Perioperative management in a patient with congenital factor VII deficiency following mechanical valve replacement: a case report

Abstract

Background

Congenital factor VII deficiency (CFVIID) is a rare hemorrhagic disorder which elevates perioperative bleeding risks. Mechanical prosthesis mandates lifelong anticoagulation, while international normalized ratio (INR) of CFVIID deviates significantly from the normal range which could not accurately reflect the real anticoagulation. Perioperative management for CFVIID patients undergoing mechanical valve replacement are highly challenging, with no clinical guidelines currently available.

Case presentation

We reported a 59-year-old CFVIID patient undergoing mechanical valve replacement. Perioperative recombinant activated factor VII (rFVIIa) replacement secured hemostasis. After postoperative cerebral thrombosis, anticoagulation of warfarin was initiated and guided by factor Ⅱ/Ⅹ activity (30–45%) rather than INR. No bleeding or recurrent thrombosis was observed.

Conclusions

Perioperative rFVIIa replacement guarantees hemostatic safety for cardiac surgery. Lifelong warfarin anticoagulation is essential for CFVIID patient with mechanical prosthesis. Monitoring factor Ⅱ/Ⅹ activity instead of INR can balance bleeding and thrombosis risks for such cases.

Background

Congenital factor VII deficiency (CFVIID) is an autosomal recessive hereditary hemorrhagic disorder resulting from mutations in the F7 gene. The majority of patients are homozygous for recessive mutations or compound heterozygous for complex mutations [1]. It is characterized by markedly diminished plasma factor VII (FVII) procoagulant activity with an estimated incidence of approximately 1 in 500,000 individuals [1]. Up to 1/3 of patients are asymptomatic, and only 10–15% have severe bleeding, with poor correlation between FVII activity and bleeding risk [2]. Management is particularly challenging when CFVIID coexists with severe valvular heart disease requiring mechanical valve replacement. These patients face a critical dilemma: congenital factor deficiency increases perioperative bleeding risk, yet mechanical valve implantation demands lifelong anticoagulation to prevent thromboembolic complications. In addition, low FVII activity levels do not confer protection against thrombosis [3]. Thromboembolic events are frequently associated with triggering factors like surgical procedures, replacement therapy or the presence of an antiphospholipid syndrome [4]. Currently, there is no specific guideline for perioperative hemostasis and anticoagulation management of such rare combined cases. This report summarizes the individualized management experience of a CFVIID patient undergoing mechanical valve replacement, aiming to provide clinical reference for similar cases.

Case presentation

A 59-year-old male was admitted for valvular disease found during physical examination. Preoperative echocardiography confirmed severe mitral regurgitation with moderate stenosis, severe aortic regurgitation with mild stenosis, severe tricuspid regurgitation, and left/right atrial enlargement. Preoperative electrocardiogram showed atrial flutter. The surgical indications were clear. International normalized ratio (INR) was found abnormal by 3.97. The patient had no chronic medical conditions and was not taking any regular medications preoperatively, including no anticoagulants or antiplatelet agents that could affect coagulation function. No improvement was seen after vitamin K1 injection and fresh frozen plasma transfusion. Further tests showed FVII activity of 0.8% (reference 50–150%) with normal factor II (FII), factor V (FV), factor IⅩ (FIⅩ) and factor Ⅹ (FⅩ) activity. He had no history of spontaneous bleeding or prior surgical bleeding complications. The results of blood tests for autoimmune disease were negative. There was no family history of bleeding disorders or confirmed factor VII deficiency in his first-degree relatives. Further whole exome sequencing showed F7 gene mutations (c.656 C > A, c.1099T > G, suspected compound heterozygous mutations) confirming congenital factor VII deficiency. Before surgery, a recombinant activated factor VII (rFVIIa, NovoSeven^® RT, Novo Nordisk Inc. New Jersey, U.S.A.) replacement test was performed. The patient’s weight was 82.5 kg. INR decreased to 1.16 6 h after 3 mg rFVIIa administration (approximately 0.036 mg/kg), and rebounded to 3.78 32 h after withdrawal, indicating the need for continuous supplementation.

