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Perioperative Monitoring with Rotational Thromboelastometry in a Severe Hemophilia A Patient Undergoing Elective Ankle Surgery
We read with great interest the report from Tsantes et al describing the ability of rotational thromboelastometry to identify patients at high risk for bleeding, transfusion requirements, and excessive bleeding in major orthopaedic surgery, as published in a recent issue of Seminars in Thrombosis and Hemostasis. We therefore wish to report a case of hemophilia A that was successfully monitored using rotational thromboelastometry (ROTEM) in orthopaedic perioperative management during arthrodesis.
Hemophilia is an X-linked recessive inherited bleeding disorder arising from FVIII deficiency. Hemophilic patients present with multiarticular joint degeneration (hemophilic arthropathy), secondary to recurrent hemarthroses. Those patients requiring elective ankle surgery can undergo such surgery with a high expectation of success. Surgery in hemophilia patients requires a multidisciplinary approach. Standard laboratory tests, including the activated partial thromboplastin time (APTT) and the prothrombin time (PT), can only partially predict bleeding or guide hemostasis management in patients with clotting factor disorders. The optimal frequency and dose of factor replacement in the perioperative period is key to surgical success. This might be challenging to accomplish using specific FVIII assays, as these results are not usually available in real time. ROTEM analysis enables the evaluation of global clotting function and the monitoring of hemostatic treatment in near real time during the perioperative period.
Our case is of a 25-year-old patient with severe hemophilia A (0.5% FVIII activity), presenting after unilateral arthrodesis with extensive hemophilic arthropathy of the second ankle joint. The patient represented the second pregnancy of his mother, in which spontaneous delivery occurred in the 40th week of her pregnancy (birth weight: 4,000 g; length: 54 cm with postpartum complications: birth trauma due to rotation of the fetal head, fracture thigh-bone on the left, and the development of cephalohematoma). Replacement treatment with plasma-derived (pd)FVIII concentrate was administered on the 4th day after birth. In October 2000, at the age of 3 years, the patient was admitted to hospital for viral hemorrhagic enterocolitis with hemorrhagic shock and critical post-hemorrhagic anemia. Prophylaxis with pdVIII concentrate was started from 2004, when the patient was aged 7 years. Despite prophylaxis, there was recurrence of bleeding in target joints (ankles). Since August 2014, aged 17 years, there has been repeated bleeding into the left ankle with the development of hemophilic arthropathy. Since April 2018, aged 21 years, the patient has been experiencing difficulty in walking, pain in the left ankle, and worsening of the quality of life. An orthopaedist indicated ankle arthrodesis due to the advanced hemophilic arthropathy. The patient underwent comprehensive preoperative hematological examination in August 2019, aged 22 years. Standard coagulation assays (PT, APTT, thrombin time, fibrinogen activity), FVIII activity, FVIII inhibitor, and ROTEM (EXTEM, INTEM) were examined preoperatively. In ROTEM, clotting time (CT) was significantly prolonged: 492 seconds (normal range: 100–240 seconds) in INTEM (“equivalent” pathway to APTT), whereas in EXTEM (“equivalent” pathway to PT) it was normal, which indicated retardation of thrombin generation via intrinsic pathway due to FVIII deficiency. In standard coagulation assays, prolonged APTT (82 seconds; normal range: 25–36 seconds) and reduced FVIII level (0.5%; normal range: 60–150%) were observed and FVIII inhibitor was negative. Other parameters such as clot formation time, waveform amplitude 10 minutes after CT (A10), and maximum clot firmness in EXTEM and INTEM were normal ([Fig. 1]). Based on the pharmacokinetics and recommendations, we administered 30 minutes preoperatively human cell line–derived recombinant factor VIII (human-cl rhFVIII) (simoctocog alfa; Octapharma AG, Switzerland) 50 IU/kg (patient's weight: 102 kg). The surgery lasted 1.5 hours under general anesthesia without significant blood loss. All blood samples were obtained and analyzed immediately after collection. Immediately after the surgery, FVIII activity was 78% and the CT of INTEM was 255 seconds. Despite the mild abnormality observed in the follow-up INTEM immediately postoperatively, the patient had no clinical bleeding. During the first 24 hours after the surgery, the patient was administered a dose of 30 IU/kg human-cl rhFVIII every 8 hours. The FVIII activity was 89 ± 1% and CT of INTEM was 200 ± 5 seconds. On the 1st and 2nd postoperative days, the dose of human-cl rhFVIII 35 IU/kg was administered every 12 hours. FVIII activity was in the range of 76 to 66% and CT of INTEM was 174 to 181 seconds. Bleeding episodes were not observed. Therefore, we decided, based on the CT of INTEM and FVIII activity, to reduce the dose of human-cl rhFVIII to 20 IU/kg every 12 hours from 3rd to 7th postoperative days. On the 4th postoperative day was a slight prolongation of CT with INTEM (289 seconds) and APTT (48.4 seconds). The clinical course was without bleeding manifestations and with normal hemoglobin level and platelet count. During this period, FVIII activity was 52 to 76% and CT of INTEM was 82 to 174 seconds. On the 7th postoperative day, the patient was discharged home with a FVIII activity of 52% and CT of INTEM of 82 seconds. At home, the patient was administered the human-cl rhFVIII dose of 20 IU/kg every 12 hours until 10th postoperative day. From 15th postoperative day, the dose was reduced to 30 IU/kg daily. The dose of human-cl rhFVIII was 30 IU/kg every day for the ensuing 8 days, and then 20 IU/kg every day until the 25th day postoperatively. At that time, the FVIII activity was 5.7%. During intensive rehabilitation, a dose of 20 IU/kg human-cl rhFVIII was administered every day.
