Abstract
Purpose of Review
Hemophilia is a rare, typically inherited, condition where a specific clotting factor is reduced or even near absent. Patients with hemophilia who present for an invasive procedure, whether elective or urgent, are at increased risk of bleeding intraoperatively and postoperatively.
Recent Findings
Ten years ago, most patients with hemophilia with moderate or severe disease were treated with standard half-life factor replacement therapy, either prophylactic or on-demand. Now, patients may present on extended half-life factor therapy, or on a non-factor hemostatic therapy, or as a recipient of gene therapy. Further complicating the challenge of caring for these patients is that most of these new modalities will typically require supplementation with traditional factor therapy when surgery is required.
Summary
An in-depth understanding of all the potential treatment options for hemophilia is essential when anesthesiologists care for a patient with hemophilia. And there are several perioperative arenas (neuraxial procedures, point-of-care coagulation tests such as ROTEM or TEG, and cardiopulmonary bypass) where hemophilia creates unique considerations.
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Introduction
The current treatment landscape for hemophilia would have been essentially unrecognizable twenty years ago. Longer acting clotting factors, antibodies that mimic clotting factors, and gene therapy advances have given patients new options beyond the standard intravenous clotting replacement therapy. Many of these new therapies are unfamiliar to anesthesiologists, yet they all have important considerations when an invasive procedure or surgery is needed in a patient with hemophilia. Below we present a review of standard perioperative care in hemophilia, an update on new treatments, and then address several unique considerations important to anesthesiologists, including neuraxial procedures, point-of-care coagulation tests, and cardiopulmonary bypass (CPB).
Background
Historical Background
Treatment for hemophilia became possible after analysis of cryoprecipitate in 1964, followed by the introduction of lyophilized factor concentrates in the 1970s[1]. With prophylactic factor infusions, as well as Factor VIII (FVIII) augmentation with desmopressin (ddAVP), surgery in people with hemophilia (PWH) became feasible without excess bleeding risk [2, 3]. Although contamination of concentrates with hepatitis B and C was common, it was viewed as an acceptable consequence given the significant benefits of concentrate. The same, however, could not be said about human-immunodeficiency virus (HIV) contamination, which claimed the life of the first hemophilia patient in 1982 [4]. As many as 80% of PWH in the US and Europe eventually became infected with HIV, with thousands later dying [5]. The development of purification and viral inactivation methods in the 1990s halted the transmission of known viruses [2, 5]. Additionally, recombinant factor development in the early 1990s made concentrate widely available and paved the way for widespread prophylactic and on-demand infusions [4].
Conventional Treatment
Clotting factor concentrates (CFC), the mainstay for hemophilia treatment, can be divided into plasma-derived and recombinant products. The World Federation of Hemophilia (WFH) guidelines do not currently offer a recommendation favoring either option [6•]. CFC purity is measured as the concentration of factor, or international units (IU) per mg protein, with high purity considered above 50 IU [7]. Goals for factor replacement focus on improving from the severe phenotype, defined as < 1 IU/dL (1% activity) FVIII/FIX, to moderate (1–5 IU/dL) or mild (> 5 IU/dL). Studies have shown an association between the amount of time spent with severe FVIII and FIX levels and increased total bleeding [8, 9]. For hemophilia A dosing, one can typically expect a 2% increase in FVIII activity for every IU per kg. For hemophilia B, a 0.8% to 1% increase in FIX activity can be expected for every IU per kg [10•].
Inhibitors and Bypassing Agents
Inhibitors are autoantibodies that develop as a response to infused CFC, and subsequently reduce the effect of circulating factor. Risk factors for inhibitor development include genetic polymorphisms, CFC exposure burden, age of prophylaxis initiation, trauma, and infection [11]. The greatest risk of inhibitor development is within the first 20–75 exposure days [12, 13]. There is no consensus on the risk of inhibitor development based on factor replacement type [14, 15]. The Bethesda assay is used to screen for inhibitors. Patients are classified as either low-titer, which is < 5 Bethesda units (BU), or high-titer (> 5 BU). Patients with low titers can be treated with standard CFC but must be frequently monitored for conversion to higher titers. Bypassing agents allow for the treatment of acute bleeding and for bleeding prophylaxis in patients with high-titer inhibitors. Current agents include activated prothrombin complex concentrate (aPCC) and recombinant Factor VIIa (rFVIIa). Hemostatic response to these agents requires clinical judgment due to a lack of available quantitative monitoring in the setting of bypassing agents [11, 16].