After considering the long-term valve durability, the risks of reintervention and economic burden, the patient ultimately chose mechanical prosthesis. The surgical procedures included mitral (Medtronic Open Pivot, 27 mm, Minneapolis, MN, USA) and aortic (Medtronic Open Pivot AP360, 24 mm, Minneapolis, MN, USA) mechanical valve replacement, tricuspid valvuloplasty and left atrial appendage ligation (cardiopulmonary bypass time 177 min). Perioperative hemostatic strategy was rFVIIa 2 mg 6 h before skin incision and rFVIIa 1 mg at incision. During cardiopulmonary bypass, heparin was administered (375 units/kg) and neutralized with protamine at conventional doses (1 mg/100 units). After heparin neutralization, 1 mg rFVIIa was administered with human prothrombin complex 600IU (Hualan Biological Engineering, Inc., Henan, China) and human fibrinogen 2000 mg (CR Boya Bio, Jiangxi, China). The pericardial/mediastinal drainage in the first 24 h was 180 ml. A total of 6 mg of rFVIIa was administered in 6 doses within 52 h postoperatively (Fig. 1A). The drainage tube was removed on postoperative day 4. The patient was transferred out of intensive care unit on postoperative day 5. Apart from rFVIIa, no other specific hemostatic replacement therapy for FVII deficiency was used. No anticoagulant therapy was initiated during this period.

Fig. 1.

(A) Schematic of perioperative hemostatic strategy (B) Cerebrovascular angiography shows left middle cerebral artery thromboembolism (red arrow). (C) Two thrombi removed by percutaneous thrombectomy (D) Vascular recanalization (red arrow) of left middle cerebral artery after percutaneous thrombectomy (E) Correlation between activity of FX and INR (F) Correlation between activity of FⅡ and INR

The coagulation indicators were rechecked, showing a FVII activity of 0.5% and an INR of 4.1–4.3. However, the patient developed right limb weakness and aphasia on postoperative day 6. Head and neck computed tomography angiography manifested middle cerebral artery thromboembolism (Fig. 1B). Two thrombi were removed by an emergency percutaneous thrombectomy (Fig. 1C), achieving complete vascular recanalization (Fig. 1D) and significant relief of neurological symptoms.

An individualized anticoagulation was initiated after percutaneous thrombectomy. Nadroparin calcium (Fraxiparine, Sanofi Winthrop Industrie, France) 0.6 ml q12h was administered for bridging until warfarin reached the target dose. Due to the deficiency of FVII, the INR deviated significantly from the normal range. After reviewing the literature of monitoring index for warfarin, we decided to monitor the activity of FⅡ and FⅩ, maintaining them at 30–45%. Following the percutaneous thrombectomy, we observed a transient but significant increase in platelet count from 347 × 10⁹/L to 583 × 10⁹/L. To further evaluate the patient’s coagulation status, we performed thromboelastography (TEG) testing. The TEG results confirmed a hypercoagulable state with a markedly elevated maximum amplitude (MA) value of 79.1 mm (reference range: 50–70 mm), indicating platelet hyperfunction. Based on these findings, we added low-dose aspirin (100 mg once daily) in addition to the anticoagulant therapy. After 6 days, aspirin was discontinued when the platelet count returned to normal, and repeat TEG showed resolution of the hypercoagulable state. The patient achieved target FII/FX levels with a maintenance dose of 3 mg Warfarin sodium (Marevan, Orion Corporation Orion Pharma, Finland) after 13 days of adjustments. The patient was discharged with stable condition. Outpatient follow-up three months postoperatively showed INR of 6.5–7.5, with no bleeding or thrombosis recurrence. Follow-up echocardiography showed normal mechanical valve function. The patient achieved complete neurological recovery with no residual deficits.

Discussion

For CFVIID patients, failure to administer perioperative replacement therapy would markedly increase the risk of bleeding and subsequent complications. Recombinant activated factor VII (rFVIIa) is preferred for prevention of perioperative hemostasis due to its high efficiency, despite its short half-life (≈ 3 h) requiring frequent administration [2]. In this case, small-dose multiple rFVIIa administration effectively ensured surgical hemostatic safety with minimal postoperative drainage and no severe bleeding. Fresh frozen plasma is not the first choice for patients undergoing high-risk surgeries, due to low FVII concentration and potential infectious disease risks [5], consistent with the ineffective transfusion result in this patient. In addition, cardiac surgery in CFVIID patients presents unique hemostatic challenges. Cardiopulmonary bypass induces significant consumption of multiple coagulation factors and fibrinogen, which exacerbates the patients’ inherent bleeding tendency and further increases the risk of postoperative hemorrhage. Therefore, we administered low-dose prothrombin complex concentrate (PCC, 600 IU) and fibrinogen (2000 mg) immediately after heparin neutralization. PCC could replenish common pathway factors Ⅱ, Ⅸ and Ⅹ to amplify the hemostatic efficacy of rFVIIa, while fibrinogen could ensure the formation of stable fibrin clots. This conservative low-dose administration achieved satisfactory perioperative hemostasis while minimizing the theoretical risk of thromboembolic complications.

