Hematologic Diseases

Hemophilia

The hemophilias are a group of X-linked recessive bleeding disorders characterized by insufficient production of coagulation factor VIII (hemophilia A) or factor IX (hemophilia B). Formation of the platelet plug (primary hemostasis) is normal; however, stabilization of the plug by fibrin (secondary hemostasis) is defective because an insufficient amount of factor VIII or IX results in ineffective thrombin generation.

Hemophilia A results from a deficiency of factor VIII and occurs in approximately 1 in 5000 males. Hemophilia B results from a deficiency of factor IX and occurs in 1 in 30,000 males. Approximately 20% to 30% of female carriers produce low factor concentrations within the hemophilia range with associated bleeding tendencies. Clinically, adequate clotting usually occurs with 40% of normal factor levels.

The diagnosis of hemophilia is confirmed by demonstration of a prolonged partial thromboplastin time (PTT) plus low functional concentrations of either factor VIII or factor IX. Genetic testing is available for both hemophilia A and B. Approximately 98% of patients with either form of hemophilia will have an identifiable pathogenic variant.

The clinical manifestations of hemophilia A and B are indistinguishable. The severity is determined by the patient’s pathogenic variant and their baseline factor level and is categorized as severe (<1%), moderate (1%–5%) or mild (>5 to <40%). Mild hemophilia may go undiagnosed for many years, whereas severe hemophilia may manifest during early infancy as a result of a traumatic delivery (intracranial hemorrhage), bleeding after circumcision, or intramuscular injections. If bleeding does not occur in early infancy, the remainder of children with severe hemophilia are typically asymptomatic until they begin to crawl or walk. Severe hemophilia is characterized by spontaneous or traumatic hemorrhages, which can be subcutaneous (palpable bruising), intramuscular, or within joints (hemarthroses). Acute hemarthroses are exquisitely painful and if repeated over time will result in progressive joint damage and subsequent disability.

Hemophilia is treated by IV administration of the appropriate coagulation factor. These factors are produced by either plasma-derived or recombinant technology. Advances have been made in prolonging the half-life of factor products through the addition of different moieties (e.g., Fc protein fragment, albumin, or PEGylation) to the factor VIII or IX molecule.

A novel antibody therapy was approved for prophylaxis in patients with factor VIII deficiency with and without an inhibitor. Emicizumab (Hemlibra) is a recombinant monoclonal antibody that bridges activated factor IX and factor X to replace the function of the missing activated factor VIII. Emicizumab improves but does not normalize baseline hemostasis. The estimated hemostatic effect is thought to be similar to a patient with mild hemophilia (equivalent factor VIII level of 10%–20%). Emicizumab has a long half-life of 28 days and takes approximately 1 month to reach steady state with initiation of therapy. Factor VIII concentrate or bypassing therapy with recombinant factor VIIa can be used concurrently with emicizumab therapy.

Emicizumab will shorten the activated prothrombin complex concentrate (aPTT) and activitated clotting time ACT. Therefore, these tests cannot be used intraoperatively to monitor a patient’s ongoing coagulation status. This drug effect may last for up to 6 months after stopping the medication. In addition, any one-stage aPTT-based factor assays are also unreliable.

Von Willebrand Disease

von Willebrand disease (vWD) is the most common hereditary bleeding disorder, present in up to 1% of the population. It results from a quantitative and/or qualitative defect of von Willebrand factor (vWF), a glycoprotein synthesized by endothelial cells and megakaryocytes. In the process of primary hemostasis, vWF acts as an adhesive bridge between the platelets and damaged subendothelium at the site of vascular injury. In the process of secondary hemostasis, it functions as the carrier protein for factor VIII.

There are different types of vWD:

• Type 1 (>85% of cases) is associated with quantitative reductions in all multimeric sizes of vWF. There is a wide variation of clinical manifestations, even for members of the same family. Children with type 1 vWD may be asymptomatic, or may have a history of frequent nosebleeds, mucosal bleeding, and easy bruising. A history of excessive bleeding during menses, or after mucosal surgery such as tonsillectomy or wisdom tooth extraction, is common. These patients are usually responsive to treatment with DDAVP.

• Type 2 is associated with quantitative and qualitative abnormalities of vWF and accounts for about 10% of cases. There are four subtypes of type 2 vWD: 2 A, 2 B, 2 M, and 2 N. Type 2 A includes genetic defects that impact multimer formation or processing. Type 2 B includes gain of function variants with vWF platelet binding and can be associated with mild thrombocytopenia. Type 2 M includes variants that result in decreased binding to platelets. Type 2 N results from pathogenic variants in the vWF FVIII binding region and results in low FVIII levels and can be mistaken for hemophilia A. Many patients with type 2 variants will not be responsive to DDAVP therapy, and require vWF replacement.

• Type 3 is the rarest and severest form, and results in a severe quantitative vWF deficiency associated with low factor VIII levels. It is associated with major bleeding requiring treatment with vWF and FVIII-containing concentrates.

Laboratory screening in patients with vWD may reveal a PTT, but many children with vWD have normal coagulation screening tests. More directed tests for vWD include a quantitative assay for vWF antigen, vWF (ristocetin cofactor) activity, plasma factor VIII activity, determination of vWF structure (vWF multimers), and a platelet count (decreased in type 2B vWD).

Treatment of vWD can be accomplished by using either DDAVP to stimulate the release of endogenous stores of vWF and factor VIII or through the use of either plasma-derived factor VIII-vWF concentrates (e.g., Humate-P) or recombinant vWF (e.g., Vonvendi). Treatment decisions are based on a patient’s type of vWD and their individual response to DDAVP.

Most commonly, children with type 1 vWD are responsive to DDAVP and are pretreated 30 minutes before surgery with IV DDAVP, 0.3 μg/kg. Additional doses can be administered every 12 to 24 hours postoperatively, but the response diminishes with repeated treatments as a result of tachyphylaxis. In general, DDAVP can be repeated for up to three to four consecutive doses. DDAVP has a known antidiuretic effect with resultant free water retention. Excessive fluid intake after DDAVP administration can result in hyponatremia and seizures. To minimize the risk for hyponatremia, fluid intake should be limited to two-thirds maintenance for 24 hours after DDAVP is given. This fluid limit includes the intraoperative period and should direct your anesthetic of choice and use of fluids. Even the use of isotonic fluids in the OR can still result in significant hyponatremia.

DDAVP is not used in patients who are nonresponders, type 3 vWD and some type 2 variants. In these patients, plasma-derived factor VIII concentrate with vWF or recombinant vWF is administered pre- and postoperatively. Plasma-derived vWF products should be dosed using ristocetin units and the half-life is approximately 12 hours. Recombinant vWF has a half-life of approximately 20 hours and contains ultra large multimers that do not exist in plasma-derived products.

Dosage formulae for recombinant and plasma derived FVIII vWF products (Humate P or Alphanate):

Dose (ristocetin units) = % Desired Rise × Weight × 0.5

As in hemophilia, antifibrinolytics can be used as a hemostatic adjuvant therapy in mucosal surgeries.