1 Introduction
1 Factor VII and factor VII deficiency
Coagulation factor VII (FVII), also known as serum prothrombin conversion accelerator (SPCA) or proconvertin is a vitamin-K dependent glycoprotein synthesized by hepatocytes and secreted into the blood as a single chain zymogen. It was discovered in the early 50’s by three independent research groups, Alexander et al., Koller et al. and Owren et al. [1–4]. FVII consists of an N-terminal gamma-carboxyglutamic acid domain (Gla domain) followed by two epidermal growth factor-like (EGF1 and EGF2) domains and a C-terminal protease domain. Activation of FVII results in a two-chain FVIIa molecule consisting of a light chain (the Gla-EGF1-EGF2 domains) and a heavy chain (the protease domain) held together by a single disulphide bond [5].
FVIIa is the factor that initiates the tissue factor (TF) dependent pathway of coagulation when an injury to the endothelium enables TF in the membrane of subendothelial cells to interact with FVII in the blood [6]. During coagulation, in the presence of calcium, the TF/FVIIa complex activates factor IX (FIX) and factor X (FX). Activated FX (FXa) converts prothrombin to thrombin resulting in fibrin formation through proteolytic reactions involving factor V (FV), fibrinogen and factor XIII (FXIII) [7].
FVII has the shortest half-life of all coagulation factors (3-6 hours). The FVIIa-TF complex is inhibited by the tissue factor pathway inhibitor (TFPI), a serine protease inhibitor synthesized by endothelial cells that consists of 3 Kunitz type domains. The mechanism of inhibition involves binding of FXa to domain 2 of TFPI and then to the TF/FVIIa complex through domain 1 [9]. Binding to FXa makes TFPI a much more potent inhibitor of the TF/FVIIa than TFPI alone.
Congenital FVII deficiency, sometimes also referred to as Alexander’s disease, is an autosomal recessive inherited bleeding disorder caused by factor VII gene (F7 gene) variants [8]. The human F7 gene is located at chromosome 13q34, close to the gene encoding for FX and comprises nine exons [9,10]. The EAHAD database (https://dbs.eahad.org/FVII) contains curated information on 271 unique variants identified in 1056 patients [11]. Approximately 90 percent of known variants are single nucleotide variants out of which between two thirds and three quarters are missense variants [11,12].
FVII activity is measured by the clotting method. In patients with certain variants e.g. FVII Padua (Arg304Gln), FVII Nagoya (Arg304Trp) and FVII Shinjo (Arg79Gln) there are discrepancies in FVII activities depending on the type of tissue thromboplastin used in the assay. Rabbit brain derived thromboplastin results in lower FVII activities without corresponding bleeding tendency whereas ox brain thromboplastins fail to detect a decreased activity in patients with these variants [13].
1.1 Recommendation for analysis of FVII activity
| For analysis of factor VII activity, human tissue or recombinant thromboplastin as clotting activator is preferred. |
2 Clinical manifestations, diagnosis and classification
FVII deficiency is the most common of the rare congenital bleeding disorders with a prevalence of about 1:500,000. There is however large variation in prevalence between different countries [14–16]. In the United Kingdom, 2,437 patients with FVII deficiency are registered, notably surpassing the number of patients with hemophilia B (1,779) and indicating a prevalence of approximately 1 in 28,000 [17].
Clinical phenotypes range from asymptomatic individuals to severe bleeding tendency. Epistaxis, bruising and menorrhagia are the most frequent bleeding manifestations but more serious manifestations such as gastrointestinal (GI), intracranial or joint and muscle bleeds may occur [18,19]. Interestingly, thrombosis has been reported in FVII deficiency although in most instances the thrombotic event occurred in association with substitution therapy or in the presence of known risk factors for thrombosis [20–22].
A study based on data from The European Network of Rare Bleeding Disorders (EN-RBD) included 224 patients with FVII deficiency and found only a weak correlation between the coagulation factor activity level and clinical bleeding severity [23]. However, when using a linear regression analysis the bleeding severity category (outlined in table 1 in this guideline) was associated to the following FVII:C activities (95% CI): asymptomatic 15-35%; grade I 8-30%; grade II 2-25% and grade III 0-21%. The factor level deemed necessary to remain asymptomatic was 25% [23]. The registry also found that the hemorrhagic diathesis varied in persons with similar FVII:C activity level and genotype [8]. There is currently no available assays to predict the bleeding tendency in FVII deficient individuals.
