2  Overview of hemostatic treatment options

1 Treatment of FVII-deficiency

The relationship between factor VII level and bleeding tendency is poor and thus, the clinical bleeding history (phenotype) is the most important predictor for bleeding tendency and surgical complications.

Treatment recommendations on bleeding episodes and optimizing hemostasis during invasive procedures and child delivery are all dependent on:

• The phenotype of FVII deficiency.

• The severity of the bleed or surgical procedure.

• The local supply of factor concentrates and/or plasma products.

2 Factor substitution therapy options

2.1 Recombinant FVIIa (rFVIIa) – NovoSeven®

rFVIIa has an approved indication for treatment and prevention of bleeding in FVII deficiency. It is a prohemostatic drug containing recombinant FVII in an active form and has a shorter half-life (2-3 hours) compared to non-activated FVII. rFVIIa acts locally on the injured vessel by accelerating thrombin formation and platelet activation.

2.1.1 Treatment recommendations

Commonly, a low bolus dose of 15-30 µg/kg body weight is given and repeated every 4 to 6 hours until bleeding is controlled [1]. More recent publications have demonstrated that one dose daily with an intermediate dosage of 60 µg/kg body weight is sufficient to treat most spontaneous bleedings, though more severe hemorrhages such as intracranial and gastrointestinal bleeds need repeated infusion for optimal effect [2,3]. For surgical procedures, repeated frequent bolus doses or an initial bolus dose followed by continuous infusion of rFVIIa is applied [4]. Please see below for more detailed recommendations.

Risk of thrombosis remains unclear. In a report from STER one hundred and one spontaneous and traumatic bleeds were analyzed in 75 patients with FVII deficiency. Of those 76 bleeds were treated with rFVIIa and majority received a single intermediate dose. No thrombosis occurred [2]. In another report from STER on treatment for surgical patients three thrombotic events were reported in 245 patients and all received several days of treatment with rFVIIa [5].

Pros	Cons
Effective	Expensive
Small amounts needed	Not available in all hospitals
No risk of virus transmission	Theoretical risk for development of inhibitors
	Theoretical risk of thrombosis

2.2 Other available sources of Factor VII

2.2.1 Plasma – fresh-frozen, fresh-stored or OctaplasLG®

Plasma contains all coagulation factors and inhibitors. Plasma can be given as fresh- frozen or fresh-stored plasma. In FFP the concentration of FVII is relatively stable compared to FV and FVIII which are halved within 24 hours. FFP needs 45 minutes to defrost, whereas the fresh-stored plasma is preferred in an emergency situation despite the concentration of coagulation factors is slightly lower. Norway and Finland only apply OctaplasLG® aiming to reduce the risk of adverse effects from plasma particularly the risk of transmitting infectious agents, severe allergic reactions or TRALI. OctaplasLG® is solvent/detergent (processed and filtered) treated FFP from male blood donors. All coagulation and hemostatic parameters are equivalent to the raw product, FFP, except the lower levels of protein S and antiplasmin.

2.2.2 Treatment recommendations

Start dose for treatment of bleed: 15-30 ml per kg body weight depending on the site and severity of bleeding and may be repeated every 4 -6 hours [2]. 10-15 ml per kg body weight should increase the patient’s plasma coagulation factor levels, including FVII by 0.15-0.25 IU/ml. If hemostasis is not achieved, increased doses are needed.

Pros	Cons
Lower costs compared to rFVIIa and factor concentrates	Risk for volume overload when repeated infusions are needed
Available at most hospitals	Insufficient in severe FVII-deficiency
	Risk for virus transmission

2.2.3 Prothrombin-complex concentrates (PCC) - Confidex®, Octaplex®, Prothromplex®

The human plasma-derived ‘Prothrombin-complex concentrate’ (PCC) contains the K- vitamin dependent coagulation factors and inhibitors; FII, FVII, FIX, FX as well as protein C and protein S.

In the Nordic countries, there are three approved PCC products by the national medical product agencies; Confidex®, Octaplex® and Prothromplex®.

2.2.4 Treatment recommendations

Recovery for FVII is estimated so that 1 IU of FVII per kg body weight increase the plasma activity of Factor VII with 1.7% or 0.017 IU/ml.

The amount of PCC needed is calculated by:

PCC content of Factor VII needed (IU) = Body weight [kg] x desired increase of FVII [IU/ml] x (1/0.017).

The concentration of FVII varies between products and batches and must be taken into account when calculating the doses.

