Anesthesiology

The Patient with a (Nonpharmacologic) Coagulation Defect (von Willebrand Disease)

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What the Anesthesiologist Should Know before the Operative Procedure

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, with a prevalence of 1% to 2% in the general population. VWD is caused by either a quantitative or qualitative defect in the Willebrand factor (VWF), and has an autosomal dominant pattern of inheritance.

Up to 6 different subtypes have been described, and these involve abnormal configurations of the multimer and varying abnormalities of plasma and platelet-associated VWF. The most common subtype found in the general population is type-1 disease (approximately 90%) and is characterized by a simple decrease in the level of plasma FVIII: VWF antigen and activity. The majority of patients who do not have type-1 disease have type-II variants.

The critical issues and possible comorbidities are that the parturient may develop an epidural hematoma if given neuraxial anesthesia, and may develop uncontrollable hemorrhage during a cesarean section or operative vaginal delivery. Pregnancy results in a hypercoagulable state and plasma levels of FVIII usually rise; therefore, the majority of patients with VWD achieve a clinical and laboratory remission of the disease during pregnancy, and treatment with 1-deamino-8-D-arginine vasopressin (DDAVP) or blood transfusion is usually not necessary.

Because the risk of bleeding varies by subtype, accurate diagnosis of the disease is essential, and consultation with a hematologist, perinatologist, and anesthesiologist are essential to diagnosing the specific subtype and to recommending treatment for labor and delivery.

1. What is the urgency of the surgery?

What is the risk of delay in order to obtain additional preoperative information?

Urgency of anesthesia/analgesia will depend on the condition of the fetus (i.e., profound fetal heart rate deceleration requiring immediate delivery) and/or the cervical dilation of the mother (i.e., advanced labor).

Emergent: It is essential that both the anesthesiologist and the obstetrician know if the patient requires treatment (i.e., DDAVP, blood products) for neuraxial anesthesia and delivery.

Urgent: Proper treatment (i.e., DDAVP, blood products) of VWD needs to be given so that adequate hemostasis can be achieved for neuraxial placement and/or delivery.

Elective: This situation should not pose a problem to the parturient because there will be ample time to work up the patient (i.e., specific VWD subtype) and decide on proper treatment (i.e., the need for DDAVP for neuraxial replacement and/or for delivery).

2. Preoperative evaluation

Up to six different subtypes of the disease have been identified, and diagnosis is based on clinical suspicion and laboratory confirmation. Accurate diagnosis is important because therapy will vary according to the subtype.

Symptoms of VWD usually involve mild-to-moderate mucocutaneous bleeds, such as epistaxis, menorrhagia, bleeding after dental extractions, ecchymoses, gingival bleeding, and prolonged bleeding from minor cuts. Patients with menorrhagia and no documented pelvic anomalies should undergo testing for VWD. Postoperative and delayed postpartum hemorrhage may also be present.

  • Medically unstable conditions warranting further evaluation: Parturients with a history of easy bruising, epistaxis, menorrhagia, or acute and delayed bleeding after surgery should be tested for VWD.

  • Delaying surgery may be indicated if: Parturients with a history of extensive mucosal bleeding (due to platelet dysfunction) and prolonged bleeding (due to factor VIII deficiency) after surgery. These patients should have their delivery delayed as complications may result from inadequate treatment of the disorder.

3. What are the implications of co-existing disease on perioperative care?

a. Evaluation and Workup

  • Perioperative evaluation: Evaluation for VWD should consist of a hematology consult to properly diagnosis the specific subtype and recommend treatment for labor and delivery. Initial evaluation for VWD would be obtaining a basic hemostasis evaluation, including a CBC with platelet count, activated partial thromboplastin time (aPTT), prothrombin time, and fibrinogen levels. Additional tests include the VWF protein (VWF:Ag) assay, functional assay (VWF:RCo), the factor VIII assay and the platelet function assay. Other tests may be indicated to further classify the disease or follow the therapeutic response to intervention as recommended by the hematologist.