Arthrodesis involves orthopaedic immobilization of the affected joints. By sacrificing the range of motion of the joint, this procedure treats joint pain and intra-articular bleeding. This procedure is performed primarily on the ankle joint. In the natural course of hemophilic ankylosis, the joints appear stark on diagnostic images in the terminal stage. Hemophilic patients who have arthropathy of the ankle joint will eventually undergo surgery, which requires correction of coagulation in the perioperative and postoperative period, noting that surgery and other invasive procedures have the potential for excessive, uncontrolled bleeding in hemophilic patients.
Basic coagulation assays have been routinely used in the perioperative management of hemophilic patients, but have been found to have several limitations. Conventional coagulation assays such as the PT and APTT lack any platelet contribution and only reflect the initiation phase of coagulation. The APTT measures the time to initiation of clot formation where only 5% of total thrombin has been generated. Basic coagulation assays do not provide information regarding the rate and strength of clot formation and lysis. In addition, these tests may show discrepancies against the clinical phenotype and FVIII activity. ROTEM can perform several different assays simultaneously: intrinsic activation, extrinsic activation, and functional fibrinogen assay and permits monitoring of results in real time, including clot formation and dissolution in whole blood. Viscoelastic testing is believed to also account for the integral role of cellular and acellular elements in clot formation, which are platelets, erythrocytes, leukocytes, and coagulation factors. 
Furthermore, it has been demonstrated that the APTT-based FVIII activity does not necessarily correlate with clinical severity. In addition, the APTT and FVIII activity can be affected by other interfering proteins. Thus, ROTEM may prove to be very useful. Our results showed that CT of INTEM was mostly in normal range, but APTT was slightly prolonged while FVIII activity was in the range of 50 to 60%. Total evaluation of these assay results may facilitate the assessment and treatment of hemophilia patients in perioperative period. Adequate amount of FVIII concentrate must be available for surgery to maintain proper postoperative dosing. In the perioperative period, this can be of great importance in personalized management and, last but not least, in the efficient usage of FVIII concentrate. In one study, Zozulya et al stated that the median total dose of human-cl rhFVIII administered for major surgeries was 591 IU/kg for 7 days. In our patient, the total dose of human-cl rhFVIII periprocedurally was 490 IU/kg. That means the total consumption of FVIII concentrate in our patient was lower by 17%, compared to the median of total consumption during major surgeries in the study by Zozulya et al.
These findings suggest that a combination of standard coagulation assays with ROTEM could lead to a better understanding of hemostasis in individual hemophilia patients, which in turn might be useful for the prediction of bleeding and the design of adequate perioperative management during and after surgery. Several other publications also demonstrated that ROTEM could be useful in the management of patients with inhibitors and perioperative management.  Nevertheless, there is a need for better reproducibility and sensitivity in evaluating the role of ROTEM in such patients.
In conclusion, systematic monitoring using ROTEM offers a promising strategy for the use of FVIII concentrates in hemophilia A in the perioperative period. Currently, the emphasis is on global hemostasis tests as new ways to assess the coagulation status also in hemophilia patients. In the future, with the development of non–factor replacement therapy, monitoring of treatment using global hemostasis tests will become necessary. Nevertheless, the current experience with ROTEM for monitoring treatment in hemophiliacs is based on small studies and case reports.   Large randomized trials are necessary to validate this approach.
Article published online:
19 April 2023
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