) muscle bleeds bleeding in the central nervous system (the brain and spinal cord) abnormal bleeding during or after injury, surgery, or childbirth Rare symptoms blood in urine (hematuria[wfh.org]
  • Bleeding into joint spaces (hemarthrosis) and blood in the urine (hematuria) occasionally occur. Many women with factor VII deficiency have heavy or prolonged menstrual bleeding (menorrhagia).[ghr.nlm.nih.gov]
  • Hematuria may occur. While in congenital disease symptoms may be present at birth or show up later, in patients with acquired FVII deficiency symptoms typically show up in later life.[en.wikipedia.org]
Intracranial Hemorrhage
  • He had anemia from an intracranial hemorrhage, and his coagulation factor assay revealed that his bleeding episode was due to severe congenital factor VII deficiency (5% of normal activity).[ncbi.nlm.nih.gov]
  • Prevalence and evolution of intracranial hemorrhage in asymptomatic term infants. Am J Neuroradiol. 2006; 29:1082-89.[ijn.mums.ac.ir]
Headache
  • Cherian Published: 01 February 2010 Editor—A 27-yr-old primigravida at 36 weeks of gestation presented to us with a history of bleeding and headache. She was known to have congenital factor VII deficiency (Alexander's disease).[academic.oup.com]
  • The patient recovered within the first few days (Glasgow coma scale 15), but then developed an elevated intracerebral pressure of 45 mm Hg accompanied by strong headache and right-sided hemiparesis.[ajnr.org]
  • They may present with life-threatening intracerebral hemorrhage manifesting as headaches, seizures, or focal deficits or with recurrent hemarthrosis leading to severe arthropathy.[emedicine.medscape.com]
  • Contact your health care professional or treatment center team if you notice any of these symptoms: Symptoms of bleeding in the brain Drowsiness or loss of consciousness Headache or muscle or neck ache Nausea and vomiting Sensitivity to light/scents/sounds[rarebleedingdisorders.com]
Seizure
  • A 9 year-old boy presented to our clinic with Factor VII deficiency, microcephaly, a seizure disorder, multiple midline abnormalities (agenesis of the corpus callosum, imperforate anus, bilateral optic nerve hypoplasia), developmental delay, hypopigmented[ncbi.nlm.nih.gov]
  • Those bleeds can cause devastating effects, including seizures and brain damage.[hemaware.org]
  • They may present with life-threatening intracerebral hemorrhage manifesting as headaches, seizures, or focal deficits or with recurrent hemarthrosis leading to severe arthropathy.[emedicine.medscape.com]
Vertigo
  • Herein, we reported a patient who had unexplained hematuria and vertigo with consanguineous parents. He has been diagnosed as having FVII deficiency based on the results of reduced FVII activity (2.0%) and antigen (12.8%).[ncbi.nlm.nih.gov]

Workup

Patients with abnormal bleeding should be evaluated with a thorough personal and family history as well as a review of any medication intake. The assessment also includes a complete physical exam and the appropriate studies.

Laboratory tests

The diagnostic tools include a complete blood count (CBC) and a coagulation panel. The typical findings include a prolonged PT with a normal aPTT. A further study is conducted using a mixture of normal plasma and the patient's plasma to repeat testing for PT. This is to rule out the presence of an FVII inhibitor.

An assay for FVII determines the activity of this clotting factor and confirms the disease. Additionally, a radioimmunoassay test may be used to measure FVII antigen. Finally, affected families can undergo genetic testing for identification of the specific mutant genes.

Hypertriglyceridemia
  • Plasma factor VII levels also increase with age and are higher in females and in persons with hypertriglyceridemia.[emedicine.medscape.com]

Treatment

The treatment of patients with FVII deficiency depends on factors such as the clinical phenotype, age, comorbidities (if present), and patient's preference. The care is best delivered by a team of a pediatrician or general physician, hematologist, genetic counselor, and other specialists as needed.

Blood replacement should be considered based on the severity of the patient's disease. FFP is utilized in developing areas but has the disadvantage since it increases blood volume and carries a rare risk of transmission of infection. FFP may be beneficial in the context of secondary prophylaxis.

Various preparations can be used in patients with FVII deficiency. Recombinant FVIIa is the optimal choice as a synthetic supply of the deficient clotting factor [13]. Another option is the pdFVII concentrate, which is accompanied by prothrombin complex concentrates. Both recombinant FVIIa and pdFVII concentrates are effective for treatment of active bleeding and prophylaxis. Since these products exhibit a short half-life, they are prescribed for multiple times daily (if possible) and may be administered at home.

Prevention of bleeding episodes is paramount, especially in children. Additionally, prophylaxis should be highly considered for patients with severe FVII deficiency undergoing surgery. One main drawback of replacement therapy is its risk for complications such as thrombosis [14].

Special considerations

Since menorrhagia is prevalent in women with FVII deficiency, they may require treatment and replacement therapy during a partial duration of the menstrual cycle. Furthermore, women undergoing childbirth may need replacement management [15]. Finally, iron deficiency anemia in women should be treated accordingly.

