Factor Vii Deficiency: Symptoms, Types, Causes and Treatment

Factor VII (FVII) deficiency is a rare bleeding disorder that can present with a wide range of symptoms, from mild to life-threatening. Despite being one of the most common among rare inherited coagulation disorders, it is often under-recognized. This article will guide you through the symptoms, types, causes, and treatments of factor VII deficiency, drawing on current research and clinical experience.

Symptoms of Factor VII Deficiency

Factor VII deficiency can manifest in many ways, making diagnosis challenging. Some individuals may experience only minor symptoms, while others confront severe, even life-threatening, bleeds. The variability is striking—even among people with similar levels of FVII activity, the severity and types of symptoms can differ widely.

Symptom	Prevalence/Severity	Typical Context	Source(s)
Epistaxis	Most common	Spontaneous, recurrent	1 4
Menorrhagia	50–69% of women	Adolescence, adulthood	1 3 4
Haemarthrosis	10–50% in severe cases	Trauma or spontaneous	3 4 13
CNS Bleeding	10–17% in severe deficiency	Newborns, trauma	3 4
GI Bleeding	Rare but serious	Any age	3 13
Asymptomatic	≈30%	Variable	3 4

Table 1: Key Symptoms

Bleeding Patterns and Severity

Factor VII deficiency is unique among bleeding disorders due to its extreme variability. Some patients with very low FVII levels have minimal or no bleeding, while others have serious or even life-threatening hemorrhages (3 4). Common symptoms include:

• Epistaxis (nosebleeds): The most frequently reported symptom, often recurring and sometimes severe enough to require medical attention (1 4).
• Menorrhagia (heavy menstrual bleeding): Especially common among women, affecting over half of female patients (1 3 4).
• Haemarthrosis (joint bleeding): Less frequent than in hemophilia A or B but can still occur, particularly in severe cases (3 4 13).
• Central Nervous System (CNS) bleeding: Though rare, CNS bleeds are among the most severe complications, sometimes leading to long-term impairment or death. They are more likely in infants and young children but can occur at any age (3 4).
• Gastrointestinal (GI) bleeding: Uncommon but potentially life-threatening when it occurs (3 13).
• Other manifestations: Gum bleeding, hematuria (blood in urine), and bleeding after surgery, dental extractions, or trauma are also reported (1 4 13).

Symptom Variability

• Mild to Severe: The same FVII activity level can result in vastly different clinical presentations—even within the same family (3 4).
• Asymptomatic Cases: Up to 30% of individuals with factor VII deficiency may not show any symptoms, highlighting the importance of thorough family and personal history in diagnosis (3 4).
• Trigger Events: Surgery, trauma, or childbirth can unmask a previously silent deficiency (1 3 4).

Types of Factor VII Deficiency

Understanding the different types of FVII deficiency is crucial for accurate diagnosis and effective management. The disorder can be classified based on inheritance pattern, clinical severity, and whether it is inherited or acquired.

Type	Description	Genetic/Acquired	Source(s)
Inherited (Congenital)	Mutation in F7 gene; autosomal recessive	Genetic	3 4 6 7 10
Acquired	Secondary to liver disease, vitamin K deficiency, warfarin, or autoantibodies	Acquired	5 9
Type 1 (Classic)	Reduced or absent FVII activity and antigen	Genetic	5 7
Type 2 (Dysfunctional)	Dysfunctional FVII protein, normal antigen	Genetic	5 8

Table 2: Classification of FVII Deficiency

Inherited (Congenital) Factor VII Deficiency

• Genetics: Most cases are caused by mutations in the F7 gene on chromosome 13; inheritance is autosomal recessive (3 4 6 7 10).
• Clinical Heterogeneity: Both homozygous and compound heterozygous individuals can have severe or mild symptoms. Heterozygotes may also bleed (3).
• Molecular Variants: Over 100 mutations have been identified, including point mutations and small deletions, often unique to individual families (6 7).

Acquired Factor VII Deficiency

• Liver Disease: The liver produces FVII; hepatic dysfunction results in reduced synthesis (9).
• Vitamin K Deficiency or Antagonism: FVII is vitamin K–dependent; deficiency or warfarin therapy impairs function (5 9).
• Autoantibodies: Rarely, immune-mediated destruction or neutralization of FVII can occur (5 9).
• Other Causes: Conditions like lupus anticoagulant have been associated with acquired FVII deficiency (9).

Functional Subtypes

• Type 1 (Classic): Both FVII activity and antigen levels are reduced or absent (5 7).
• Type 2 (Dysfunctional): The FVII protein is present but dysfunctional; activity is low, but antigen levels are normal (5 8).
• Clinical Relevance: The specific subtype can impact both bleeding risk and treatment response.

Causes of Factor VII Deficiency

The underlying causes of FVII deficiency include genetic mutations and acquired conditions that decrease FVII levels or impair its function.

