Successful Perioperative Management of Titanium Cranioplasty in a Patient with Severe Hemophilia A

Abstract

Background: Hemophilia A is an X-linked recessive bleeding disorder associated with high risk for intracranial hemorrhage, requiring complicated neurosurgical interventions. Perioperative management is based on quick factor replacement therapy, control of hemostasis, and deciding whether surgery will be beneficial. Methods: We report the case of a 49-year-old male with severe hemophilia A who had purulent secernation via a skin fistula as a late complication of decompressive craniectomy for epidural hematoma at younger age. Results: Revision surgery was successfully managed with perioperative administration of clotting factor VIII, and the patient showed indications of titanium cranioplasty. Conclusions: A direct preoperative preparation prior to surgery in a postoperative period with controlled hemostasis has been shown to reduce hemorrhagic complications in hemophilic patients, increasing the quality of life and significant neurological complications.

1. Introduction

Hemophilia A is an X-linked recessive bleeding disorder caused by coagulation factor VIII (FVIII) deficiency [1]. The deficiency is a result of mutations of the respective clotting factor genes [2]. Hemophilia severity is classified according to factor activity level as follows: mild (6–30 IU/dL or 6–30% of normal), moderate (1–5 IU/dL or 1–5% of normal), and severe (less than 1 IU/dL or less than 1% of normal) form [1]. The prevalence of hemophilia is approximately 1 in 5617 live male births according to the US Centers for Disease Control and Prevention (CDC). The incidence of complications of hemophilia A and treatment access is about 25–40% of individuals, especially in the severe type. Hemophilic arthropathy occurs in 30–40% of patients, inhibitors develop in 25–30% of patients, and about 10% of patients with severe hemophilia have intracranial bleeding [3,4]. Initial laboratory results demonstrate normal platelet count, normal prothrombin time (PT), and prolonged activated partial thromboplastin time (APTT) [1]. Hemophilic patients present with spontaneous and recurrent bleeding into muscles and joints, multiarticular joint degeneration (hemophilic arthropathy), and prolonged bleeding times after minor traumas. In severe hemophilia, internal bleeding can be found in multiple organ systems. One of the worst and life-threatening complications is intracranial hemorrhage, which can result in significant morbidity and mortality [1,5,6]. The severity of bleeding is generally correlated with the clotting factor level. In the differential diagnosis of inherited bleeding disorders, we have to consider similar rarer causes such as hemophilia B [2].

The most common hemophilia treatment is the replacement of the missing coagulation factor to stop (episodic or on-demand therapy) or to prevent (prophylaxis) bleeding episodes [7,8,9]. The recommended regular prophylactic factor replacement should maintain circulating factor levels of >1 IU/dL (1%), which has been shown to be associated with a substantial reduction in bleeding and related complications and, consequently, with an improvement in the quality of life and life expectancy [10,11].

Surgery and the perioperative period in hemophilic patients require a multidisciplinary approach. Surgical interventions or invasive procedures are based on the optimal frequency and dose of factor replacement. New strategies and advances in available therapies, such as the use of long-term scheduled factor replacement, which enables the extension of the dosing interval, have improved both the lifespan and quality of life. This report emphasizes the need for standardized long-term patient care to ensure a decreasing rate of fatal bleeding manifestations [5,6,12].

2. Case Report

We present the case of a 49-year-old male with severe hemophilia A (less than 1% FVIII activity) undergoing on-demand FVIII treatment, who was monitored only at the regional outpatient department and not in a national hemophilic center. He had undergone several cranial surgeries. Initially, the patient suffered from severe traumatic brain injury requiring left-sided decompressive craniectomy and evacuation of extensive epidural hematoma in the left fronto-temporo-parietal region. Primary emergency surgery was performed in 2000 at the age of 25 years in a peripheral hospital, and there was no further information regarding preoperative preparation or specific management in the perioperative period. Calvarian reconstruction was primarily performed with bone cement Palacos the same year, and there was no postoperative complication reported. However, the brain trauma resulted in right-sided residual hemiparesis and expressive aphasia worsening of the quality of life. The patient also had repeated bleeding in various joints including the knees, ankles, metacarpophalangeal joints, left elbow, and left shoulder. In 2015, he was admitted to a hospital due to bleeding into the left ankle requiring osteotomy and arthrodesis. In June 2018, there was a development of advanced hemophilic arthropathy and a need for total knee arthroplasty.

In March 2020, the patient was admitted to our hospital with a history of headaches and purulent secernation via a skin fistula formed in at the surgical site, being highly suspicious from a deep infection. Since admission, there was close cooperation between the neurosurgeon and hematologist. A contrast-enhanced brain CT scan revealed an extensive epidural empyema in a cranioplasty site that measured 12.3 × 2.2 × 8.2 cm. The patient‘s FVIII activity was 0.008 IU, hemoglobin was 14.0 g/dL, platelets were 184 × 10⁹/μL, prothrombin time (PT) was 109%, and the activated partial thromboplastin time (APTT) was prolonged at 102.9 s (

Table 1. Preoperative laboratory results.