Prognosis

The majority of patients with the severe forms of FVII deficiency are diagnosed early in life, especially in infancy. Approximately 60% to 70% of hemorrhagic cases emerge from bleeding in the CNS or gastrointestinal (GI) tract [8] [9].

Patients with serious bleeding are at risk for mortality. One of the leading causes of death is an intracerebral hemorrhage. Additionally, thrombosis is a complication of FVII deficiency [10]

Etiology

This coagulation disorder is the result of mutations in the F7 gene, which encodes FVII. More than 100 mutations, especially of the missense type, have been reported [2] [3]. Genetic defects influence the levels of this clotting factor. The deficiency can arise from reduced synthesis or dysfunction of FVII.

Acquired FVII deficiency, which is more common than the inherited form of the disease, is attributed to factors that cause vitamin K [4]. Examples include vitamin K deficiency, liver disease, or drugs that affect this vitamin such as oral anticoagulants, penicillin, and cephalosporins.

Epidemiology

The prevalence of FVII deficiency is 1 per population of 500,000. The patient demographics reveals no gender or age preference. While this disease does not have a predilection for racial or ethnic background, certain populations such as Moroccan and Iranian Jews possess mutations that predispose them to this disease. Specifically, the missense Ala244Val mutation is responsible for the deficiency. Additionally, there are polymorphisms that have been observed in specific groups. For example, the sequence involving the Arg353Gln substitution is more frequently present in Gujaratis and Dravidian Indians [5]. Additionally, geographical regions with higher prevalence of consanguinity have a greater occurrence of this disease.

Sex distribution
Age distribution

Pathophysiology

The pathogenesis of FVII deficiency arises from genetic mutations in the F7 gene located on chromosome 13. This bleeding disorder may also be acquired.

Inherited

Studies have investigated the underlying mechanisms responsible for specific phenotypes. It remains a challenge to establish a relationship between certain mutations and the effects [6]. One study identified 19 distinct mutations, of which 12 were previously undiscovered. The majority were missense defects of the serine protease domain and almost half were homozygous. Molecular analysis of FVIIa and the FVIIa–tissue factor complex suggested that the genetic mutations resulted in the dysfunction of the catalytic portion [6].

Acquired

This type of deficiency most frequently results from the effects of vitamin K antagonists and liver disease. Warfarin is an example of the former, as it is an inhibitor of vitamin K-dependent enzymes. Furthermore, liver pathologies such as Dubin-Johnson syndrome and Gilbert's syndrome exhibit reduced FVII concentration [7]. Additionally, acquired FVII can emerge from disorders such as myeloma, aplastic anemia and conditions such as sepsis.

Prevention

Patients are advised to exercise caution with physical activities by avoiding contact sports, selecting safer sports, and engaging in regimens that strengthen the muscles and joints.

Additionally, parents and children should learn about the disease, how to treat it, and when to seek emergency care. Affected individuals should wear a medical alert bracelet or carry documents in case of emergency or trauma.

Genetic counseling is offered to patients and family members in order to provide them with information about the disease, its mode of inheritance, expectations, and other important details.

Summary

Factor VII (FVII) deficiency is an autosomal recessive hemorrhagic disorder arising from a mutation in the F7 gene, which codes for clotting factor VII (FVII). This rare condition is the most prevalent coagulation disorder. FVII plays a key role in hemostasis and clot formation. Hence, an insufficiency or impairment of this clotting factor leads to abnormal bleeding in homozygotes and compound heterozygotes while heterozygotes are asymptomatic. This disease can also be acquired from the effects of medications or liver disease on vitamin K, which is essential for the production of FVII.

The clinical presentation of FVII deficiency is variable. Furthermore, the severity of this disease does not correlate with the levels of FVII [1]. Mild disease is characterized by mucosal hemorrhages such as epistaxis and menorrhagia or bleeding in response to surgical procedures. Severe disease is associated with mortality since it typically manifests in early infancy and causes intracerebral bleeding.

Patients with abnormal bleeding patterns should be assessed with a detailed account of the personal and family history, a physical exam, and laboratory tests. The latter includes coagulation studies and specific assays for confirmation of the diagnosis. The results that are consistent with this disease include a normal activated partial thromboplastin time (aPTT) and a prolonged prothrombin time (PT).

The management of these patients consists of treatment and prophylaxis. The medical team will take into account the patient's symptomology, age, coexisting diseases and other factors while carefully weighing the benefits and the drawbacks of each blood preparation. Blood replacement products such as fresh frozen plasma (FFP), recombinant FVIIa and plasma-derived FVII (pdFVII) can be used for patients with active bleeding and may be administered in the perioperative setting as well.

Since this disease has a high risk of mortality in a subset of patients, early diagnosis and treatment are essential. Parents and affected children should receive education about the disease, how to treat it, and understand the precautions.

Patient Information

What is Factor VII deficiency?

This is an inherited bleeding disease that results from decreased or impaired activity of clotting factor VII. The body makes numerous clotting factors which are very important for proper clot formation. Therefore, if clotting factor VII is not normal, then patients will have prolonged and abnormal bleeding.

What are the causes?

Factor VII deficiency is caused by mutations in the F7 gene, which produces clotting factor VII. This disease may also be acquired from certain medications such as warfarin or even certain liver diseases.