New Treatment Modalities
Long-Acting Agents
Extended half-life (EHL) CFCs of recombinant Factor VIII (rFVIII) and recombinant Factor IX (rFIX) have been developed for both hemophilia A and B in response to the logistical barriers of standard half-life (SHL) factor administration. Benefits to patients include reduced treatment burden with less frequent infusions, improved treatment adherence, and subsequently improved patient satisfaction [17, 18]. Methods of EHL generation involve various forms of factor molecule protein modification: fusion to either immunoglobulin (Fc) domains or albumin to reduce degradation and promote recirculation, linkage of non-immunogenic polyethylene glycol (PEG) chains to block clearance receptors, and direct modification of a factor’s primary protein sequence to improve stability [19]. Effective half-lives of EHL products are variable for both hemophilia subtypes based on concentrate type and patient age; half-lives increase linearly with age throughout life for rFVIII and up to age 30 for rFIX [20]. Prior retrospective studies have generally found equivocal rates of inhibitor development between EHL and plasma derived SHL treatments, although this understanding may be shifting toward recombinant therapies posing higher risk in certain patient populations [14, 21]. Inhibitor development rates do not appear to be increased, however, within the perioperative window, when these treatments are administered at greater frequency [22].
For an agent to be reasonably classified as EHL, it must maintain factor levels within safe trough concentrations over longer dosing intervals versus SHL products. Unfortunately, no strict guidelines exist outlining thresholds for classifying SHL versus EHL [6•]. Studies have demonstrated a meaningful improvement in treatment burden when rFVIII half-lives are greater than or equal to 1.3 times longer than standard plasma derived factors. Historically, EHL studies strive for factor trough levels above 1 IU/dL (preventing the severe hemophilia phenotype) and dosing intervals of twice weekly for rFVIII and weekly to biweekly for rFIX for bleed prophylaxis [23]. Unlike rFIX, the half-lives of rFVIII products are generally biologically limited by the half-life of vWF because these molecules form a complex which facilitates circulation [24]. However, Altuviiio® (Efanesoctocog alfa, Sanofi) decouples rFVIII from VWF, permitting once-weekly dosing for bleed prophylaxis [25]. Overall, there are nine total EHL formulations for hemophilia A and B approved by the U.S. Food and Drug Administration (FDA) [26]. Their characteristics are summarized in Table 1.
Ensuring adequate hemostasis during surgery is a significant challenge for PWH, with factor replacement therapies remaining standard of care [6•]. Infusions of SHL clotting factors have been historically utilized perioperatively to maintain consistent protective factor trough levels. Studies have demonstrated that the benefits of SHL infusions over SHL bolus doses include reduced infection rates and improved wound healing [6•, 36]. Recent studies on EHL therapies have demonstrated an equivalent ability to control bleeding and promote healing without the need for continuous infusions in both major and minor surgeries, with variability in dosing dependent on patient characteristics and surgery type. Surgery data from patients enrolled in Phase III clinical trials for rFVIIIFc and rFIXFc showed patients receiving major and minor surgery had hemostatic response consistent with SHL therapies. Additionally, the EHL cohort experienced equivalent hospital stays and comparable or lower transfusion needs [22]. PEGylated rFVIII, PEGylated rFIX, and albumin-bound rFIX demonstrated similar efficacy in major and minor surgeries toward controlling bleeding and supporting wound healing [27, 31, 32, 34, 35]. Case reports have also shown no bleeding complications following intracranial neurosurgery in PWH receiving EHL concentrate perioperatively [37]. Table 1 summarizes dosing guidelines of all FDA approved EHL concentrates, where available.