  • Perioperative risk reduction strategies: The hematologist's recommendations regarding the use of DDAVP or specific blood products for labor and delivery should be available prior to delivery.

b. Cardiovascular system

  • Acute/unstable conditions: Most parturients are healthy and do not have cardiovascular disease. They are able to tolerate the hemodynamic changes associated with labor and delivery. Approximately 6% of the pregnant population will have preeclampsia, which may be associated with a drop in the platelet count to less than 100 K. This would further complicate the patient with VWD.

c. Pulmonary

The most common conditions associated with the parturient include asthma, pulmonary edema, and pneumonia, but these are unrelated to VWD.

i. Reactive airway disease (Asthma): Unrelated to VWD, it is important to treat the underlying disorder: asthma (beta agonists, respiratory therapy, inhalers), pulmonary edema (diuretics), or pneumonia (antibiotics).

ii. Airway Management: All parturients after the first trimester are considered "full stomachs" and are at risk for aspiration under general anesthesia. Airway edema and swelling can necessitate the utilization of smaller endotracheal tubes for securing the airway.

d. Renal-GI:

Problem with the renal-GI system are rare and unrelated to VWD. In the event of renal signs, such as anuria or oliguria with preeclampsia, it is important to maintain an adequate urinary output by optimizing volume status with crystalloid or colloid and treating the vasospasm associated with preeclampsia (i.e., magnesium therapy).

e. Neurologic:

N/A

f. Endocrine:

N/A

g. Additional systems/conditions which may be of concern in a patient undergoing this procedure and are relevant for the anesthetic plan (eg. musculoskeletal in orthopedic procedures, hematologic in a cancer patient).

N/A

4. What are the patient's medications and how should they be managed in the perioperative period?

It is essential to review all medications and discontinue any that may affect coagulation in order to avoid worsening coagulation problems, such as neuraxial hematoma associated with neuraxial anesthesia postpartum hemorrhage after vaginal or cesarean delivery.

h. Are there medications commonly seen in patients undergoing this procedure and for which should there be greater concern?

Patients with VWD may require DDAVP to ensure adequate hemostasis for surgical procedures. It is important to determine if DDAVP is required as well as the correct dosage and amount and when the medication should be given (i.e., at neuraxial placement, at delivery, before surgical incision, etc.). Consultation with the obstetrician and hematologist will assist in determining the appropriate medication and blood product availability to ensure adequate hemostasis.

i. What should be recommended with regard to continuation of medications taken chronically?

Generally, all medications taken during the pregnancy should be continued during labor and delivery. The primary goal is to maintain adequate hemostasis. Drugs that affect hemostasis, including over-the-counter medications such as NSAIDs and aspirin, are contraindicated in the patient with VWD.

j. How to modify care for patients with known allergies -

Patients with known allergies to specific medications should be given alternate medication to prevent allergic reaction.

k. Latex allergy- If the patient has a sensitivity to latex (eg. rash from gloves, underwear, etc.) versus anaphylactic reaction, prepare the operating room with latex-free products.

N/A

l. Does the patient have any antibiotic allergies- [Common antibiotic allergies and alternative antibiotics]

If a patient has an antibiotic allergy, a different class of antibiotic covering the same microorganisms should be substituted.

m. Does the patient have a history of allergy to anesthesia?

Malignant hyperthermia

Avoid all trigger agents such as succinylcholine and inhalational agents. A proposed general anesthetic plan should include: aspiration prophylaxis with a nonparticulate antacid, left uterine displacement, preoxygenation, rapid sequence induction with cricoid pressure, and confirm tracheal tube placement with end-tidal CO2 monitor.

Local anesthetics/muscle relaxants

Local anesthetics and muscle relaxants can be used unless the patient has a true allergic reaction. Often, the local anesthetic can be substituted (amide vs ester), as well as the muscle relaxant (different classification/moiety) can be used. If the patient has an underlying system disorder, a short-acting muscle relaxant may be indicated to ensure a quicker return to full motor control.

5. What laboratory tests should be obtained, and has everything been reviewed?

Basic hemostasis evaluation includes a complete blood cell count (CBC), platelet count, activated partial thromboplastin time (aPTT), prothrombin time (PT), and fibrinogen levels.

The aPTT is often normal in VWD, and only the most severe deficiencies with very low levels of Factor VIII will have a prolonged aPTT. Further work-up includes the following three tests: (1) VWF protein (VWF:Ag) assay, which is an immunoassay that measures the VWF protein in plasma; (2) Functional assay (VWF:RCo) that measures the interaction between VWF and platelets. The binding between these and the subsequent formation of platelet clumps is stimulated by the addition of the antibiotic ristocetin; and (3) Factor VIII assay, which measures the activity of FVIII, a surrogate for the activity of VWF as a carrier protein for FVIII.