This disease is inherited in an autosomal recessive pattern. To be affected with this disease, the patient will inherit a bad copy from each parent. This means that each parent is a carrier of the disease.

What are the signs and symptoms?

The symptoms vary as some patients experience no symptoms, some may have mild symptoms, and others may have serious complications. The features may include:

How is it diagnosed?

When an individual presents with abnormal bleeding patterns, the clinician will obtain the patient and family history, perform a physical exam, and order the following tests:

  • Complete blood count (CBC)
  • Clotting tests such as activated partial thromboplastin time (aPTT) and prothrombin time (PT): these patients will a normal aPTT and a prolonged PT
  • Specialized tests known as assays are also performed to confirm the diagnosis

How is it treated?

Treatment and preventative therapy depend on the severity of the disease, the symptoms, the age of the patient, other health problems in the patient, and the patient's wishes. Treatment options include blood products such as:

  • Recombinant factor VIIa (rFVIIa): this a synthetic form of factor VII
  • Prothrombin complex concentrates (PCCs)
  • Fresh frozen plasma (FFP)

Generally, these medications can increase the risk of developing blood clots. Therefore, doctors and patients should discuss the pros and cons of these medications.

Patients undergoing surgery may need prophylactic (preventative) medicine. Women with heavy periods due to this disease may also require special treatment.

Can it be prevented?

The disease is inherited and cannot be prevented. However, genetic counseling is offered to affected individuals and their family members to provide them with education about the disease, how it is inherited, how it is treated, and other specific details.

Patients are advised to:

  • Avoid contact sports
  • Choose safer sports
  • Participate in activities that strengthen muscles and joints

Also, parents and children should learn about the disease, how to treat it, and know when to seek emergency care. Patients should wear a medical alert bracelet or carry medical documents in case of emergency or trauma.

What is the prognosis?

Severe bleeding is associated with a high risk for death. Therefore, early diagnosis and treatment are important, especially in affected infants.

References

Article

  1. Triplett DA, Brandt JT, Batard MA, Dixon JL, Fair DS. Hereditary factor VII deficiency: heterogeneity defined by combined functional and immunochemical analysis. Blood. 1985; 66(6):1284-7.
  2. Cooper DN, Millar DS, Wacey A, et al. Inherited factor VII deficiency: molecular genetics and pathophysiology. Thrombosis and Haemostasis. 1997;78(1):151–160.
  3. Mariani G, LoCoco L, Bernadi F, et al. Molecular and clinical aspects of factor VII deficiency. Blood Coagulation and Fibrinolysis. 1998;9(Suppl 1):S83–S88.
  4. Biron C, Bengler C, Gris JC, Schved JF. Acquired isolated factor VII deficiency during sepsis. Haemostasis. 1997;27(2):51–56.
  5. Seligsohn U, White GC. Inherited deficiencies of coagulation factors II, V, VII, XI and XIII and the combined deficiencies of factors V and VII and of the vitamin K-dependent factors. Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. William's Hematology. 6th ed. New York, NY: McGraw-Hill; 2001: 1617-38.
  6. Peyvandi F, Jenkins PV,Mannucci PM, et al. Molecular characterisation and three-dimensional structural analysis of mutations in 21 unrelated families with inherited factor VII deficiency.Thrombosis and Haemostasis. 2000; 84(2):250–257.
  7. Roberts HR, Lefkowitz JB. Hemostasis and Thrombosis :Inherited disorders of prothrombin conversion. In: Colman RW, Hirsh J, Marder VJ, et al, eds. Lippincott Williams & Wilkins, Philadelphia, PA: 200–218.
  8. Mariani G, Dolce A, Marchetti G. Clinical picture and management of congenital factor VII deficiency.Hemophilia. 2004;10(Suppl 4):180–183.
  9. Ingerslev J, Kristensen L. Clinical picture and treatment strategies in factor VII deficiency. Hemophilia.1998;4(4):689–696.
  10. Escoffre M, Zini JM, Schliamser L, et al. Severe arterial thrombosis in a congenitally factor VII deficient patient. British Journal of Haematology. 1995; 91(3):739–741.
  11. Peyvandi F, Mannucci PM, Asti D, et al. Clinical manifestations in 28 Italian and Iranian patients with severe Factor VII deficiency. Haemophilia. 1997; 3(4):242–246.
  12. Mariani G, Mazzucconi MG. Factor VII congenital deficiency. Clinical picture and classification of the variants. Haemostasis. 1983;13(3):169–177.
  13. Mariani G, Konkle BA, Ingerslev J. Congenital factor VII deficiency: therapy with recombinant activated factor VII—a critical appraisal. Haemophilia. 2006; 12(1): 19-27.
  14. Marty S, Barro C, Chatelain B et al. The paradoxical association between inherited factor VII deficiency and venous thrombosis. Haemophilia. 2008; 14(3): 564-570
  15. Kulkarni AA, Lee CA, Kadir RA. Pregnancy in women with congenital factor VII deficiency. Haemophilia. 2006; 12(4): 413-416.

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Last updated: 2019-07-11 20:58