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6 June 2003

Uremic Bleeding: Uremic Bleeding: Pathogenesis and TherapyPathogenesis and Therapy

麻醉科 林子富麻醉科 林子富

Clinical ManifestationsClinical Manifestations

renal disease and bleeding (Morgagni 1764) renal disease and bleeding (Morgagni 1764) purpura (Bright 1836)purpura (Bright 1836) hemorrhagic pleural effusion and hemorrhagic hemorrhagic pleural effusion and hemorrhagic

pericarditis from serosal irritationpericarditis from serosal irritation

characterized by ecchymoses and prolonged characterized by ecchymoses and prolonged bleeding from puncture sites and mucous bleeding from puncture sites and mucous membranes (epistaxis, GI and GU tract bleeding)membranes (epistaxis, GI and GU tract bleeding)

Subdural hematoma (hypertension, Subdural hematoma (hypertension, anticoagulation with heparin) anticoagulation with heparin)

Menorrhagia Menorrhagia

Laboratory EvaluationLaboratory Evaluation

• The only clinically reliable test available to evaluate the The only clinically reliable test available to evaluate the risk of bleeding in uremic patients and their response to risk of bleeding in uremic patients and their response to therapeutic interventions is bleeding time.therapeutic interventions is bleeding time.

• Mild thrombocytopenia may develop in uremia, but it is Mild thrombocytopenia may develop in uremia, but it is not sufficient to account for the abnormality in not sufficient to account for the abnormality in hemostasishemostasis

• Abnormalities in the prothrombin time(PT) or partial Abnormalities in the prothrombin time(PT) or partial thromboplastin time (PTT) may occur but usually denote thromboplastin time (PTT) may occur but usually denote other associated clotting problems or drugs.other associated clotting problems or drugs.

TherapyTherapy

DialysisDialysis Uremic plasma elicits changes in the function of platelets from Uremic plasma elicits changes in the function of platelets from

normal donors. ( toxins, inhibitory peptides)normal donors. ( toxins, inhibitory peptides) Peritoneal dialysis: less bleeding risk ( lack of systemic Peritoneal dialysis: less bleeding risk ( lack of systemic

heparinization and of platelet activation by contact with a heparinization and of platelet activation by contact with a bioincompatible membrane )bioincompatible membrane )

preferred over hemodialysis in the high-risk patient with active preferred over hemodialysis in the high-risk patient with active bleeding or subdural hematoma bleeding or subdural hematoma

TherapyTherapy

CryoprecipitateCryoprecipitate rich in vWf and fibrinogen, was found to improve the uremic rich in vWf and fibrinogen, was found to improve the uremic

bleeding diathesisbleeding diathesis effect is rapid, but not invariably present.effect is rapid, but not invariably present. Within 1 hour after infusion of approximately 10 units, there is Within 1 hour after infusion of approximately 10 units, there is

normalization of bleeding time in about 50% of uremic normalization of bleeding time in about 50% of uremic patients. patients.

As many as 50% of patients fail to respond.As many as 50% of patients fail to respond. risk of transmission of infectious agents risk of transmission of infectious agents

TherapyTherapy

Desmopressin Desmopressin (1-(1-deamino-8-D-arginine-vasopressin) or deamino-8-D-arginine-vasopressin) or DDAVP DDAVP a derivative of vasopressin with less vasoconstrictor effect, a derivative of vasopressin with less vasoconstrictor effect,

has been used successfully in some forms of von Willebrand has been used successfully in some forms of von Willebrand disease disease

Intravenous administration of 0.3 to 0.4 µg/kg over 20 to 30 Intravenous administration of 0.3 to 0.4 µg/kg over 20 to 30 minutes improves bleeding time within 1 hour, and this effect minutes improves bleeding time within 1 hour, and this effect is maintained for 4 to 8 hours is maintained for 4 to 8 hours

induces the release of vWf from its endothelial storage pools induces the release of vWf from its endothelial storage pools Repeated use of desmopressin may deplete these stores of Repeated use of desmopressin may deplete these stores of

vWf, resulting in tachyphylaxis after two or three doses vWf, resulting in tachyphylaxis after two or three doses