Poor correlation between genotype and phenotype has also been found in an even larger cohort including 717 subjects [12]. Heterozygote patients were sometimes displaying bleeding symptoms [12] while homozygotes and compound heterozygotes were found among asymptomatic patients [18]. The share of homozygote and compound heterozygote patients do however decrease with decreasing bleeding severity [18] and no severe hemorrhages (defined as intracranial and gastrointestinal) were found among heterozygotes among 717 studied patients [12]. As the bleeding phenotype cannot be predicted from the gene variant, genotyping is not recommended as standard of care. The diagnosis of FVII deficiency is currently made by analyses of FVII:C, but different cut-off levels are applied as diagnostic in the literature [24,25]. From a practical point of view, our recommendation would be to avoid the diagnosis of FVII deficiency in patients with levels between 35-50% and no bleeding symptoms. They should be informed that they have low levels of FVII that affects the result of some other coagulation assays (most importantly the PT INR) but has no clinical implications.
2.1 Recommendation for definition of FVII deficiency
| FVII:C > 50%: | Normal |
| FVII:C 35-50%: | Low FVII level |
| FVII:C <35%: | FVII deficiency |
Di Minno et al. found that major bleeding at diagnosis is an independent predictor for the patients’ bleeding risk in FVII deficiency [19]. Another study suggested that the type and number of bleeding symptoms might be used to classify the clinical phenotype, ranging from severe, moderate to mild to guide substitution therapy. The EN-RBD suggests that the bleeding phenotype in FVII deficiency should be classified as outlined in Table 1 [23]. The clinical utility of this classification has not been validated.
Case reports suggest that FVII:C levels are increased during pregnancy thus, diagnostic samples should not be taken during pregnancy or in the post partum period [26–28].
| Clinical severity | Definition |
|---|---|
| Asymptomatic | No clinical bleeding tendency |
| Grade I | Bleeding after trauma or drug |
| Grade II | Spontaneous minor bleeding |
| Grade III | Spontaneous major bleeding |
2.2 Recommendation for FVII genotyping
| In clinically severe factor VII deficiency, genotyping allows for prenatal counseling and is recommended. In moderate, mild or asymptomatic cases, genotyping is not recommended for routine care. |
2.3 Recommendation for classification
| Severity of factor VII deficiency should be classified according to bleeding phenotype in addition to factor level. |
3 Management of factor VII deficiency
Treatment principles for FVII deficiency are similar to treatment of hemophilia, i.e. replacement of the deficient coagulation factor to a hemostatic level that prevents or stops bleeding [29]. Prophylaxis therapy may be indicated in patients with frequent joint or muscle bleeds with subsequent increased risk of long-term joint destruction and impaired daily life performance.
Several treatment options are available for treatment of FVII deficiency. Recombinant FVIIa (rFVIIa) is the recommended first line therapy because it is highly effective and is associated with low prevalence of serious adverse events.
The dose needed in FVII deficiency (15-30 µg/kg) is lower than required in hemophilia patients with inhibitors where a high dose (90-270 µg/kg) is necessary to achieve hemostasis [30]. During major surgery or major bleeds, the short half-life of rFVIIa of 2-3 hours necessitates repeated bolus injections for sustained hemostasis [31]. Other FVII containing products such as plasma-derived (pd) FVII, prothrombin complex concentrates (PCC) and fresh-frozen plasma (FFP) have also been demonstrated useful [29,32]. However, some safety concerns have been raised as venous thrombosis has been reported in association with the use of pdFVII and PCC [20]. Although known risk factors for venous thrombosis (VT) were present in these cases, the reports demonstrate that FVII deficiency does not protect the patients from thrombotic complications and replacement therapy should be used with caution in this patient population. FFP contains only a small amount of FVIIa and carries a potential risk of volume overload and blood borne viral infections [33]. However, FFP may be a valuable hemostatic agent in case rFVIIa, pdFVII or PCC are not available for treatment or prevention of bleeds in FVII deficient patients.
4 Current challenges and future perspectives
There is currently no validated laboratory method to predict bleeding risk in patients with FVII deficiency. It is therefore challenging to select the patients who will benefit from replacement therapy before bleeding occurs. Some patients have increased bleeding tendency and carry a high risk of developing hemarthroses. These patients will likely benefit from regular prophylactic treatment similarly to that in hemophilia patients. Nevertheless, selection of patients, optimal dosing and frequency of infusions remains to be established. It was hypothesized that global hemostatic assays might have the potential to predict the bleeding risk in patients with severe FVII deficiency but as shown by Tran et al. this was not useful [34]. Moreover, further insight into mechanisms underlying the diversity in genotype-phenotype in factor FVII deficiency is warranted in order to extend our understanding of the coagulation process. During surgery, rFVIIa is commonly administered as frequent bolus injections (BI) to prevent bleeding in patients with FVII deficiency but the optimal dose and frequency of BI remain to be determined. Continuous infusion has been shown to be hemostatically equivalent and more economic since less concentrate is needed [35]. Continuous infusion is therefore recommended at centers where handling of intravenous pumps at the surgical wards is a safe option.