Overall, EHL therapies behave similarly across concentrate types and within factor type for managing surgical bleeding and are not associated with increased risk of thromboembolic events or inhibitor formation versus SHL CFCs [38]. EHL CFCs may require a higher initial dose or second infusion in children undergoing surgery; postoperative levels should be measured daily to adapt treatment appropriately. Some studies recommend preoperative pharmacokinetics testing to determine patient specific half-life and more accurately determine perioperative dosing intervals, although this is not universal [38]. Lastly, there is limited data regarding the stability of EHLs when compounded for continuous infusion, so currently only SHLs are compounded for continuous infusion.
Non-factor Hemostatic Therapies
Nonfactor therapies aim to correct defects in the coagulation process without replacing the missing protein. Benefits of these agents include less frequent dosing than even EHL CFCs, subcutaneous rather than intravenous administration, and preserved function in the presence of inhibitors [39]. Broadly, these therapies function by either mimicking existing factor interactions without resembling factor structure or downregulation of natural coagulation inhibitors to rebalance hemostasis. Currently, just one of these therapies (emicizumab) is approved by the FDA and only for use in bleed prophylaxis. All other therapies are either awaiting approval (fitusiran) or are currently undergoing Phase II/III studies (concizumab, marstacimab, serpinPC, denecimig) [40]. The WFH does not currently recommend emicizumab monotherapy for treating acute bleeding episodes or managing perioperative bleeding [6•]. Thus, the most likely scenario for an anesthesiologist to encounter these therapies in the perioperative space is as a home medication for general bleed prophylaxis in PWH who present for surgery.
Emicizumab is a recombinant bispecific monoclonal antibody for treatment of hemophilia A that functionally serves as an analogue to activated FVIII by bridging activated factor IX and factor X [41]. For bleeding prophylaxis, dosing can be extended from once weekly to once monthly administration due to the biologic’s half-life of roughly 30 days [42]. Phase III trials demonstrated increased risk of hypercoagulability with co-administration of aPCC, with thromboembolism events ranging from 0.5% to 5.4% when patients received at least one dose of aPCC [42]. Thrombotic events improved following aPCC cessation and without anticoagulation therapy. Hypercoagulable sequelae did not occur when high concentrations of rFVIII were co-administered [41]. No thrombotic events occurred in subsequent trials with emicizumab when aPCC was dosed at lower than 100 IU/kg/day [41]. Similar to the pharmacokinetics of clotting factors, pediatric patients tend to clear emicizumab at a faster rate than adults [42].
Emicizumab interferes with conventional laboratory coagulation monitoring assays that are dependent on FVIII, including ACT, aPTT, and one-stage FVIII activity assays [42, 43]. This interference can overestimate its hemostatic potential, yielding seemingly safe coagulation parameters at subtherapeutic levels. As a result of emicizumab’s long half-life, effects on these assays may persist for up to 6 months from the last dose [43]. Non-aPTT based assays such as viscoelastic testing or thrombin generation assays (TGA) are not affected and can accurately measure coagulation intraoperatively [44]. FVIII activity in the presence of emicizumab can only be measured using non-human-component derived chromogenic substrate assays (CSA). Bovine FVIII CSA is currently the easiest method to provide accurate measurement of infused or endogenous FVIII irrespective of emicizumab [43]. No reversal agent exists which targets emicizumab.
Early data on the perioperative management of patients on emicizumab demonstrate appropriate ability to control bleeding with maintenance of patient safety [45•]. The largest summary to date of the HAVEN studies analyzed 215 minor and 18 major surgeries in patients on emicizumab for prophylaxis. For the 66% of minor procedures that did not utilize additional prophylactic factor concentrates, 86% did not develop postoperative bleeds with emicizumab alone. Major surgeries were generally managed with rFVIIa or infusions of CFCs, with 80% associated with no intraoperative or postoperative bleeds [46]. No thrombotic events, deaths, or inhibitor development occurred in any patient during the perioperative window. In other case reports, adequate hemostasis was achieved in patients undergoing major orthopedic surgeries [47] and coronary artery bypass graft (CABG) with CPB [48]. The decision to pursue additional hemostatic support in all studies was left to the discretion of treating physicians, with no standard yet developed for choice and dosing of these agents to ensure maximal safety and efficacy.