Cause	Mechanism	Population	Source(s)
F7 Gene Mutations	Point mutations, deletions, compound heterozygosity	Congenital cases	6 7 10
Consanguinity	Increased risk of homozygosity	Some populations	4
Liver Disease	Decreased FVII synthesis	Acquired cases	9
Vitamin K Deficiency/Warfarin	Impaired FVII carboxylation or synthesis	Acquired cases	5 9
Autoantibodies	Neutralization of FVII protein	Rare, acquired	5 9

Table 3: Causes of FVII Deficiency

Genetic Causes

• F7 Gene Mutations: The majority of congenital cases are due to diverse mutations in the F7 gene, leading to either reduced synthesis or production of dysfunctional FVII protein (6 7 10).
  • Over 100 mutations have been identified, including missense and nonsense mutations, small deletions, and compound heterozygosity (7).
  • Mutations may affect the protein’s stability, secretion, activation, or its ability to bind tissue factor (8).
  • Consanguinity increases the risk of inheriting the disorder, as seen in some regional populations (4).

Acquired Causes

• Liver Disease: The liver is responsible for FVII synthesis; any significant liver dysfunction can lead to deficiency (9).
• Vitamin K Deficiency or Warfarin Therapy: FVII is vitamin K–dependent; deficiency impairs gamma-carboxylation, while warfarin directly inhibits this process (5 9).
• Autoimmune Mechanisms: Rarely, autoantibodies can develop that neutralize FVII activity (5 9).
• Other Factors: Acquired deficiency may also be associated with certain infections or autoimmune diseases, though these are rare (9).

Special Considerations

• Phenotypic Variability: The relationship between FVII level and bleeding risk is poor; genetic background, environmental exposures, and possibly other modifying genes influence the phenotype (3 4).
• Family History: A detailed family and personal bleeding history is crucial for identifying at-risk individuals, especially before surgery or childbirth (3).

Treatment of Factor VII Deficiency

Management of FVII deficiency is tailored to the individual, based on symptom severity, type of deficiency, and clinical scenario. Treatment options have evolved rapidly, with recombinant therapies now at the forefront.

Treatment	Use/Indication	Benefits/Limitations	Source(s)
Recombinant FVIIa	Bleeding episodes, surgery, prophylaxis	No infection risk, effective	11 12 13 14
Plasma-derived FVII	Bleeding episodes, surgery	Limited availability	2 13 14
Fresh Frozen Plasma	Bleeding episodes, surgery	Virus transmission risk	2 13 14
Prothrombin Complex Concentrates	Bleeding episodes, less common	Potential thrombosis	2 13 14
Long-term Prophylaxis	Severe/recurrent bleeds	rFVIIa preferred, effective	12 13
Supportive Care	Mild cases, monitoring	No bleeding risk	3 4

Table 4: Treatment Options

Replacement Therapy

• Recombinant Activated Factor VII (rFVIIa):

  • Gold standard for replacement therapy (11 12 13 14).
  • Effective for treating acute bleeds, surgical prophylaxis, and long-term prevention in severe cases.
  • Dosing: Single or multiple doses, typically 15–60 µg/kg per episode; higher doses for surgery or severe bleeds (11 13 14).
  • Advantages: No risk of blood-borne pathogen transmission; low immunogenicity (11).
  • Rarely, inhibitor development has been reported (13 14).

• Plasma-derived FVII Concentrates and Fresh Frozen Plasma (FFP):

  • Used where rFVIIa is unavailable (2 13 14).
  • FFP requires large volumes and carries a risk of viral transmission.
  • Plasma-derived concentrates may be associated with increased risk of thrombosis, especially impure preparations (2 14).

• Prothrombin Complex Concentrates (PCC):

  • Contain multiple vitamin K–dependent factors.
  • Used less frequently due to risk of thrombosis and variable FVII content (2 13 14).

Prophylaxis

• Long-term Prophylaxis:
  • Indicated for patients with severe, recurrent or life-threatening bleeding (e.g., CNS bleeds, frequent haemarthroses) (12 13).
  • rFVIIa, administered two to three times weekly, has proven effective and safe (12).
  • Prophylaxis can reduce bleeding frequency and improve quality of life.

Supportive and Preventive Care

• Mild Cases: May not require regular treatment; monitoring and avoidance of bleeding triggers are key (3 4).
• Surgical/Obstetric Prophylaxis: Preoperative assessment and planned replacement therapy are crucial in surgical or childbirth settings (3 13 14).
• Management of Acquired Cases: Treat underlying cause (e.g., vitamin K administration, liver disease management), with replacement therapy used as needed (9).

Emerging and Experimental Therapies

• Gene Therapy: Not yet available but under investigation.
• Novel Mutations: Understanding genotype-phenotype relationships may guide future personalized therapies (6 7 8).

Conclusion

Factor VII deficiency is a rare but clinically diverse bleeding disorder. Understanding its symptoms, types, causes, and modern treatment options is key for both affected individuals and healthcare providers.

Key Points:

• Factor VII deficiency shows wide variability in symptoms, from mild to severe bleeds or even asymptomatic cases.
• The disorder can be inherited (most commonly due to F7 gene mutations) or acquired (often due to liver disease, vitamin K deficiency, or autoantibodies).
• Treatment is individualized, with recombinant FVIIa now the therapy of choice for most scenarios.
• Long-term prophylaxis is effective for those with severe bleeding, and supportive care is essential for mild cases.
• Ongoing research is expanding our understanding of genetic subtypes and may soon offer new treatment avenues.

By recognizing the complexity and diversity of factor VII deficiency, clinicians and patients can work together to tailor management and improve outcomes.