Hemostasis and von Willebrand Disease

Effective coagulation and clotting are necessary to achieve adequate hemostasis. The process begins with primary hemostasis, during which interactions between the endothelium, von Willebrand factor (vWF), and platelets act to initiate coagulation and clotting. Secondary hemostasis involves activation of the coagulation factors of the intrinsic and extrinsic pathways – the coagulation cascade. Thrombin generation and formation of cross-linked fibrin monomers anchor the thrombus (clot) during this phase. In tertiary hemostasis, clot retraction and cross-linking of fibrin monomers by factor XIII stabilize the hemostatic plug. Hemostasis functions most efficiently when normothermia, normal pH, and normal ionized calcium levels are present.

Pregnancy is a unique physiologic state encompassing all organ systems. Numerous changes within the hematopoietic system occur progressively during pregnancy and cause an overall hypercoagulable state. Compared with prepregnancy levels, procoagulant factors VII, VIII, IX, X, and XII, fibrinogen, and vWF increase, factors II and V remain at a similar level, and factors XI and XIII decrease. In addition, pregnancy is associated with decreased levels of the anticoagulant protein S and resistance to activated protein C. The in vitro laboratory effects are demonstrated by a decreased prothrombin time (PT) and decreased activated partial thromboplastin time (aPTT). The relative thrombocytopenia of pregnancy and enhanced fibrinolysis work to offset the hypercoagulable state.

vWD is the most common inherited disorder of hemostasis, with a prevalence of up to 1 percent in certain populations. First described in 1926 in a Finnish population,¹ vWD is characterized by mucocutaneous bleeding including epistaxis, easy bruising, gastrointestinal bleeding, and intraoperative and postoperative surgical/dental bleeding. In women, vWD is often diagnosed after first menses (75 percent of women with vWD have menorrhagia) or after a postpartum hemorrhage.

vWD is caused by quantitative or qualitative defects in vWF, a large multimeric protein synthesized in endothelial cells and megakaryocytes (platelet precursors). It is stored in the Weibel-Palade bodies of endothelial cells and the alpha granules of platelets. vWF has three main functions in promoting hemostasis:

1. 
   

   1. vWF binds to the collagen on the exposed subendothelial matrix after tissue damage.

   
   
2. 
   

   2. vWF binds glycoprotein (GP) Ib receptors on platelets, thereby cross-linking the platelets to damaged tissue and with other platelets.

   
   
3. 
   

   3. vWF directly associates with factor VIII, preventing its degradation by serum proteases and increasing its half-life from 24 minutes to 12 hours.

vWD is classified into three types (Table 17.1). Type 1 vWD (70–80 percent of all vWD cases) is an autosomal-dominant inability to release vWF from cellular stores, resulting in a quantitative decrease in circulating vWF levels. The far more uncommon homozygous autosomal-recessive type 3, comprising approximately 1 percent of patients with vWD, is characterized by nearly absent production of functional vWF, resulting in an almost complete degradation of factor VIII and a severe disease pattern closely resembling X-linked recessive hemophilia A. Type 2 vWD comprises four subtypes of qualitative vWF defects.² Expert hematology input is necessary during pregnancy as part of a multidisciplinary approach for delivery, including the suitability and safety of neuraxial anesthesia. Disease severity and treatment depend on the type of vWD. Establishing the diagnosis is paramount for optimal patient care. Mild cases of vWD can be difficult to diagnose and depend on patient blood type, estrogen level, inflammation, stress, and smoking. Laboratory diagnosis of vWD often involves the assays listed in Table 17.2.

Although routine screening of normal pregnant women for coagulopathy is not indicated, patients may present to the obstetric anesthesiologist for consultation regarding an isolated elevated aPTT. An elevated aPTT prompts a differential diagnosis that includes hypo- and hypercoagulable states and laboratory error or artifact. In fact, the most common cause of an isolated elevated aPTT level is an inadequate amount of blood in the collection tube. To differentiate between the presence of a hypocoagulable (e.g., vWD) and a hypercoagulable state (e.g., anti-phospholipid antibody syndrome), a mixing study is performed with normal serum. Correction of the aPTT after mixing indicates a deficiency in the intrinsic coagulation cascade factors (e.g., factor VIII), whereas maintenance of the elevated aPTT indicates the presence of an inhibitor (e.g., lupus anticoagulant or anti-cardiolipin antibodies).