Fitusiran will likely be the next nonfactor hemostatic agent on the market, having completed Phase III trials for general bleed prophylaxis [39]. Fitusiran is a small interfering ribonucleic acid (siRNA) designed to rebalance homeostasis by reducing antithrombin synthesis in hepatocytes [49]. This non-factor approach administered via monthly subcutaneous injection has demonstrated efficacy at reducing bleeding frequency in both hemophilia A and B patients with and without inhibitors. Notably, clinical trials were briefly put on hold when a patient developed fatal sinus thrombosis when receiving high dose FVIII concurrently with fitusiran to treat breakthrough bleeding [50]. Reversal of fitusiran is possible with the administration of antithrombin. Data regarding the perioperative use of fitusiran is limited, with a single report demonstrating five surgeries ranging from dental extraction to thoracotomy where bleeding was adequately controlled on a combination of fitusiran, rFVIIa, varying amounts of FVIII peri- and post-operatively, and no thromboprophylaxis [51].
Gene Therapy
In the quest to provide patients with the ability to produce their own functional clotting factors, gene therapy is a promising development toward a long-term treatment for PWH. In this form of gene therapy, an adeno-associated virus (AAV) vector is used to deliver deoxyribonucleic acid (DNA) containing the target gene into the nucleus of host cells without extensive integration into the host’s genome [52].
Initial work targeted the smaller FIX gene F9, implicated in hemophilia B [53]. Following success in murine and canine models, initial human trials attempted to introduce an AAV vector containing the gene encoding FIX into the skeletal muscle of adults with severe hemophilia B[54]. Unfortunately, the transduced muscle cells were unable to produce therapeutic levels of circulating FIX [55, 56]. Subsequent trials involving the transduction of hepatocytes produced non-sustained elevations of FIX to therapeutic levels for a period of eight weeks [57]. A change in vector type from AAV2 to AAV8 proved less immunogenic and produced sustained elevations in circulating FIX to 2–11% of normal levels over 6 to 16 months in a subsequent trial [58]. Further improvements in the degree of FIX expression came with the use of the FIX-Padua variant gene, a spontaneous gain-of-function mutation initially discovered in a thrombophilic family [59, 60].
The HOPE-B trial was the first phase III clinical trial of gene therapy for hemophilia B. The investigators administered an infusion of AAV serotype 5 (AAV5) vector expressing the FIX-Padua variant (etranancogene dezaparvovec) to men with moderately severe or severe hemophilia B with resultant increase in FIX activity by 34.8% and a significant decrease in the annualized bleeding rates of participants at 18 months [61]. Subsequently, etranacogene dezaparvovec was approved by the FDA in 2022 as a one-time IV infusion under the brand name Hemgenix® (CSL Behring) for the treatment of adult patients with hemophilia B who “currently use factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes” [62]. Patients with FIX inhibitors and children are not currently eligible for treatment [62].
Building off this work in hemophilia B, in 2017 a dose-escalation Phase I-II trial using a AAV5 vector encoding a B-domain-deleted human factor VIII (valoctocogene roxaparvovec) for the treatment of hemophilia A demonstrated normalized FVIII levels and decreased bleeding events at one year post-injection in the high-dose group [63]. Analogous to the HOPE-B trial, the GENEr8-1 phase III clinical trial found that gene therapy with valoctocogene roxaparvovec in men with severe hemophilia A led to an increase in FVIII activity to a mean of 41.9 IU/dL (up from < 1 IU/dL pre-infusion) and a significant decrease in bleeding events at 48 to 52 weeks [64]. Follow up two years post-infusion demonstrated ongoing FVIII activity and a reduction in bleeding events, with models suggesting the FVIII activity would be consistent with a mild hemophilia A phenotype at five years post-infusion [65]. Of note, neither trial had any severe treatment-related adverse events, and the most common event was elevation of transaminases, which was treated with corticosteroid therapy and resolved in most patients. Shortly thereafter, the FDA approved valoctocogene roxaparvovec under the brand name Roctavian™ (BioMarin) as a one-time infusion for the treatment of adults with severe hemophilia A. To be eligible, patients must test negative for both FVIII inhibitor and antibodies against AAV5 [66].