Pros	Cons
Compared to FFP smaller volumes are needed	Costs
Efficient	Wide variability in the concentration of FVII between batches
	Repeated doses of PCC may lead to accumulation of the other K-vitamin dependent coagulation factors due to longer half-life compared to FVII, and thereby increase the risk of thrombotic complications
	PCC contains low amounts of heparin implying a risk of heparin-induced thrombocytopenia – HIT (low)
	Risk for viral transfusion (low)
	Development of inhibitors (low)

2.2.5 Plasma derived factor VII

Is rarely applied. PdFVII is available in Denmark, but not in the other Nordic countries.

3 Antifibrinolytics: Tranexamic acid - Cyklokapron®

Tranexamic acid is an inhibitor of fibrinolysis and can be used alone or as adjunctive therapy to factor concentrates such as rFVIIa. The general use of tranexamic acid for treatment and prevention of bleeding has recently been thoroughly described by Tengborn et al. [6]. The British Guidelines on rare coagulation disorders do not comment on tranexamic acid (TXA) as adjunctive therapy to factor concentrate, but only recommend that is should be considered as monotherapy in mild bleeding [7].

Tranexamic acid as adjunctive therapy is largely absent in case series on bleeding in FVII deficiency available from the literature. However, tranexamic acid is widely used in Scandinavia as adjunctive therapy in bleeding disorders including FVII deficiency [4]. In other patient groups, it is clearly demonstrated that tranexamic acid reduces bleeding, and may often be sufficient treatment of non-severe mucosal hemorrhages [6].

Tranexamic acid has also been shown to reduce the risk of death in bleeding trauma patients, particularly when administered within 3 hours of traumatic injury [6,8].

3.1 Recommendations for antifibrinolytics

Tranexamic acid can be applied as monotherapy for treatment or prevention of mild bleeding or as adjunctive therapy to factor replacement in more severe cases. Intravenous injection with tranexamic acid 10 mg/kg body weight every 8 hours or an oral dose of tranexamic acid 20-25 mg/kg (max. 2 g) 3-4 times daily. Maximum daily dose of tranexamic acid is 4 – 6 g. As tranexamic acid is excreted in the urine it should not be used in renal tract bleeding [8].

4 Monitoring of therapy

FVII has a short half-life of four to six hours, why factor replacement treatment needs to be closely monitored. Normalized PT/INR in the upper reference levels (<1.2) is roughly close to 50 percent of the reference FVII plasma concentration. For more accurate monitoring, the FVII activity (FVII:C) needs to be measured [4,9].

1.

Mariani G, Konkle BA, Ingerslev J. Congenital factor VII deficiency: therapy with recombinant activated factor VII – a critical appraisal. Haemophilia 2006;12:19–27. doi:10.1111/j.1365-2516.2006.01180.x.

2.

Napolitano M, Dolce A, Garrido RP, Batorova A, Karimi M, Platokouki H, et al. Replacement therapy for bleeding episodes in factor VII deficiency: A prospective evaluation. Thrombosis and Haemostasis 2013;109:238–47. doi:10.1160/th12-07-0476.

3.

Bernardi F, Mariani G. Biochemical, molecular and clinical aspects of coagulation factor VII and its role in hemostasis and thrombosis. Haematologica 2021;106:351–62. doi:10.3324/haematol.2020.248542.

4.

Tran HTT, Tjønnfjord GE, Paus A, Holme PA. rFVIIa administered by continuous infusion during surgery in patients with severe congenital FVII deficiency. Haemophilia 2011;17:764–70. doi:10.1111/j.1365-2516.2011.02596.x.

5.

Napolitano M, Siragusa S, Mariani G. Factor VII Deficiency: Clinical Phenotype, Genotype and Therapy. Journal of Clinical Medicine 2017;6:38. doi:10.3390/jcm6040038.

6.

Tengborn L, Blombäck M, Berntorp E. Tranexamic acid – an old drug still going strong and making a revival. Thrombosis Research 2015;135:231–42. doi:10.1016/j.thromres.2014.11.012.

7.

Mumford AD, Ackroyd S, Alikhan R, Bowles L, Chowdary P, Grainger J, et al. Guideline for the diagnosis and management of the rare coagulation disorders: A United Kingdom Haemophilia Centre Doctors’ Organization guideline on behalf of the British Committee for Standards in Haematology. British Journal of Haematology 2014;167:304–26. doi:10.1111/bjh.13058.

8.

Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019;133:415–24. doi:10.1182/blood-2018-06-820738.

9.

Mariani G, Bernardi F. Factor VII Deficiency. Seminars in Thrombosis and Hemostasis 2009;35:400–6. doi:10.1055/s-0029-1225762.