Factor XI Deficiency and Obstetrical Anesthesia
- Amarjeet Singh, MBBS, DA, FRCA*,
- Miriam J. Harnett, MB, FFARCSI*,
- Jean M. Connors, MD† and
- William R. Camann, MD*
+Author Affiliations
- Address correspondence and reprint requests to Dr. William Camann, Department of Anesthesiology, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Address e-mail to wcamann@partners.org.
Abstract
Factor XI (FXI) deficiency is a rare inherited coagulation disorder associated with prolonged activated partial thromboplastin time. The severity of bleeding often does not correlate with plasma factor levels. We reviewed the medical and anesthetic records of 13 parturients with FXI deficiency that presented for delivery. Nine cases were managed with neuraxial anesthesia. (epidural, seven; spinal, one; combined spinal-epidural, one). Three received general anesthesia for cesarean delivery, and one had an unmedicated vaginal delivery. Baseline factor levels ranged from severe (<15%) to mild (near 50%) deficiency. Fresh frozen plasma was administered to correct activated partial thromboplastin time in most, but not all, cases. Hematology consultation was obtained for all. No hematological or anesthetic complications were noted. FXI deficiency is not an absolute contraindication to neuraxial anesthesia, provided appropriate hematology consultation has been obtained, and factor replacement is provided as guided by clinical and laboratory hemostatic evaluation.
Factor XI (FXI) deficiency is a rare inherited coagulation disorder associated with prolonged activated partial thromboplastin time (aPTT). FXI deficiency, also known as hemophilia C, plasma thromboplastin antecedent deficiency, or Rosenthal syndrome, was first described in 1953.1 Initial presentation often occurs with unexpected bleeding during surgical procedures or after a traumatic injury and has been predominantly, but not exclusively, identified in the Jewish population of eastern European descent (Ashkenazi) with a prevalence of around 8%.2–11 Diagnosis of FXI deficiency should be considered in patients with postoperative bleeding and prolonged aPTT, especially in a demographically high-risk population, such as Ashkenazi Jews. Although commonly described as one of the factor levels that decrease during normal pregnancy, the evidence to support this is conflicting, and more recent reports indicate no change in FXI levels in normal pregnancy.6
The severity of bleeding often does not correlate with the plasma FXI level.2–10Levels lower than 15% usually require fresh frozen plasma (FFP) during surgical procedures, while levels above 50% are less likely to cause clinically significant bleeding. However, there is no consensus on the safe level of FXI necessary for neuraxial anesthesia. We report the anesthetic management of a series of 13 women with FXI deficiency who presented for labor analgesia and delivery.
CASE SERIES
IRB approval was granted for this investigation. Patients were identified through our antenatal anesthesia consultation database in conjunction with our hematology consultant’s database. We analyzed the medical and anesthetic records of patients with FXI deficiency who presented to our hospital for labor and delivery between February 2000 and December 2007. Patients with a combination of bleeding disorders were excluded from this review. Obstetric, anesthesia, and coagulation data are summarized in Table 1.
View this table:
Table 1. Anesthetic and Coagulation Data
Our high-risk obstetric anesthesia antenatal consultation service had evaluated all women who presented with a diagnosis of FXI deficiency during the antenatal period and a plan was formulated for their obstetric anesthesia care, in conjunction with the obstetric and hematology teams. aPTT was noted to be abnormal in all cases with severe or moderate FXI deficiency. Two patients were categorized as severe FXI deficiency with factor levels <15%; the remaining had mild to moderate deficiency. Patients 1, 2, 5, 7, and 9 were diagnosed after abnormal bleeding during a prior surgical or dental procedure but were otherwise asymptomatic. Patient 6 was diagnosed as part of a work-up for easy bruising. The others were diagnosed based on family history, except Patient 11, who was diagnosed as part of a routine hematological screen before enrollment as a subject in a medical research project. All patients except Patient 6 (with the easy bruising) were essentially asymptomatic as part of their daily life activities.