Case reports of general and orthopedic surgeries performed on hemophilia A and B patients post-gene therapy demonstrated the FIX and FVIII activity post-infusion was sufficient to provide normal hemostasis without the need for additional factor supplementation [67, 68]. A case report of a patient with hemophilia A who had received gene therapy prior to undergoing on-pump CABG demonstrated a reduction in the required dose of FVIII replacement compared to patients with hemophilia A who had not received gene therapy [69].
This new treatment modality offers much promise. A one-time infusion can result in a sustained increase in factor activity levels. Essentially, severe or moderately severe disease can be rendered mild. Patients are liberated from prophylaxis but will likely still need additional treatment for invasive procedures and/or breakthrough bleeds.
Perioperative Care
Preoperative planning for patients with hemophilia should be a multidisciplinary undertaking, involving not only the anesthesiologist, but surgeons, hematologists, experienced nurses, physiotherapists, dentists, pharmacists, social workers and a multidisciplinary coordinator. The WFH recommends undergoing surgery at, or in consultation with, designated hemophilia treatment centers, where such multidisciplinary teams are already established. The WFH guidelines further recommend that operating room support conditions be optimized when patients with hemophilia undergo surgery. To this end, the guidelines suggest that surgeries should be scheduled early in the day and early in the week for optimal laboratory and blood bank support, adequate quantities of factor concentrate should be stocked, and ideally anesthesia providers should be experienced in the care of bleeding disorders [6•].
Hemophilia is marked by excessive bleeding response to trauma, with common bleeding locations including intramuscular, intraarticular, mucosal, and epidermal [4, 6•, 9]. Thus, some anesthesiologists advocate for the avoidance of succinylcholine due to the theoretical risk of muscle fasciculations worsening hemarthroses and intramuscular hematomas [70]. Airway manipulation and intubation represent high-risk periods for mucosal trauma causing significant bleeding. To decrease this risk, thorough lubrication of all airway equipment, consideration of video laryngoscopy, caution with placement of temperature probes, and complete avoidance of nasal intubation have been advised. Additional care and extra padding of joints and especially pressure points should be used during surgical positioning due to both the mobility limitations imposed by prior hemarthroses, most commonly occurring in the ankles, knees, and elbows, and the risk of provoking intramuscular hematomas via pressure injury [6•, 70,71,72].
Intraoperative and postoperative VTE prophylaxis is routine for many invasive surgeries given the associated immobility and post-surgical inflammatory state. While PWH are generally considered to be at low risk for VTE due to their inherent coagulopathy, the risk of VTE can increase in the postoperative setting if excess factor replacement is administered and/or additional blood products (platelets, cryoprecipitate, fresh frozen plasma) are transfused. There is no evidence-based consensus regarding post-surgical VTE prophylaxis. The WFH primarily recommends the use of mechanical thromboprophylaxis, such as compression devices, due to the lack of associated bleeding risk [6•]. Early mobilization after surgery and intensive physiotherapy treatment have also been suggested [6•]. While routine pharmacologic thromboprophylaxis is not recommended, for PWH in which the risk of VTE is deemed to outweigh the risk of uncontrolled bleeding, the WFH recommends pharmacologic VTE prophylaxis only after hemostatic control has first been achieved with factor replacement therapy. The WFH further recommends against the use of pharmacologic prophylaxis in patients with inhibitors [6•].