Implications of vWD in Obstetric Anesthesia

A parturient with vWD poses unique challenges to the obstetric anesthesiologist. Concerns include provision of adequate labor analgesia and management of postpartum hemorrhage (PPH). Depending on the type and severity of vWD, parturients may not be candidates for neuraxial anesthesia or analgesia without prior laboratory assessment of coagulation or receiving empirical treatment due to the risk of epidural hematoma. Devastating neurologic injury related to neuraxial analgesia or anesthesia has not been reported in this population. In fact, multiple case reports and case series have described the efficacy and safety of neuraxial analgesia and anesthesia in this population after undergoing proper testing and/or treatment.^3–7

In addition, vWD elevates the risk of early and delayed PPH. Patients with type 1 vWD, who comprise the majority of patients with vWD, often have normal laboratory values for factor VIII, VWFA, RISTOC, and aPTT by the third trimester of pregnancy; neuraxial anesthesia and analgesia are considered safe under these circumstances. However, because these levels will return to baseline within 7–21 days, 20–25 percent of patients with type 1 vWD will experience delayed (mean 15.7 days) PPH.⁸

Women on estrogen-containing oral contraceptives will have an increase in vWF antigen levels, similar to the increase found in pregnancy. Making a diagnosis of vWD in a woman on combination oral contraceptives can be difficult. The patient in this case was on levonorgestrel, a second-generation synthetic progestin, which has no impact on vWF antigen levels. Therefore, the levels in this patient can be considered to be true baseline levels.

If laboratory values do not normalize by the time of delivery, treatment based on the specific type of vWD is indicated, regardless of whether neuraxial analgesia or anesthesia is desired, because of the risk of early PPH.⁹ In types 1 and 2 vWD, vWF and factor VIII generally begin increasing in the mid-second trimester. However, because of type-specific and individual variability in magnitude increase, frequent monitoring of factor VIII levels in the antepartum and postpartum periods is necessary. Treatment of vWD in the peripartum period aims to achieve vWF:RCo and FVIII activity levels at or above 50 percent, which is accepted as safe for regional anesthesia and delivery. Scheduled labor induction or cesarean delivery is optimal for those requiring replacement therapy. If laboratory values have not normalized in the third trimester of pregnancy, a multidisciplinary meeting involving the obstetrics, hematology, and obstetric anesthesia services is ideally performed in the antepartum period to formulate a treatment plan for delivery. If delivery is imminent and the factor status of the patient is unknown, treatment is indicated and should not be delayed for laboratory results.

For type 1 vWD, in which there is adequate vWF production and storage but impaired release, the synthetic antidiuretic hormone analogue DDAVP (1-deamino-8-d-arginine vasopressin, desmopressin) is the preferred treatment.¹⁰ This drug, often administered as a 0.3 µg/kg IV infusion in 50–100 ml normal saline (NS) over 30 minutes, triggers release of stored vWF from Weibel-Palade bodies of endothelial cells, resulting in a three- to fivefold increase in factor VIII and vWF levels within 30 minutes and lasting at least 8–10 hours; redosage can occur at 12- or 24-hour intervals.¹¹ Side effects include headache, hypertension, flushing, nausea, vomiting, hyponatremia, seizures, and uterine contractions; tachyphylaxis can be seen after 3 days of treatment.

Because type 3 vWD involves the severely impaired synthesis of vWF, DDAVP administration, which acts to release intracellular stores, is not an effective treatment. The use of DDAVP in type 2B vWD is generally contraindicated because a transient thrombocytopenia can occur and further aggravate bleeding risk.¹² For types 2A, 2M, and 2N vWD, the response to DDAVP is variable, and a predelivery DDAVP response test is indicated. The results of this test may guide peripartum management.

If DDAVP is contraindicated or does not normalize factor VIII levels after administration, direct replacement of factor VIII with factor VIII–vWF concentrates (Humate P, Alphanate) can be considered. In patients with type 3 vWD, who almost completely lack vWF, administration of factor VIII–vWF has been shown to elicit an immune response to the vWF antigen in some patients, resulting in neutralization of vWF activity. In these patients, factor VIII is the treatment of choice. Cryoprecipitate contains a two- to threefold higher factor VIII and ninefold higher vWF concentration than fresh-frozen plasma (FFP),¹³ although neither is used routinely if factor VIII–vWF concentrate is available. The safety, efficacy, and pharmacokinetics of recombinant vWF are currently being studied in clinical trials.^{14, 15}