Laboratory Parameter	Result	Reference Range
Hemoglobin	14.0 g/dL	14–17 g/dL
RBC Count	4.75 × 106/μL	4.5–6.0 × 106/μL
Packed Cell Volume	43.0%	39–54%
Mean Corpuscular Volume	89.7 fl	82–98 fl
Mean Corpuscular Hemoglobin	29.4 pg	26–34 pg
MCHC	33 g/dL	31–36 g/dL
RDW	13.8%	11.6–14.5%
Platelet	184 × 109/μL	180–400 × 109/μL
MPV	8.5 fl	7.5–12.0
Total Leukocyte Count	5.3 × 103/μL	3.9–10.0 × 103/μL
Neutrophils	45.5%	45–72%
Lymphocytes	42.2%	25–46%
Monocytes	8.6%	2–10%
Eosinophils	3.1%	1–5%
Fbg	3.32 g/L	1.80–4.20 g/L
PT	109%	75–120%
INR	0.95 s	0.8–1.2 s
TT	12.4 s	14–18 s
APTT	102.9 s	25–36 s
Control	35.4 s	0.85–1.25 s
FVIII	0.008 IU/mL	0.600–1.500 IU/mL
ATIII	102.6%	80–130%
Fe	15.0 μmol/L	12.5–32.2 μmol/L
VB12	750 pg/mL	250–950 pg/mL

).

Revision surgery was indicated after appropriate preoperative preparation involving an intravenous administration of 60 IU/kg (patient’s weight: 75 kg) of plasma-derived FVIII (pd-FVIII) 30 min prior to surgery. The operating time was 59 min, while excessive or prolonged bleeding was not encountered. A significant amount of infected mass was evacuated, and the original Palacos plate was removed (Figure 1 and Figure 2).

The postoperative period was uneventful, with ongoing therapy and dose reduction in pd-FVIII to 40 IU/kg q8h. On the second postoperative day, the dose was reduced to 25 IU/kg q8h, on the fourth day to 25 IU/kg q12h, and on the tenth day to 20 IU/kg q12h. The patient was discharged on the 18th postoperative day. Follow-up was achieved in three months with no complications reported. Monitoring of FVIII activity and APTT in the perioperative period is shown in Scheme 1A,B.

Considering the patient’s recovery and appropriate local findings, a secondary reconstructive surgery was indicated with a three-month delay. Due to previous infection of the Palacos plate, a custom-made titanium implant known for a low infection rate compared to other widely used synthetic material was opted for [13,14,15,16,17]. After obtaining patient-specific data based on a native brain CT scan, an individualized titanium prosthesis was manufactured.

In June 2020, the patient was operated on with a total operative time of 157 min after a preoperative intravenous administration of 60 IU/kg of pd-FVIII. Titanium cranioplasty was performed in a standard manner—an incision was made using a pre-existing scar resulting from previous surgeries and, consequently, the identification of bony rims of the defect was performed. Due to the multiple previous interventions, severe fibrosis was present, involving mostly temporal muscle. During soft tissue dissection, an iatrogenic dural tear arose with the need for its fixation by suturing. The titanium prosthesis was then fixed to the surrounding calvarian bones using multiple micro-screws (Figure 3). Tissue waste and the retraction of skin and subcutaneous tissue in the parietooccipital region as a result of previous interventions led to difficulties while performing skin closure, and a secondary skin incision had to be made, forming a rotational skin flap enabling mobilization of the skin and proper wound closure. Finally, a drainage tube was inserted in the subgaleal layer.

No complications were encountered in the early postoperative period. After the surgical intervention, the patient was given an intravenous administration of tranexamic acid at a dosage of 500 mg q6h and vitamin K at a dosage of 10 mg q12h for three days following surgery. The draining tube was removed on the fifth postoperative day due to diminished production. However, there was no sign of excessive neither abnormal bleeding in terms of length nor amount, as daily production varied from 20 mL to 90 mL of blood. Blood count, coagulation parameters, and antithrombin III levels were monitored daily during hospital stay, with an adjustment of the dose of pd-FVIII. After surgery, pd-FVIII was administered at a dosage of 40 IU/kg q8h. On the second postoperative day, the dose was reduced to 25 IU/kg q8h and then every other day, a further reduction was implemented—20 IU/kg q8h and 20 IU/kg q12h—with a final dose of 20 IU/kg once daily. One week after cranioplasty, a control brain CT scan was performed, showing no signs of intracranial hemorrhage following surgery (Figure 4).