All patients with and carriers of hemophilia should undergo preoperative screening that includes current factor and inhibitor levels. For patients with mild hemophilia A, a preoperative ddAVP test can help predict response to intraoperative ddAVP, but generally FVIII levels rise three- to six-fold [73, 74]. The WFH guidelines detail varying practice patterns, which will be explored further below and in Table 2. Higher- and lower-dose practice patterns are informed by resource availability, with lower-dose protocols requiring closer monitoring to ensure control of bleeding. In brief, for hemophilia A, higher-dose practice patterns aim for peak FVIII levels of 80–100 IU/dL initially for major surgery and 50–80 IU/dL initially for minor surgery. For lower-dose practice patterns, peak FVIII levels target 60–80 IU/dL initially for major surgery and 40–80 IU/dL for minor surgery. For hemophilia B: On the higher-dose practice patterns, peak FIX levels are 60–80 IU/dL initially for major surgery and 50–70 IU/dL initially for minor surgery. For lower-dose practice patterns, peak FIX levels are 50–80 IU/dL initially for major surgery and 40–80 IU/dL for minor surgery [11]. Maintenance of peak factor levels as well as clinical evaluation of estimated blood loss serve as goals to guide intraoperative therapy. Excellent and good surgical hemostasis are defined as intraoperative blood loss within 10% and between 10 to 25%, respectively, of expected blood loss by patients without hemophilia undergoing similar procedures [6•].
Continuous SHL FVIII infusion has been shown to be more effective than boluses for decreasing perioperative bleeding and decreasing overall factor requirements [75, 76]. Postoperatively, WFH Guidelines suggest maintaining high peak factor activity levels for postoperative days 1–3 and then decreasing factor level goals thereafter [6•]. The duration and intensity of factor support perioperatively depend on many factors, including the type of surgery (and thus, the bleeding risk), provider discretion regarding intensity of factor dose and frequency postoperatively, presence of inhibitors, etc. As outlined in Table 2, treatment guidelines differ between major and minor surgery. However, the WFH guidelines rather ambiguously define major surgery as “one that requires hemostatic support for periods exceeding five consecutive days” [6•]. Clinician judgement is therefore required to differentiate major and minor surgeries based on bleeding risk, with risk including factors such as likelihood of a bleed, volume of blood loss, and sequelae of peri or post-operative bleeding based on location of surgery.
In patients with hemophilia A, the required dose of CFC (in IU) to raise FVIII to the desired level (in IU/dL) is calculated by the following formula:
Typically, in the absence of inhibitors, for every 1 IU/kg of FVIII concentrate, FVIII activity will increase by 2 IU/dL.
In patients with hemophilia B, the required dose of CFC (in IU) to raise FIX to the desired level (in IU/dL) is calculated by the following formula:
Typically, in the absence of inhibitors, for every 1 IU/kg of FIX concentrate, FIX activity will increase by 0.8 IU/dL to 1 IU/dL. Peak factor activity should be measured 15–30 min following administration to confirm the desired effect has been achieved, most commonly using a one-stage clotting assay [6•, 10•]. rFVIII and rFIX may require alternative laboratory testing (see Table 1). Dosing and administration guidelines should always be confirmed with the package inserts for each specific CFC or based on pharmacokinetic data specific to the patient if available or already known.
In the presence of inhibitor titers greater than 5 BU, CFC treatment is ineffective and alternative bypassing agents must be used for hemostasis. aPCC and rFVIIa are the two bypassing agents approved for the treatment of bleeding in patients with high inhibitor levels. Both can be used in hemophilia A, but only rFVIIa can be used in hemophilia B [6•].
Additional Considerations
Symptomatic Female Carriers
While the most severe forms of hemophilia typically affect males, females with an abnormal copy of FVIII or FIX, deemed “carriers”, can also demonstrate mild, moderate, or even severe hemophilia symptoms depending on the lyonization of their X chromosomes and/or the presence of a second coagulation defect. All known or potential carriers of hemophilia should undergo factor level testing prior to major procedures, surgery, or pregnancy. Carriers of hemophilia who are found to have low factor levels should be treated and managed the same as males with hemophilia [6•].
