Factor VII Deficiency Treatment & Management: Medical Care, Surgical Care, Consultations


Medical Care

Replacement therapy for persons with factor VII deficiency depends on the site and severity of bleeding and the baseline factor VII activity.

Long-term prophylaxis with 10-50 U/kg 1-3 times per week has been successful in children with severe factor VII deficiency. Mild bleeding associated with bruising and skin lacerations may not require any replacement and can be controlled by applying local pressure at the bleeding site. Minimal mucosal bleeding episodes, such as occurs with epistaxis and during dental procedures, can be managed with antifibrinolytic agents or fibrin glue.

For spontaneous hemorrhage or mild trauma, therapeutic factor VII levels of 5-10% are sufficient to stop bleeding. This level may be achieved by administering plasma at a dose of 5-10 mL/kg of body weight and repeating the dose every 8-12 hours for 1-2 days.

For major hemorrhage or surgery, plasma may be administered in a loading dose of 15-20 mL/kg and followed by 3-6 mL/kg every 8-12 hours until the surgical wound heals. This may require 5-7 days of treatment. Plasma infusion may be associated with disadvantages such as volume overload, infectious complications, or an inability to achieve high levels of factor VII. Highly purified factor VII concentrates are useful in patients with severe bleeding or as prophylaxis for surgery. Unlike factor VIII and factor IX deficiencies, for which levels of 100% are required before surgery, factor VII deficiency requires levels in the range of 10-15% to produce efficient hemostasis. For major surgery, trough levels of factor VII must not fall to less than 20 U/dL.

Prothrombin complex concentrates are also a source of factor VII but carry the risk of infectious complications and thrombosis. When prothrombin concentrates are used, doses of 50 U/kg every 8 hours for 24 hours, followed by plasma infusions, have been shown to be effective for major orthopedic surgery.

Recombinant factor VIIa (rFVIIa) has proven effective in clinical trials as a treatment for bleeding in hemophilia A patients with inhibitors and in limited numbers of factor VII–deficient patients. rFVIIa is produced by recombinant technology and thus does not carry the risk of infectious complications. Note the following:

  • rFVIIa may be the treatment of choice for previously untreated patients with factor VII deficiency but is currently an expensive treatment. An online registry, the Seven Treatment Evaluation Registry (STER) has been set up, which helps in prospective study to evaluate the efficacy and safety of various therapies with which FVII-deficient patients may be treated. [19]
  • rFVIIa has been effective in the treatment of blood loss associated with various conditions, but reports from larger studies are not yet available to confirm these findings. [20Off-labeled use of rFVII for 5 in-hospital indications including intracranial hemorrhage, cardiac surgery, trauma, liver transplantation, and prostatectomy were reviewed in a systematic literature review (16 RCTs and 6 observational studies) by Yank et al. [21]This analysis suggested no mortality reduction for any of the above indicated off-label conditions. In addition, there was an increased risk for thromboembolism. With the rapid increase over the past few years of the drug for off-label indications, [22it is necessary to reconsider rFVII treatment given the limited efficacy without proven mortality benefit, costs involved, and the risks associated with thromboembolism.
  • rFVIIa is reportedly effective in controlling intracranial bleeding when administered within 3-4 hours of onset (from phase II studies, class IIb, level of evidence B), this is being confirmed in larger studies. [23There is no proven efficacy for mortality reduction from systematic analysis of various studies.
  • In a comprehensive study of 35 randomized clinical trials of rFVIIa, patients, particularly elderly persons, who were treated with high doses of rFVIIa on an off-label basis experienced a substantially higher risk of arterial, but not venous, thromboembolic events. [24Pooled data analysis reported by Levi et al showed an increased risk of arterial thrombosis when rFVIIa was administered in large doses for off-label indications to patients older than 65 years compared to younger patients. [24]
  • A single-center case series involving 15 patients who received rFVIIa for acute liver failure did not show any benefit in terms of length of hospital stay or mortality. [25]
  • A retrospective study of rVIIa use compared with standard therapy in warfarin-induced intracranial hemorrhage did not find any increased incidence of thrombotic complications when adjusted for preexisting thromboembolic risk factors in both groups. [26]
  • A retrospective review of 63 patients with warfarin-associated intracranial hemorrhage comparing fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), and rVIIa (all in conjunction with vitamin K) found both PCC and rVIIa to be superior to FFP in speed of reversal and less INR rebound, but rVIIa was more expensive than the other two. [27]
  • A Cochrane systematic review of 2 clinical trials involving nearly 500 patients with upper gastrointestinal bleeding secondary to liver disease was inconclusive, and a benefit of rVIIa in this scenario could not be established. [28]
  • Off-label attempts to correct newer anticoagulants such as dabigatran (in conjunction with hemodialysis) with rVIIa have been reported but remain experimental. [29]
  • A large systematic review evaluated the studies involving off-label use of rVIIa for in-hospital indications, including intracranial hemorrhage, cardiac surgery, trauma, prostatectomy, and liver transplantation, failed to show any mortality benefit, although the risk of arterial thromboembolism increased with several indications. [30]

Surgical Care

Prophylactic administration of factor VII concentrates or plasma may help minimize bleeding during surgery. For surgery, factor VII concentrates have been used in doses ranging from 8-40 U/kg every 4-6 hours.

 Fibrin glue or fibrin tissue adhesives have been used as adjunctive therapy to achieve hemostasis. Fibrin glue contains fibrinogen, thrombin, and factor XIII.
Antifibrinolytic agents such as epsilon-aminocaproic acid and tranexamic acid have been used to enhance hemostasis during dental procedures as an adjunct to replacement therapy.

Consultations

Obtain consultations with orthopedists, physical therapists, general surgeons, dental surgeons, and genetic counselors as needed.

Diet

Instruct patients to maintain a regular, healthy diet without restrictions.

Activity

Recommend that patients limit activity of the involved joints or muscles during acute bleeding episodes. Early physical therapy is recommended once bleeding is resolved to prevent contractures or deformity.

Medication Summary

Recombinant factor VIIa

rFVIIa is licensed by the US Food and Drug Administration for the treatment of bleeding in individuals with hemophilia A and B with acquired inhibitors and for persons with congenital factor VII deficiency. rFVIIa is produced in vitro in baby hamster kidney cells that are transfected with F7. [31]

Although originally developed for the treatment of inhibitor-complicated hemophilia A and B, novel indications for rFVIIa (based on case reports and smaller clinical trials) include use in patients with liver disease, thrombocytopenia, or qualitative platelet dysfunction and in patients with no coagulation disorders who are bleeding as a result of extensive surgery or major trauma. [532143334Use of rFVIIa to control bleeding has increased among patients with intracranial bleeding, cardiac surgery, prostatectomy, trauma, and liver transplantation over the past few years. [22]The benefits of rFVII is uncertain, and no mortality reduction is seen. The various dosages used in the above-mentioned conditions vary and are outlined in the review by Logan et al.

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