Although CFVIID is associated with bleeding risk, it is reported 3–4% of patients may develop thrombotic episodes (both venous and arterial) [4]. Perioperative replacement therapy is reported to be the most common trigger for thrombosis in CFVIID patients [3]. Both recombinant activated factor VII (rFVIIa) and PCC have been linked to thrombotic events. In our case, considering the conservative low-dose of PCC and the short half-life of rFVIIa, all perioperative administration theoretically had been completely metabolized by postoperative day 6 when the acute cerebral thrombosis occurred. The patient’s thrombotic event was most likely associated with delayed anticoagulation, indicating the importance of timely anticoagulation after MHV replacement in CFVIID patients. To our knowledge, reports describing anticoagulation management in CFVIID patients undergoing mechanical valve replacement are extremely limited [6]. Though these patients have elevated early postoperative bleeding risk requiring hemostasis-adjusted anticoagulation timing, anticoagulation should be initiated as early as possible once active bleeding is excluded. Initiating heparin or low molecular weight heparin bridging within 24 h after surgery should be considered to reduce thrombosis risk.

Evidence-based practice guidelines recommend lifelong vitamin K antagonist anticoagulation (Warfarin) for mechanical valve (MHV) replacement [7]. Direct oral anticoagulants are not recommended to prevent thrombosis in patients with an MHV. Warfarin works by inhibiting the synthesis of FⅡ, FVII, FⅨ and FⅩ, as well as the anticoagulant proteins C and S [8]. INR is the conventional monitoring index for warfarin, reflecting changes in FⅡ/FVII/FⅩ activity. However, for CFVIID patients with congenital FVII deficiency, baseline FVII activity is extremely low, so INR alone cannot accurately reflect the real anticoagulation effect [9]. Other indicators are needed to represent the degree of coagulation ability. There is evidence showing that not all of the clotting factors are affected equally by warfarin [10]. FVII and FⅨ are suppressed to a significantly greater degree than FII and FX, with no significant difference between the levels of FII and FX [11]. Also, there are studies have validated that monitoring based on FⅡ and FX activity (Fiix‑PT / Fiix‑NR) provides a stable and accurate measure of warfarin’s antithrombotic effect, which reduces thromboembolic events by approximately 56% compared with standard PT‑INR, without increasing bleeding risk [12]. These findings suggest that appropriate anticoagulation therapy should be based on factor activity level, and INR can only be used as a reference. It is reported that once the INR was in the range of 1.6 to 2.5, the mean FX activity was 23%, while the mean activity levels of factors II, VII, and IX remained at 35% to 45% [8]. Other studies observed a moderate inverse correlation between INR and both FII and FX activity within the usual INR therapeutic range (2.0-3.5) [13]. Considering our patient’s baseline FVII activity was far below the minimum hemostatic levels, we guided anticoagulation by FⅡ/FⅩ activity, targeting 30%-45% as the safe therapeutic range. Figure 1 (E, F) illustrates the poor correlation between the patient’s FⅡ/FⅩ activity and INR. Notably, no bleeding was observed even when INR was maintained at 6.0–8.0, confirming that INR does not accurately reflect anticoagulation intensity in CFVIID patients. Follow-up mechanical valve function indicated that this individualized FⅡ/FⅩ activity-based monitoring strategy could balance bleeding and thrombosis risks.

Conclusion

Perioperative rFVIIa replacement therapy effectively ensures hemostatic safety and avoids severe bleeding complications for CFVIID patient undergoing cardiac surgery. CFVIID patients after mechanical valve replacement are at high risk of thromboembolic complications, as demonstrated by the acute cerebral thrombosis in our case, and require lifelong warfarin anticoagulation. Anticoagulation management in CFVIID patients with mechanical valves should shift from INR-based monitoring to a coagulation factor–based strategy. Anticoagulation initiation should be carefully timed to balance hemostatic status and thrombosis risk, avoiding unnecessary delays.

Abbreviations

CFVIID

Congenital factor VII deficiency

INR

International normalized ratio

FVII

Coagulation factor VII

FII

Coagulation factor II

FV

Coagulation factor V

FIⅩ

Coagulation factor IⅩ

rFVIIa

Recombinant activated factor VII

MHV

Mechanical valve

PCC

Prothrombin complex concentrate

Author contributions

X.Luo: Formal analysis, Writing – Original Draft. X.Yang: Writing – review and editing, Methodology. T.Sun: Conceptualization, Methodology. X.Yan: Conceptualization, Writing – review and editing, Funding.All authors reviewed the manuscript.

Funding

This study was supported by grants from Xinjiang Key Laboratory of Artificial Intelligence Assisted Imaging Diagnosis Fund (XJRGZN2024001).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Ethical approval was obtained from the Ethics Committee of Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences). Written informed consent was obtained from the patient for the publication of this case report and all relevant clinical data.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.