Nine patients were managed with neuraxial anesthesia. Three had general anesthesia for elective cesarean delivery, and one had an unmedicated vaginal delivery. Eight of the women had prophylactic administration of FFP within 24 h before delivery. Patient 7 had a mild reaction to the FFP consisting of hives and wheezing, which resolved after diphenhydramine and hydrocortisone administration. None had intrapartum bleeding requiring additional blood products. One patient (10) had postpartum hemorrhage on Day 1 after vaginal delivery due to bleeding from a torn vulvar artery that required embolization; she had uneventful vaginal delivery in a subsequent pregnancy. Another patient (4) had postpartum hemorrhage on the 11th day after vaginal delivery due to retained products of conception; she underwent dilation and evacuation under general anesthesia, requiring transfusion of additional packed red blood cells and FFP. Both of these events were considered to be of obstetrical etiology and not caused by the FXI deficiency. One of the patients (7) had general anesthesia for elective cesarean delivery because she refused a neuraxial technique, despite preoperative FFP administration and documented normalization of aPTT. Overall, 9 of 13 deliveries had neuraxial anesthesia with no complications. Five of the patients who received neuraxial anesthesia were treated with FFP before anesthetic administration; the ones who did not receive FFP had mild disease and no clinical bleeding history. The clinical decision to proceed with neuraxial anesthesia in the absence of FFP administration was made after a full discussion of the risks and options. All patients were assessed in the postpartum period for any neurological complications and to ensure full resolution of neuraxial anesthesia. No adverse outcomes were noted related to the anesthetic techniques.
DISCUSSION
Our series of 13 patients with FXI deficiency suggests that it may be safe to administer neuraxial anesthesia to this patient population, especially if factor replacement is performed. Diagnosis of FXI deficiency should be considered in patients with delayed postoperative bleeding and prolonged aPTT, especially in a demographically high-risk population, such as Ashkenazi Jews. Women with severe FXI deficiency and prolonged aPTT can be managed with FFP transfusion before neuraxial anesthesia. FFP can be administered the day or night before elective procedures, as the half life of FXI is 70 h.12 Patients usually receive FFP to normalize their aPTT for vaginal cesarean delivery. This may provide a window of opportunity for the anesthesiologist to initiate neuraxial anesthesia.
In general, the aPTT will be prolonged outside the normal range when the level of any factor involved in the intrinsic pathway decreases below 30%.13 FXI deficiency is unique among coagulation factor deficiencies as it is the only factor associated with bleeding in which the plasma levels do not correlate with bleeding tendency. Severe FXI deficiency is defined as FXI levels <15%; these patients are usually homozygotes or compound heterozygotes for FXI mutations. Heterozygous FXI-deficient patients have factor levels between 15% and 70%.3The clinical distinction between patients who bleed and those who do not cannot be made by factor levels alone as equal frequencies of bleeding and nonbleeding are found in homozygotes and heterozygotes.14
Of interest, although not correlated with FXI levels, the likelihood of bleeding is consistent within families. In one study, among 12 families in which the proband was asymptomatic, no other FXI-deficient family member was found to bleed; to contrast in 13 families in which the proband had clinical bleeding, other family members were also symptomatic.15 Both the patient’s personal history in response to trauma and surgical procedures, as well as family history, should be obtained in addition to aPTT and FXI levels to guide treatment decisions for surgical and obstetrical procedures.
Given the often asymptomatic presentation of this syndrome, it is almost certain that there are patients without prior knowledge of FXI deficiency who have had neuraxial anesthesia without complications. However, because of the potential, but quantifiably unknown, risk for epidural-spinal hematoma, it seems prudent that factor replacement therapy should be given in severe cases and response to therapy documented. In a patient with known severe deficiency with a low-baseline FXI level and prolongation of the aPTT, measurement of the aPTT after FFP infusion can be used as a surrogate for FXI level. When the aPTT is normalized in these patients, the FXI level in our experience has increased to 25%–30%, which is sufficient for hemostasis. In patients with FXI levels close to the normal range or more than 50%, personal and family history can be useful in guiding treatment decisions.
The standard dose of FFP for replacement in severe disease is 10–20 mL/kg. We routinely use the upper end of this range (20 mL/kg) for our pregnant patients. The risks of FFP infusion include intravascular volume overload, allergic reaction, and blood-borne infection, although the risk of infection with FFP is less than with cellular blood components.