Other tests may be indicated to further classify the disease as recommended by a hematologist. Reference laboratories will frequently perform a ratio to compare the amount of qualitative-to-quantitative dysfunction present (VWF:RCo/VWF:Ag).

A value that is lower than 30 IU/dL is diagnostic for VWD; however, some patients with VWD may have values between 30 and 50 IU/dL. Occasionally, repeated testing for VWD is needed because conditions such as pregnancy, stress, surgery, and inflammation will increase levels of VWF and mask lower baseline values.

FVIII is the best predictor of bleeding complications. It is recommended that VWF:RCo and FVIII levels be checked in the third trimester close to delivery. Levels of more than 50 IU/dL are considered normal and safe for delivery.

  • Hemoglobin levels: Because of the potential for hemorrhage, hemoglobin levels should be normal adult pregnant values (i.e., >10 gm/dL). Iron supplementation should be assured.

  • Electrolytes: Repeated infusions of DDAVP can cause hyponatremia and rarely, seizures.

  • Coagulation panel: Values should be within normal laboratory limits prior to delivery, with specific treatments as recommended by the hematologist.

  • Other tests: Because VWD involves interaction with the endothelial surface, the thromboelastogram (TEG) has limited value has not been recommended in patients with VWD despite recent articles indicating it may be useful for detecting response to DDAVP. It is useful in the management of parturients with other types of coagulation defects, as it measures clot formation, platelet aggregation, coagulation, and fibrinolysis. Platelet function assay, while not specific for VWD, is useful for detection of platelet abnormalities and in following therapeutic response.

Peripartum laboratory examination includes:

a. CBC with platelet count, aPTT, PT, and INR (international normalized ratio)

b. Factor VIII levels

c. VWF:RCo assay

d. Type and cross match for two units of packed red blood cells (RBC).

Intraoperative Management: What are the options for anesthetic management and how do I determine the best technique?

Management of VWD during pregnancy should include consultation with an obstetrician, hematologist, and blood bank personnel. The mainstays of VWD therapy are desmopressin (DDAVP; 1-deamino-8-D-arginine vasopressin) and plasma concentrates that contain von Willebrand factor. At least three Von Willebrand Factor Replacement products are FDA approved for the treatment of VWD.

Fibrinolysis inhibitors (antifibrinolytics) are considered adjuvant (second-line) therapy. Bleeding complications during pregnancy are more frequent when levels of von Willebrand ristocetin cofactor assay and factor VIII levels are less than 50 IU/dL. The usual dose of DDAVP is 0.3 μg/kg intravenously (maximum dose, 25-30 μg) given over 30 minutes. The observed peak increment in FVIII and VWF levels usually occurs 30 to 90 minutes after the infusion. Alternatively, DDAVP may be administered intranasally at a dose of 300 μg.

Intravenous administration is the preferred route for prophylaxis of surgical bleeding. Because elevation of factors lasts for only 8 to 10 hours after administration, DDAVP should be administered every 12 to 24 hours. The main problem with repeat dosing of DDAVP is tachyphylaxis through depletion of endothelial stores. In general, if treatment is required for more than 3 days, VWF concentrates should be used as a supplement to therapy with DDAVP.

If there is acute bleeding, hemostasis may be achieved with 10 units of cryoprecipitate. Fresh frozen plasma can also be used; however, large amounts of volume will be needed to achieve hemostasis. Platelet concentrates contain only 15% of total blood VWF; consequently, platelet transfusions are considered to be an adjunctive therapy in cases in which bleeding is not controlled. After initial treatment and control of hemostasis, treatment is best managed by point of care laboratory value testing.

Regional anesthesia

Regional anesthesia can be used safely in a patient with VWD provided levels of von Willebrand ristocetin cofactor assay and factor VIII levels are above 50 IU/dL. Because coagulation factors increase in pregnancy, and because the majority of patients will have type-1 disease, characterized by a simple decrease in the level of plasma FVIII:VWF antigen and activity, patients can successfully receive neuraxial anesthesia without complication (i.e., epidural hematoma). Consultation with a hematologist can determine if regional anesthesia is appropriate and if treatment (i.e., DDAVP) is indicated before neuraxial placement.

Neuraxial anesthesia

In VWD, levels of von Willebrand ristocetin cofactor assay and factor VIII levels should be above 50 IU/dL, and if the coagulation screen is normal, regional anesthesia can be used. Values above 50 IU/dL should be maintained for at least 3 to 5 days after delivery to prevent further bleeding. The block should be performed by the most experienced clinician, and in the midline long axis of the spine to minimize the risk of puncturing an epidural vein.

