Chapter 110. Coagulation Disorders (Part 4)

Chapter 110. Coagulation Disorders (Part 4)Factor VIII and Factor IX are dosed in units. One unit is by definition the amount of FVIII (100 ng/mL) or FIX (5 µg/mL) in 1 mL of normal plasma. One unit of FVIII per kilogram of body weight increases the plasma FVIII level by 2%. One can calculate the dose needed to increase FVIII levels to 100% in a 70-kg severe hemophilia patient (
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Chapter 110. Coagulation Disorders (Part 4) Chapter 110. Coagulation Disorders (Part 4) Factor VIII and Factor IX are dosed in units. One unit is by definition theamount of FVIII (100 ng/mL) or FIX (5 µg/mL) in 1 mL of normal plasma. Oneunit of FVIII per kilogram of body weight increases the plasma FVIII level by 2%.One can calculate the dose needed to increase FVIII levels to 100% in a 70-kgsevere hemophilia patient ( The FVIII half-life of 8–12 h requires injections twice a day to maintaintherapeutic levels, whereas the FIX half-life is longer, ~24 h, so that once-a-dayinjection is sufficient. In specific situations such as postsurgery, continuousinfusion of factor may be desirable because of its safety in achieving sustainedfactor levels at a lower total cost. Cryoprecipitate is enriched with FVIII protein (each bag contains ~80 IU ofFVIII) and was commonly used for the treatment of hemophilia A decades ago; itis still in use in some developing countries, but because of the risk of bloodbornediseases, this product should be avoided in hemophilia patients when factorconcentrates are available. Mild bleeds such as uncomplicated hemarthroses or superficial hematomasrequire initial therapy with factor levels of 30–50%. Additional doses to maintainlevels of 15–25% for 2 or 3 days are indicated for severe hemarthroses, especiallywhen these episodes affect the target joint. Large hematomas, or bleeds intodeep muscles, require factor levels of 50% or even higher if the clinical symptomsdo not improve, and factor replacement may be required for a period of 1 week orlonger. The control of serious bleeds, including those that affect the oropharyngealspaces, central nervous system, and the retroperitoneum, require sustained proteinlevels of 50–100% for 7–10 days. Prophylactic replacement for surgery is aimed atachieving normal factor levels (100%) for a period of 7–10 days; replacement canthen be tapered depending on the extent of the surgical wounds. Oral surgery isassociated with extensive tissue damage, which usually requires factorreplacement for 1–3 days coupled with oral antifibrinolytic drugs. Non-Transfusion Therapy in Hemophilia DDAVP (1-Deamino-8-D-Arginine Vasopressin) DDAVP is a synthetic vasopressin analogue that causes a transient rise inFVIII and von Willebrand factor (vWF), but not FIX, through a mechanisminvolving release from endothelial cells. Patients with moderate or mildhemophilia A should be tested to determine if they respond to DDAVP before atherapeutic application. DDAVP at doses of 0.3 µg/kg body weight infused over a20-min period is expected to raise FVIII levels by two- to threefold over baseline,peaking between 30–60 min postinfusion. DDAVP does not improve FVIII levelsin severe hemophilia A patients, as there are no stores to release. Repeated dosingof DDAVP results in tachyphylaxis because the mechanism is an increase inrelease rather than de novo synthesis of FVIII and vWF. More than threeconsecutive doses become ineffective and if further therapy is indicated, FVIIIreplacement is required to achieve hemostasis. Antifibrinolytic Drugs Bleeding in the gums, in the gastrointestinal tract, and during oral surgeryrequires the use of oral antifibrinolytic drugs such as ε-aminocaproic acid (EACA)or tranexamic acid to control local hemostasis. The duration of the treatmentdepending on the clinical indication is 1 week or longer. Tranexamic acid is givenat doses of 25 mg/kg three to four times a day. EACA treatment requires a loadingdose of 200 mg/kg (maximum of 10 g) followed by 100 mg/kg (maximum 30 g/d)every 6 h. These drugs are not indicated to control hematuria because of the risk offormation of an occlusive clot in the lumen of genitourinary tract structures. Complications Inhibitor Formation The formation of alloantibodies to FVIII or FIX is currently the majorcomplication of hemophilia treatment. The prevalence of inhibitors to FVIII isestimated at 5–10% of all cases and approximately 20% of severe hemophilia Apatients. Inhibitors to FIX are detected in only 3–5% of all hemophilia B patients.The high-risk group for inhibitor formation includes severe deficiency (>80% ofall cases of inhibitors), familial history of inhibitors, African descent, mutations inthe FVIII or FIX gene resulting in deletion of large coding regions, or gross generearrangements. Inhibitors usually appear early in life, at a median of two years ofage, and after 10 cumulative days of exposure.