Unique to carriers, however, is the management of pregnancy, labor, delivery, and the postpartum period. Ideally, carriers of hemophilia should deliver in a hospital with access to the same resources discussed previously for PWH undergoing surgery. Due to the high bleeding risk associated with delivery, pregnant carriers of hemophilia should undergo factor testing in the third trimester of pregnancy regardless of their baseline bleeding phenotype. FVIII levels increase in the early stages of pregnancy before later normalizing, while FIX levels do not typically change. Factor levels should be maintained above 50 IU/dL for labor and delivery and then sustained at this level for at least 3 days after vaginal delivery and at least 5 days after a cesarean delivery. Instrumented delivery should be avoided [6•].
Neuraxial Anesthesia
Neuraxial anesthesia techniques provide many benefits to patients, anesthesiologists, and surgeons including shorter hospital stays, reduced 30-day mortality, and decreased morbidity [77, 78]. There are limited data to guide the use of neuraxial techniques and manage the accompanying risk of bleeding in patients with hemophilia. There are currently no anesthesia consensus guidelines specifying a clotting factor threshold prior to neuraxial anesthesia, however guidelines based upon expert opinion from hematological societies recommend FVIII and FIX levels should be > 50 IU/dL prior to neuraxial techniques in PWH [79,80,81]. The limited evidence available from case studies and case series supports this recommendation, encouraging factor supplementation as necessary to achieve this goal [81,82,83]. Similarly, in pregnant carriers of hemophilia, factor levels should be maintained above 50 IU/dL prior to undergoing neuraxial anesthesia for labor and delivery [6•]. The risk of developing either a spinal or epidural hematoma is higher in epidural anesthesia versus spinal anesthesia in the general population [84]. Thus, some experts recommend removal of the catheter as soon as possible while maintaining factor levels, including troughs, above 50 IU/dLfor the duration of catheter insertion and up to 24 h after removal [82, 85].
Point-of-Care Coagulation Testing
The intraoperative monitoring of hemophilia requires a multi-pronged approach, involving both laboratory assays and point-of-care testing [10•]. FVIII and FIX activity are traditionally measured via either a one-stage clotting assay or a two-stage chromogenic assay, both of which may require hours before resulting [86]. Viscoelastic coagulation tests, such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM), can provide point-of-care information on the functional clotting ability of patients with hemophilia and guide intraoperative factor replacement [10•]. In PWH, TEG and ROTEM demonstrate prolonged reaction time (R)/clotting time (CT), prolonged kinetics (K) time, and shallower alpha angles than in patients with normal coagulation [87]. With the addition of CFC, viscoelastic testing may begin to normalize, allowing clinicians to titrate and monitor treatment [10•].
Looking ahead, the Quantra® hemostasis analyzer, a novel point-of-care ultrasound-based coagulation test using sonic estimation of elasticity via resonance (SEER) sonorheometry, is now FDA approved for use in adult cardiac surgical patients. There are no clinical studies to date detailing the use of Quantra® in the management of patients with hemophilia, however a case report by Rajasekhar et al. in 2022 described successful coronary artery bypass graft surgery in a patient with hemophilia A in which Quantra® was used and found to correlate with TEG[88]. Further investigation is required to determine how best to use Quantra® in the intraoperative management of PWH.
No clot formation at all may be seen during viscoelastic testing in patients with untreated severe hemophilia or in patients with high inhibitor titers, despite treatment with CFCs [87]. Viscoelastic testing may be uniquely useful in the selection and monitoring of bypass agent therapy as bypass agent activity is not reflected in aPTT and the traditional thrombin generation assay is both technically challenging and often not available [10•, 89].