  1. Benefits: An awake mother participating in the birth. Avoidance of morbidity and mortality as a result of a difficult airway, rapid desaturation, or aspiration when utilizing general anesthesia.

  2. Drawbacks: There is the potential for an epidural hematoma with resultant paraplegia.

  3. Issues: Patients will need neurologic checks during labor and postpartum if her coagulation status is being corrected to allow use of neuraxial anesthesia.

Peripheral nerve block

Pudendal or paracervical blocks are best avoided because of the potential for delayed hemorrhage or hematoma. Procedures that potentially could result in bleeding complications (e.g., pudendal blocks, episiotomies, fetal scalp electrodes, or operative vaginal deliveries) should be avoided, if possible. Vaginal delivery is considered safe for women with VWD types 1 and 2. In patients with type 3 disease, a prolonged second stage of labor should be avoided, and early cesarean delivery should be considered. Consultation with a hematologist can determine optimal management.

General anesthesia

General anesthesia is usually reserved for cesarean section in a patient in whom neuraxial anesthesia is contraindicated.

  • Benefits: Avoids the risk of epidural hematoma.

  • Drawbacks: There is always the risk of a difficult airway, desaturation during induction and apnea, aspiration at induction or extubation. The mother misses the birth of her baby. Fathers are generally not allowed in the operating room during general anesthesia.

Monitored anesthesia care

  • Benefits: Can be of benefit for labor analgesia if neuraxial analgesia is contraindicated. Narcotics such as fentanyl are administered by intravenous patient-controlled pump.

  • Drawbacks: Not an option for cesarean delivery.

  • Other Issues: Monitored anesthesia care may not provide adequate analgesia for the delivery/procedure, and alternative forms of anesthesia may be indicated (i.e., general anesthesia for an instrumented delivery or extensive perineal repair).

6. What is the author's preferred method of anesthesia technique and why?

What prophylactic antibiotics should be administered?

For cesarean section, appropriate antibiotics should be ordered by the obstetrician and given before surgical incision to prevent wound infection: typically, 2 to 3 grams of cefazolin.

What do I need to know about the surgical technique to optimize my anesthetic care?

After surgical delivery of the fetus, uterotonics must be given to prevent uterine atony and postpartum hemorrhage (PPH). Without adequate uterine contraction and hemostasis, hemorrhage could become profound, especially in the patient with a coagulation defect such as VWD.

What can I do intraoperatively to assist the surgeon and optimize patient care?

In preparation for the potential for postpartum hemorrhage (PPH), cell salvage, blood products (PRBCs, cryoprecipitate, platelets, and FFP), and oxytocics (oxytocin, methylergonovine, prostaglandins) should be readily available. In the event of hemorrhage, place an additional large-bore intravenous catheter for blood product replacement and resuscitation, an arterial line to monitor blood pressure and to draw laboratory values, and consider a central line for delivering and monitoring fluid resuscitation in the event of inadequate peripheral intravenous catheters.

What are the most common intraoperative complications, and how can they be avoided/treated?

Intraoperative, postpartum, and delayed hemorrhage are the most common complications. Consider use of DDAVP when indicated.

  • Cardiac complications: If postpartum hemorrhage occurs, myocardial ischemia and decompensation can occur as a result of massive fluid administration and blood product administration. The patient should be monitored in the ICU until hemodynamically stable.

  • Pulmonary: Pulmonary edema can occur as a result of massive fluid overload and blood product administration. The patient should be monitored in the ICU until her respiratory status is stable.

  • Neurologic: Epidural hematoma from neuraxial placement can occur. The patient should be monitored with neurologic checks during epidural analgesia and postpartum. If unexpected motor or sensory block or back pain occurs, a stat neurosurgical consult and intervention may be necessary to prevent permanent paralysis.

a. Neurologic:

N/A

b. If the patient is intubated, are there any special criteria for extubation?

Provided the patient is otherwise healthy and able to protect her airway, and assuming massive fluid resuscitation nor extensive hemodynamic changes (sustained hypotension, massive administration of fluids and blood products) has occurred, the patient can be extubated immediately after surgery. Otherwise, the patient should be monitored in the intensive care unit (ICU) until extubated and hemodynamically stable.

b. Postoperative management

What analgesic modalities can I implement?

