|Year : 2021 | Volume
| Issue : 3 | Page : 206-208
A rare bleeding disorder with an expensive factor defect
Harish Sudarsanan, CN Kamalarathnam
Department of Neonatology, Institute of Child Health, Madras Medical College, Chennai, Tamil Nadu, India
|Date of Submission||27-Nov-2020|
|Date of Decision||07-Jun-2021|
|Date of Acceptance||11-Jun-2021|
|Date of Web Publication||28-Jul-2021|
Department of Neonatology, Saveetha Medical College and Hospital, Thandalam, Kanchipuram - 602105, Tamil Nadu
Source of Support: None, Conflict of Interest: None
A 14-day-old baby girl was admitted with fever, profuse bleeding from umbilicus, and encephalopathy. Neuroimaging showed intracranial bleed and coagulopathy remained uncorrected with fresh frozen plasma. Coagulation profile characteristically demonstrated prolonged prothrombin time, international normalized ratio, and normal activated partial thromboplastin time. Factor VII assay was done which showed very low levels of Factor VII. Factor VII deficiency or Alexander disease, an autosomal recessive disorder, is the most common among rare bleeding disorders with a global prevalence of 1/5, 00,000. Defect can be either quantitative or qualitative. Clinical manifestations range from severe to nonsevere. Severe forms manifest in newborns with intracranial bleed. It is the least common presentation. Recombinant Factor VII remains the most effective therapy but is currently unavailable and very expensive even for the affordable considering short half-life of 4–6 h. Prenatal diagnosis with genetic testing remains the only promising preventive strategy.
Keywords: Bleeding disorder, Factor VII deficiency, clotting factor defect
|How to cite this article:|
Sudarsanan H, Kamalarathnam C N. A rare bleeding disorder with an expensive factor defect. J Clin Neonatol 2021;10:206-8
| Introduction|| |
A bleeding neonate is commonly encountered in a neonatal referral unit with a variety of manifestations. Most of them are secondary to Vitamin K-dependent factors and are easily correctable. However, some bleeding disorders are very rare making the treatment either unavailable or expensive. In our center, we encountered a baby with Factor VII deficiency unresponsive to conventional therapy. The global prevalence of this disorder is 1/5,00,000, it is the most common among rare bleeding disorders.
| Case Report|| |
A 14-day-baby was born to a Primi mother through 3rd degree consanguineous marriage and uneventful pregnancy. The baby was delivered by normal vaginal delivery at 39 weeks, weighed 2740 g, and discharged on day 5 of life. On day 15 of life, the baby was admitted with complaints of fever for 3 days, lethargy, and profuse bleeding from the umbilicus for 1 day. Examination revealed the baby to be drowsy, comatose, tense anterior fontanel with sutures separated, and head circumference of 37 cm. The baby was pale, was bleeding from the umbilicus with features of shock. There was no organomegaly. At this juncture, our provisional diagnosis was sepsis, hemorrhagic disease of newborn and clotting factor deficiency. Septic workup and prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR) was done and the baby was started on intravenous antibiotics, Vitamin K and the whole blood was transfused. Inotrope and ventilator support was commenced. Initial investigation: hemoglobin – 12.4 g/dL, hematocrit – 40%, total white blood cell count – 26,300/μL, platelet count – 692,000/μL, liver function test – within the normal limits, C-reactive protein/blood culture-negative, and arterial blood gas – within the normal limits. PT – 30.3 s, aPTT – 45.2 s, and INR – 2.98. Fresh frozen plasma (FFP) and packed red blood cells (PRBC) were transfused. Inotropes were stopped after 12 h and antibiotics stopped after negative septic workup. Repeat coagulation profile on Day 3: PT – 28.3 s, aPTT – 41.2 s, and INR – 2.4. In view of isolated prolonged PT despite Vitamin K and FFP transfusion, Factor VII deficiency was thought of. Coagulant activity of Factor VII (Factor VII: C) was 3.6% (70%–120%). Neuroimaging revealed hemorrhage involving brain stem and subdural space [Figure 1] and [Figure 2]. Since neurosurgeons ruled out intervention in the setting of deranged PT, the baby was continued on ventilation and repeated FFP and PRBC transfusions. The baby expired on day 25 of life.