The patient was discharged on the 15th postoperative day with a postoperative check-up three months after the cranioplasty, and treatment continued with administration of a prophylactic dose of 25 IU/kg of pd-FVIII three times a week. Another follow-up was performed three months after surgery, one year after surgery, and two years after surgery, with no need for further observation. The postoperative course was completely uneventful and there was no neurologic deficit except for mild right-sided hemiparesis, which was already present before cranioplasty.

3. Discussion

Hemophilia A may be associated with life-threatening spontaneous intracranial hemorrhage, which requires prompt recognition and management.

Our patient, who was undergoing on-demand therapy, had a history of headaches and purulent secernation via a skin fistula formed at a surgical site resulting from a late complication of decompressive craniectomy for epidural hematoma at a younger age. He was at risk of permanent neurological deficits. Decompressive craniectomy, prior to the onset of significant neurological complications, can be lifesaving in patients with uncal herniation by reversing secondary ischemia due to refractory intracranial hypertension [1]. He was recommended for titanium cranioplasty and was given an intravenous administration of pd-FVIII in perioperative management, while hemostasis was strongly monitored. No significant intraoperative or postoperative bleeding was observed during this type of procedure, concluding that good control of hemostasis was achieved. After surgery, the patient continued with prophylaxis and has not had any other bleeding complications reported to this day.

When head trauma or early symptoms occur in hemophilia patients, it is important to immediately raise the patient’s FVIII level and perform the CT or MRI brain scan. If bleeding is confirmed, we have to maintain the FVIII level for 10–14 days during hospitalization. Intracranial hemorrhage may be an indication for prolonged secondary prophylaxis lasting at least 3–6 months, especially if patients have high risk of recurrence [4].

Surgical interventions and other invasive procedures mean particular risk to hemophilic patients due to an increased risk of perioperative hemorrhagic events during prolonged period of bleeding compared to patients with normal levels of FVIII. However, they can be performed safely with careful perioperative management, adequate laboratory support, appropriate hemostasis with sufficient quantities of FVIII and other supportive therapies during and after surgery, and optimal postoperative rehabilitation. According to 2020 World Federation of Hemophilia (WFH) guidelines, the recommended peak FVIII level for intracranial procedures is 0.8–1.0 IU/mL [18]. We achieved higher levels of FVIII (1.0–1.7 IU/mL) in te perioperative period because of the clinical phenotype, history of complications, severity of surgery, and high risk of bleeding. Hemophilia patients pose a challenge, especially to neurosurgeons. There are well-described techniques reducing the risk of bleeding, namely clotting factor substitution and hemodynamic maintenance. Specific attention must be paid to hemostasis during the intraoperative period [1,19]. The negative effect of raised intracranial pressure is known to be an important predictor of mortality; hence, the normal value should be sustained [20].

Guidelines issued by the World Federation of Hemophilia specify the use of FVIII concentrate, cryoprecipitate, fresh frozen plasma (FFP), desmopressin, tranexamic acid, and epsilon aminocaproic acid as the preferred products for the management of hemophilia and bleeding manifestations [1]. Recent major treatment advances in hemophilia include the development of new recombinant extended half-life (EHL) FVIII (EHL-rFVIII) products with improved pharmacokinetic properties, with the aim of reducing the burden of prophylaxis. Several studies have demonstrated that different EHL-rFVIII are effective and well tolerated for the prevention and treatment of bleeding during major surgeries, as well as for other minor invasive procedures [21]. We also plan to use EHL-rFVIII in our patient to reduce the number of injections and to ensure a safe and sufficient level of FVIII. The development of non-factor replacement therapies and gene therapies for hemophilia has also advanced and opened new strategies in hemophilia treatment. Hemophilic patients must have access to safe and effective treatment of any spontaneous, breakthrough, or trauma-related bleeding, including prevention [18,22].

Prophylactic therapy should be the goal of therapy to prevent bleeding and joint destruction and to preserve normal musculoskeletal function. All forms of prophylaxis provide superior benefits over on-demand therapy [4]. Conventional high-dose and intermediate-dose prophylaxis should be initiated early in life, as they are associated with over a 90% reduction in joint bleedings and a significant reduction in joint deterioration, degenerative diseases, and other hemorrhagic complications [18].

4. Conclusions

It is important to note that prophylaxis for hemophilic patients reduces the risk of severe bleeding and related complications, which improves the overall quality of life. These patients should always be monitored at national hemophilic centers, and their preoperative management requires multidisciplinary approach. Surgical procedures are well documented in the literature; however, there is a lack of evidence with regard to specific neurosurgical procedures. This was the first case of titanium cranioplasty performed in a patient with hemophilia in our department with an excellent result. According to our case, a direct preoperative preparation consisting of FVIII administration prior to surgery in a postoperative period with thorough hemostasis has the potential to reduce significant hemorrhaging in patients with hemophilia.