Analgesic modalities include oral and intravenous narcotic analgesics. Because of the risk for postoperative hemorrhage, NSAIDs are contraindicated.

What bed acuity level is appropriate?

If the parturient has delivered without complication (i.e., no significant hemorrhage with no hemodynamic instability), she can recover in the labor or delivery suite or post-anesthesia care unit (PACU). If there has been significant hemorrhage, the patient should recover in the PACU or intensive care unit (ICU) until the hemorrhage is controlled and she is hemodynamically stable. Hematology should follow her closely in the postpartum period.

What are common postoperative complications and the ways to prevent and treat them?

Pregnant women with VWD are at higher risk of hemorrhagic complications, mainly during the postpartum period. Delayed post-partum hemorrhage may occur despite adequate prophylaxis with DDAVP. Frequent monitoring and continued prophylaxis or treatment are recommended for at least 2 weeks after delivery. Pregnancy-induced elevation of VWF and FVIII levels is a transient event, and levels will return to baseline within 7 to 21 days. This drop explains the high incidence of delayed postpartum hemorrhage and why continued monitoring of the patient after discharge is indicated.

What's the Evidence?

Pacheco, LD, Costantine, MM, Saade, GR, Mucowski, S, Hankins, GD, Sciscione, AC.. "von Willebrand disease and pregnancy: a practical approach for the diagnosis and treatment". Am J Obstet Gynecol. vol. 203. 2010 Sep. pp. 194-200.

(Review article on the diagnosis and treatment of VWD.)

Ahohen, J, Stefanovic, V, Lassila, R.. "Management of post-partum haemorrhage". Acta Anaesthesiol Scand. vol. 54. 2010 Nov. pp. 1164-78.

"Management of Postpartum Hemorrhage: Current State of the Evidence". Comparative Effectiveness Review Summary Guides for Clinicians. Agency for Healthcare Research and Quality (US). 2016.

(Review article on management of PPH.)

Benedetto, C, Marozio, L, Tavella, AM, Salton, L, Grivon, S, Di Giampaolo, F.. "Coagulation disorders in pregnancy: acquired and inherited thrombophilias". Ann N Y Acad Sci. vol. 1205. 2010 Sep. pp. 106-17.

(Discussion on thrombophilia in pregnancy.)

Montagnana, M, Franchi, M, Danese, E, Gotsch, F, Guidi, GC.. "Disseminated intravascular coagulation in obstetric and gynecologic disorders". Semin Thromb Hemost. vol. 36. 2010 Jun. pp. 404-18.

Erez, O, Mastrolia, SA, Thachil, J.. "Disseminated intravascular coagulation in pregnancy: insights in pathophysiology, diagnosis and management". Am J Obstet Gynecol. vol. 213. 2015. pp. 452-63.

(Review of DIC in pregnancy.)

Alamelu, J, Liesner, R.. "Modern management of severe platelet function disorders". Br J Haematol. vol. 149. 2010 Jun. pp. 813-23.

(Management of platelet function disorders.)

Szecsi, PB, Jorgensen, M, Klajnbard, A, Anderson, MR, Colov, NP, Stender, S.. "Haemostatic reference intervals in pregnancy". Thromb Haemost. vol. 103. 2010 Apr. pp. 718-27.

Macafee, B, Campbell, JP, Ashpole, K, Cox, M, Matthey, F, Acton, L, Yentis, SM.. "Reference ranges for thromboelastography (TEG®) and traditional coagulation tests in term parturients undergoing caesarean section under spinal anaesthesia". Anaesthesia. vol. 67. 2012. pp. 741-47.

Armstrong, S, Fernando, R, Ashpole, K, Simons, R, Columb, M.. "Assessment of coagulation in the obstetric population using ROTEM® thromboelastometry". IJOA. vol. 20. 2011. pp. 293-298.

(Normal reference, pregnancy hemostatic laboratory values.)

Topf, H, Weiss, D, Lischetzki, G, Strasser, E, Rascher, W, Rauh, M.. "Evaluation of a modified thromboelastography assay for the screening of von Willebrand disease". Thromb Haemost. vol. 105. 2011 Jun. pp. 1091-9.

(Utility of TEG in VWD.)

Favolor, E.. "The Utility of the PFA-100 in the Identification of von Willebrand Disease: A Concise Review". Semin Thromb Hemost.. vol. 32. 2006 Jul. pp. 537-45.

(Utility of PFA in VWD.)
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