| Discussion|| |
Hereditary Factor VII deficiency is also known as Alexander disease after its discovery in 1951. It is also called as “Labile Factor” or “Proconvertin” deficiency. Although the global prevalence of this disorder is 1/5,00,000, it is the most common among rare bleeding disorders. The mode of inheritance is autosomal recessive due to a defect in the Factor VII gene is located on chromosome 13q34. There are 250 different mutations causing this condition of which 80% are missense. The normal plasma level of Factor VII is 0.35–0.6 mg/L and the normal coagulant activity is between 70% and 140%. Clinical manifestations will usually result in coagulant activity <30%. The half-life of Factor VII is only 4–6 h.,
Factor VII deficiency can be both acquired and inherited
- Pseudo isolated deficiency due to short half-life
- Decrease synthesis
- Defective synthesis
- Hypovitaminosis K
- Decreased intake
- Anti-Vitamin K medications
- Increased consumption
- Type 1
- Type 2
- Qualitative defect clinical manifestations have no correlation with Factor VII: C levels and include:
- Epistaxis (60%)
- Easy bruising (36%)
- Gum bleeds (34%)
- Hematoma (20%)
- Hematuria (7%)
- Extensive bruise (19%)
- Hemarthrosis (19%)
- Gastrointestinal Bleed (15%)
- Central Nervous System bleed (2.5%).
The laboratory diagnosis of Factor VII defect can be suspected when coagulation profile which shows prolonged PT, prolonged INR, and normal aPTT with levels not normalizing following Vitamin K administration. The condition can be confirmed by low Factor VII: C level. The Type I (Quantitative defect) and Type II (Qualitative defect) conditions can be differentiated by Factor VII antigen levels (Factor VII: Ag) by enzyme-linked immunosorbent assay technique.,
The treatment options for Factor VII deficiency include FFP, prothrombin complex concentrates, plasma-derived Factor VII (pdFVII), and recombinant Factor VII (rFVIIa). The effectiveness of therapy depends on the Factor VII content in the above therapy options and are as follows: FFP (1 IU/ml), prothrombin complex concentrates (5–10 IU/ml), pdF7 (20–40 IU/ml), and rFVII a – (25000 IU/ml)., Recombinant Factor VII with the highest Factor VII levels is the most effective therapy for this condition and the least effective being FFP though it is the most easily available and most commonly used therapy. The dosage of rFVII is 15–30 μg/kg and available as 1.2 and 2.4 mg vials. However, the cost of 1.2 mg vial is 35,000 Indian Rupee (480 USD) and 2.4 mg vial is 75,000 Indian Rupee (1029 USD), and considering the short half-life of Factor VII, the patient will need multiple dosages/vials per day. Prophylaxis can be given for conditions such as severe disease, hemarthrosis, and central nervous system bleed. The options used for prophylaxis include rFVIIa – 15–25 μg/kg and pdFVII – 10–30 μg/kg.
Prenatal diagnosis is possible with amniocentesis for genetic analysis. If the genetic analysis is not possible, then cordocentesis can be done at 17–21 weeks for Factor VII: C levels and reconfirm postnatally. Detecting Factor VII: C in parents has no role as levels do not correlate with clinical symptoms in the offspring.
| Conclusion|| |
Factor VII deficiency, congenital or acquired is still a rare disorder. Although the condition is easy to diagnose, it is still difficult to treat. The clinical symptoms do not correlate with levels and there are still no clear guidelines for prophylaxis and treatment. The treatment still not affordable for the majority of the population.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]