Salomon et al.4 have described obstetrical outcomes in a series of 62 patients with FXI deficiency. Owing to a low incidence of severe peripartum bleeding in their series, they conclude that not all women with severe FXI deficiency need factor replacement before labor and delivery, and that replacement should be limited to those who experience hemorrhage. Others may take a more conservative approach. Moreover, report by Salomon et al. does not describe anesthetic management. David et al.16 described one twin vaginal delivery and two elective cesarean deliveries in patients with FXI deficiency; all received FFP and epidural anesthesia, and all deliveries were uneventful. One case report in the anesthesia literature describes a general anesthetic for cesarean delivery.17 In this case, the patient had severe FXI deficiency and the presence of a FXI inhibitor. The preoperative aPTT of 74 s failed to correct with 2 U of FFP. General anesthesia and the operative course were uneventful, and estimated blood loss was 1000 mL. A spontaneous epidural hematoma, presenting as acute myelopathy (Brown-Sequard syndrome) has been reported in a male patient with FXI deficiency.18This patient made a full and spontaneous nonsurgical recovery.
FXI concentrate is an effective treatment for FXI deficiency and is available in a number of European countries. Thrombotic complications and death with the use of FXI concentrate in elderly individuals have been described. These reports should be taken in context; earlier preparations of all factor concentrates may more likely have been associated with thrombosis, particularly in populations with other risk factors for thrombosis.19
Recombinant factor VIIa has been proposed as a treatment for almost all coagulation factor deficiencies.20–22 A prospective study of the use of recombinant factor VIIa in 15 patients with FXI deficiency for minor or major surgical or dental procedures has been reported; there was one fatal thrombotic event in an elderly patient.20 These authors conclude that recombinant factor VIIa may be an effective alternative to plasma replacement, but caution should be used in patients with preexisting risk factors for thrombosis.
As with other bleeding disorders, avoiding IM injections may be prudent. It may also be prudent to avoid vacuum and forceps for vaginal delivery, or fetal blood scalp sampling and electrode placement; however, there are no reports of these complications and clinical judgment is warranted. Consultation with a hematologist is critical in determining the optimal management of these women during labor and delivery. Obstetrical involvement is also important to appropriately plan timing of delivery. Often these patients are managed with elective induction of labor (or cesarean delivery if indicated for obstetrical reasons) to allow scheduled factor replacement. We propose the involvement of a hematologist and obstetrician in formulation of the overall plan of management for labor and delivery, including early anesthesia consultation.
Pediatric consultation may be useful to assess neonatal concerns. The ethnic background of the father of the baby should be assessed to determine the risk of FXI deficiency in the offspring. It is possible that the infant may be more severely affected than the mother if the father is also heterozygous for FXI deficiency. However, bleeding complications, such as bleeding from circumcision, are extremely rare, even in newborns with severe FXI deficiency.
This series of 13 patients, in conjunction with the other published case reports and series, cannot confer complete safety of neuraxial anesthesia in women with factor XI deficiency. A risk/benefit discussion needs to be conducted with each patient; a willingness to accept the risks and benefits of various approaches may differ from patient to patient and from anesthesiologist to anesthesiologist and may depend on the presence or absence of other risk factors (e.g., difficult airway). For example, one of our patients insisted on general anesthesia (rather than spinal) for her elective cesarean delivery, despite her asymptomatic clinical status and laboratory documentation of normalized aPTT after FFP administration. Other patients and their anesthesiologists felt comfortable proceeding with epidural analgesia for labor in the absence of FFP prophylaxis. The absolute plasma factor level that is consistent with safety is not known, thus clinicians need to use surrogate markers, including clinical history and other laboratory markers of coagulation, before procedures that may induce bleeding, with recognition that these surrogate markers may be imperfect. It is reassuring that patients with both mild and severe disease, some of whom have received factor replacement products and some not, have undergone both major surgical procedures, childbirth, and neuraxial anesthesia, without reported complications deemed attributable to their disease.
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