Hemostatic uses of DDAVP - Uremia, VWD type I, and Hemophilia A
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Background
DDAVP is frequently used for hemostatic indications in patients with hemophilia A, vin Willebrand's disease (Type I) and uremic platelet dysfunction.
Hemophilia A
DDAVP Injection 4 mcg/mL is indicated for patients with hemophilia A with factor VIII coagulant activity levels greater than 5%. DDAVP will often maintain hemostasis in patients with hemophilia A during surgical procedures and postoperatively when administered 30 minutes prior to scheduled procedure. DDAVP will also stop bleeding in hemophilia A patients with episodes of spontaneous or trauma- induced injuries such as hemarthroses, intramuscular hematomas or mucosal bleeding. In certain clinical situations, it may be justified to try DDAVP in patients with factor VIII levels between 2% to 5%; however, these patients should be carefully monitored. DDAVP is not indicated for the treatment of hemophilia A with factor VIII coagulant activity levels equal to or less than 5%, or for the treatment of hemophilia B, or in patients who have factor VIII antibodies.
von Willebrand's Disease
von Willebrand's Disease (Type I): DDAVP Injection 4 mcg/mL is indicated for patients with mild to moderate classic von Willebrand's disease (Type I) with factor VIII levels greater than 5%. DDAVP will often maintain hemostasis in patients with mild to moderate von Willebrand's disease during surgical procedures and postoperatively when administered 30 minutes prior to the scheduled procedure.
DDAVP will usually stop bleeding in mild to moderate von Willebrand's patients with episodes of spontaneous or trauma-induced injuries such as hemarthroses, intramuscular hematomas or mucosal bleeding. Those von Willebrand's disease patients who are least likely to respond are those with severe homozygous von Willebrand's disease with factor VIII coagulant activity and factor VIII von Willebrand factor antigen levels less than 1%. Other patients may respond in a variable fashion depending on the type of molecular defect they have. Bleeding time and factor VIII coagulant activity, ristocetin cofactor activity, and von Willebrand factor antigen should be checked during administration of DDAVP to ensure that adequate levels are being achieved. DDAVP is not indicated for the treatment of severe classic von Willebrand's disease (Type I) and when there is evidence of an abnormal molecular form of factor VIII antigen.
Renal failure with uremia
Bleeding of uremic patients can be shortened by administration of conjugated estrogens or DDAVP, reinforcing speculation that interaction between platlets and factor VIII and vWF is the primary hemostatic defect in uremia. In some uremic patients, prolonged bleeding times can be markedly shortened by simply raising the hematocrit.
The normal physiologic response to vessel injury begins with local vasoconstriction. Primary hemostasis requires 3 critical steps: (a) platelet adhesion, (b) granule release, and (c) platelet aggregation. In the first step, endothelial cells secrete von Willebrand’s factor (vWF), which binds to subendothelial structures and receptor molecules of platelet glycoprotein (GP) Ib; in this way platelets are attached to the sites of endothelial disruption. In the second step, platelet adhesion triggers release of various mediators, including adenosine diphosphate (ADP) and thromboxane A2, which stimulate further aggregation and vasoconstriction. Fibrinogen binds platelets to each other, but activation of receptor molecules of the platelet GPIIb-IIIa complex is essential both to enable this binding to occur and to support irreversible adhesion to surface-bound vWF. In the final step, platelet interaction with coagulation factors leads to generation of thrombin, which activates fibrinogen to produce fibrin, thus forming fibrin clots.
The platelet dysfunction characteristic of uremia is complex. Platelet count is usually within the normal range or slightly low in patients with uremia. It has been suggested that these patients have a complex platelet dysfunction and an abnormal platelet-vessel wall interaction. Radioligand studies have indicated that the binding of fibrinogen to ADP-stimulated platelets in uremic media is impaired. Notably, the ability of the vessel wall to generate the potent antiaggregatory substance prostacyclin (prostaglandin I2) increases in uremia; moreover, endothelial cells seem to generate an abnormal complex of coagulation factor VIII (antihemophilic factor) and vWF. Finally, the largest polymers of vWF, which are primarily responsible for the adhesion process, are deficient in patients with uremia, although the serum level of vWF in these patients is usually high or within the normal range.
Some studies have found a defective interaction between vWF and the GPIIb-IIIa complex that is responsible for decreased spreading of uremic platelets that adhere to the subendothelium. Platelets from patients with uremia exhibit abnormal adhesive function; a reduced aggregating response to ADP, epinephrine, and collagen; and an altered arachidonic acid metabolism. Numerous biochemical changes in platelets have been reported, including a decrease in serotonin and ADP levels, an increase in the cyclic adenosine monophosphate level, and a decreased ability to generate thromboxane A2.
Anemia exacerbates the bleeding tendency in patients with uremia, most likely because of altered radialt ransport of platelets, decreasing their contact with the endothelium. For the average patient undergoing dialysis, blood losses from bleeding in the gastrointestinal tract, from menstruation (for women), from blood draws, and in the dialyzers after each treatment collectively amount to approximately 2.5 L/year. This does not include occasional large losses caused by surgical procedures or bleeding from access devices. In addition, recent studies have suggested that abnormal production of nitric oxide (NO) also is involved in the bleeding tendency in patients with uremia. A specific inhibitor of NO formation, N-monomethyl-L-arginine, completely normalized the prolonged bleeding time in uremic rodents. NO is a potent vascular relaxing factor that might, to some extent, counter the vasoconstriction after vessel injury. NO also is known to inhibit platelet adhesion to the vascular endothelium by elevating intracellular levels of cyclic guanosine monophosphate. Limited evidence also has been obtained showing that leukocytes might play a role in blood coagulation; leukocytes have the ability to express different types of clot-promoting activities (their so-called procoagulant activity).
General dosing ranges
For Diabetes Insipidus (intranasal & parental); bleeding due to hemophilia A and Type I von Willebrand's dz (parental); bleeding from esophageal varices; head trauma. DDAVP can transiently correct the bleeding time in most patients with chronic renal failure and other acquired disorders of platelet function.
DI: Intranasally: Adult: 0.1-0.4 mL (10-40 ug) daily in 2-3 divided doses
Peds: (3 mo-12yr): 0.05-0.3ml qd in 2-3 divided doses;
Parentally: Adult: 0.5-1.0 ml (2-4 ug) qd in 2-3 DD; if converting from intranasal to parental dosing,
use 1/10th of intranasal dose;
Hemophilia A and von Willebrand's dz (Type I):
Adults and Peds: > 10 kg: 0.3 ug/kg diluted to 50 ml with NSS infused slowly over 15-30 min;
Peds < 10 kg: same as above with dilution to 10 ml with NS;
Bleeding from esophageal varices: IV infusion of 0.2-0.4 U/min with max rate of 0.9 u/min;
Note: in very young and old patients, adjust fluid intake to avoid water intoxication.
Notes & References
[1] Salman S. Uremic bleeding: pathophysiology, diagnosis, and management. Hospital Physician. 2001;76:45-50.
[2] Wheeless' Textbook of Orthopaedics. Desmopressin (Synthetic Arginine Vasopressin). Available online at: http://www.wheelessonline.com/ortho/desmopressin_synthetic_arginine_vasopressin_ddavp_stimate. Last accessed on Sept 5, 2008.
Credits & Notices
Authors-contributors to this page (listed alphabetically, last name, first & middle initial only, no institutional affiliations, no scientific titles):
Stawicki SP
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