Good Morning 6 June 2003

Uremic Bleeding: Pathogenesis and Therapy 麻醉科 林子富

Clinical Manifestations  renal disease and bleeding (Morgagni 1764)  purpura (Bright 1836)  hemorrhagic pleural effusion and hemorrhagic pericarditis from serosal irritation

 characterized by ecchymoses and prolonged bleeding from puncture sites and mucous membranes (epistaxis, GI and GU tract bleeding)  Subdural hematoma (hypertension, anticoagulation with heparin)  Menorrhagia

Laboratory Evaluation The only clinically reliable test available to evaluate the risk of bleeding in uremic patients and their response to therapeutic interventions is bleeding time.The only clinically reliable test available to evaluate the risk of bleeding in uremic patients and their response to therapeutic interventions is bleeding time. Mild thrombocytopenia may develop in uremia, but it is not sufficient to account for the abnormality in hemostasisMild thrombocytopenia may develop in uremia, but it is not sufficient to account for the abnormality in hemostasis Abnormalities in the prothrombin time(PT) or partial thromboplastin time (PTT) may occur but usually denote other associated clotting problems or drugs. Abnormalities in the prothrombin time(PT) or partial thromboplastin time (PTT) may occur but usually denote other associated clotting problems or drugs.

Therapy  Dialysis  Uremic plasma elicits changes in the function of platelets from normal donors. ( toxins, inhibitory peptides)  Peritoneal dialysis: less bleeding risk ( lack of systemic heparinization and of platelet activation by contact with a bioincompatible membrane )  preferred over hemodialysis in the high-risk patient with active bleeding or subdural hematoma

Therapy  Cryoprecipitate  rich in vWf and fibrinogen, was found to improve the uremic bleeding diathesis  effect is rapid, but not invariably present.  Within 1 hour after infusion of approximately 10 units, there is normalization of bleeding time in about 50% of uremic patients.  As many as 50% of patients fail to respond.  risk of transmission of infectious agents

Therapy  Desmopressin (1-deamino-8-D-arginine-vasopressin) or DDAVP  a derivative of vasopressin with less vasoconstrictor effect, has been used successfully in some forms of von Willebrand disease  Intravenous administration of 0.3 to 0.4 µg/kg over 20 to 30 minutes improves bleeding time within 1 hour, and this effect is maintained for 4 to 8 hours  induces the release of vWf from its endothelial storage pools  Repeated use of desmopressin may deplete these stores of vWf, resulting in tachyphylaxis after two or three doses

Therapy  Estrogen  von Willebrand disease and hereditary hemorrhagic telangiectasia sometimes improve during pregnancy  The beneficial effect of high-dose estrogens has been attributed to the stimulation of an alternative enzymatic route which reduces the L-arginine concentration in cells.  0.6 mg/kg per day IV for 4 or 5 days, or oral estrogens, 50 mg/kg per day, cause slower but more sustained improvements in bleeding time  The onset of action is about 6 hours after the initial intravenous dose or 2 days after initiation of oral treatment  effect lasts about 2 weeks after completing 5 days of intravenous treatment, but only 4 or 5 days after oral doses are stopped.

Therapy  Correction of Anemia  Unless there is coincidental severe thrombocytopenia, platelet transfusions are generally ineffective.  transfusion of red cells corrects the prolonged bleeding time promptly after a hematocrit of about 30% is reached  The risks associated with repeated red cell transfusions can be circumvented with human erythropoietin therapy.  50 to 100 U/kg 3 times per week can improve the anemia of renal insufficiency to the target hematocrit of 30% in an average of 6 weeks

Summary  multifactorial nature ; flexible therapeutic strategy  Bleeding time is the best guide to assess the bleeding risk and to monitor the efficacy of treatment in a given patient.  adequacy of dialysis and the hematocrit influence the bleeding risk  erythropoietin to avoid the risks associated with transfusions  prophylactic red cell transfusion for actively bleeding or urgent surgical intervention  desmopressin for short-term interventions such as vascular access placement or renal biopsy

Summary  recurrent gastrointestinal or other internal hemorrhage occurs, desmopressin may still be useful acutely, but the sustained effect of estrogens makes them a more appealing option  elective surgery, particularly if the risks of bleeding are high (eg, in orthopedic surgery), pretreatment with estrogens is usually advisable  Emphasis on dialytic adequacy and appropriate hematocrit should not be overlooked when therapeutic interventions such as desmopressin or estrogens are being implemented.

References 1.Uremic Bleeding: Pathogenesis and Therapy. The American Journal of the Medical Sciences. Volume 316(2) August 1998 p ) 2.Management of Bleeding with Uremia and Liver Disease. Current Opinion in Hematology.Volume6(5) Sep.1999 P Estrogen for Uremic Bleeding. Hospital Pharmacy.Volume 33(8) Aug.1998 P

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