A consensus has not yet been reached regarding the optimal activators for viscoelastic testing in PWH due to insufficient evidence. The International Society on Thrombosis and Haemostasis Scientific and Standardization Committee (ISTH SSC) recommends the exclusive use of kaolin as the activator for TEG testing as kaolin stimulates coagulation through the intrinsic pathway. Similarly, the ISTH SCC recommends the use of the INTEM test when using ROTEM. While extrinsic factor activation with tissue factor may be more physiologic, there is concern for increased variability in the test. The ISTH SCC also recommends the use of a 21-gauge or larger needle and avoidance of tourniquet application when obtaining samples. Lastly, it is suggested to assess a patient’s hematocrit and platelet count at the time of viscoelastic testing as both a low hematocrit and a low platelet count can affect testing [10•, 89, 90].
Cardiopulmonary Bypass (CPB)
With advancements in hemophilia treatment improving the life expectancy of patients, more procedures requiring CPB are being performed on PWH. The World Federation of Hemophilia recommends that, in patients with hemophilia A, factor levels be maintained at 80–100 IU/dL during cardiac surgery and for postoperative day zero. In patients with hemophilia B, factor levels should be maintained at 60–80 IU/dL during the same periods [6•]. Continuous infusion of CFC may be superior to bolus dosing in these patients. There is some evidence that higher trough levels are achieved with continuous infusion and a lower total dose of factor is required compared to bolus dosing [10•, 76, 91].
A review of case reports suggests that heparin and antifibrinolytic agents may be administered per standard protocol for the initiation of CPB [6•, 92]. In patients whose factor activity has successfully been increased to near 100 IU/dL, activated clotting time (ACT) can be monitored per standard protocol [93].
Upon initiation of CPB, factor levels are expected to decrease by 30–40% due to hemodilution [94, 95]. To combat this, techniques to reduce hemodilution during CPB such as retrograde autologous priming, ultrafiltration, and limiting the use of cell salvage products should be considered [10•]. While on CPB, viscoelastic testing with heparinase can be used to monitor factor deficiency while heparinized, however additional factor supplementation does not appear to be necessary during CPB [92, 93]. Fibrinogen and platelet counts should be obtained prior to the cessation of CPB to guide coagulation management [10•].
Upon separation from CPB and administration of protamine for reversal of heparin, viscoelastic testing with heparinase should be used to evaluate for residual coagulopathy [93]. The coagulopathies seen following CPB are usually multifactorial in origin: hemodilution, surgical losses, tissue factor activation of the extrinsic pathway, activation of the intrinsic pathway on the circuit itself, and residual heparin activity [96]. Similar to patients without hemophilia, suspected factor deficiencies should be sequentially addressed under guidance from viscoelastic testing and/or laboratory coagulation assays as per the 2019 Society of Cardiovascular Anesthesiologists clinical practice advisory statement [97]. Obtaining FVIII and FIX activity levels following bypass is also recommended to guide further factor replacement therapy to achieve the goals stated above [10•].
Conclusion
The perioperative management of hemophilia is challenging due to the increasing complexity and diversity of treatment options for patients. Many surgical patients will still require traditional CFCs to maintain hemostasis, and thus anesthesiologists must be comfortable with both new and old therapies. Consultation with a hematologist is also recommended particularly in the setting of rapid bleeding or uncertain home treatment regimens. Increases in overall life expectancy, combined with these improvements in treatment modalities, will likely lead to an increase in both routine and urgent surgical interventions within this population. Thus, an understanding of EHL factors, non-factor hemostatic agents, and gene therapies alongside established standards of care is instrumental to delivering optimal perioperative care for PWH.
Data Availability
No datasets were generated or analysed during the current study.
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This was an invited review paper from Dr. Kenichi Tanaka. J.M., the senior author, created the outline with the assistance of L.M.. A.L., M.C., and J.C. drafted the majority of the content, which was then reviewed and edited by all five authors. M.C. prepared both tables. A.L. and M.C. did the bulk of the revisions, and all authors read and approved the final manuscript.
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Lowell, A.E., Calgi, M.P., Caruso, J.J. et al. Perioperative Management of Hemophilia Patients. Curr Anesthesiol Rep (2024). https://doi.org/10.1007/s40140-024-00635-y
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DOI: https://doi.org/10.1007/s40140-024-00635-y