TherapyTherapy

EstrogenEstrogen von Willebrand disease and hereditary hemorrhagic telangiectasia von Willebrand disease and hereditary hemorrhagic telangiectasia

sometimes improve during pregnancysometimes improve during pregnancy The beneficial effect of high-dose estrogens has been attributed to The beneficial effect of high-dose estrogens has been attributed to

the stimulation of an alternative enzymatic route which reduces the the stimulation of an alternative enzymatic route which reduces the L-arginine concentration in cells. L-arginine concentration in cells.

0.6 mg/kg per day IV for 4 or 5 days, or oral estrogens, 50 mg/kg 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 per day, cause slower but more sustained improvements in bleeding timetime The onset of action is about 6 hours after the initial intravenous dose or 2 The onset of action is about 6 hours after the initial intravenous dose or 2

days after initiation of oral treatmentdays after initiation of oral treatment effect lasts about 2 weeks after completing 5 days of intravenous treatment, effect lasts about 2 weeks after completing 5 days of intravenous treatment,

but only 4 or 5 days after oral doses are stopped.but only 4 or 5 days after oral doses are stopped.

TherapyTherapy

Correction of AnemiaCorrection of Anemia Unless there is coincidental severe thrombocytopenia, platelet Unless there is coincidental severe thrombocytopenia, platelet

transfusions are generally ineffective.transfusions are generally ineffective. transfusion of red cells corrects the prolonged bleeding time transfusion of red cells corrects the prolonged bleeding time

promptly after a hematocrit of about 30% is reachedpromptly after a hematocrit of about 30% is reached The risks associated with repeated red cell transfusions can The risks associated with repeated red cell transfusions can

be circumvented with human erythropoietin therapy.be circumvented with human erythropoietin therapy. 50 to 100 U/kg 3 times per week can improve the anemia of 50 to 100 U/kg 3 times per week can improve the anemia of

renal insufficiency to the target hematocrit of 30% in an renal insufficiency to the target hematocrit of 30% in an average of 6 weeks average of 6 weeks

SummarySummary

multifactorial nature ; flexible therapeutic strategymultifactorial nature ; flexible therapeutic strategy Bleeding time is the best guide to assess the bleeding risk Bleeding time is the best guide to assess the bleeding risk

and to monitor the efficacy of treatment in a given patient. and to monitor the efficacy of treatment in a given patient. adequacy of dialysis and the hematocrit influence the bleeding adequacy of dialysis and the hematocrit influence the bleeding

risk risk erythropoietin to avoid the risks associated with transfusions erythropoietin to avoid the risks associated with transfusions prophylactic red cell transfusion for actively bleeding or urgent prophylactic red cell transfusion for actively bleeding or urgent

surgical interventionsurgical intervention desmopressin for short-term interventions such as vascular desmopressin for short-term interventions such as vascular

access placement or renal biopsy access placement or renal biopsy

SummarySummary

recurrent gastrointestinal or other internal hemorrhage recurrent gastrointestinal or other internal hemorrhage occurs, desmopressin may still be useful acutely, but the occurs, desmopressin may still be useful acutely, but the sustained effect of estrogens makes them a more appealing sustained effect of estrogens makes them a more appealing option option

elective surgery, particularly if the risks of bleeding are high elective surgery, particularly if the risks of bleeding are high (eg, in orthopedic surgery), pretreatment with estrogens is (eg, in orthopedic surgery), pretreatment with estrogens is usually advisable usually advisable

Emphasis on dialytic adequacy and appropriate hematocrit Emphasis on dialytic adequacy and appropriate hematocrit should not be overlooked when therapeutic interventions should not be overlooked when therapeutic interventions such as desmopressin or estrogens are being implemented. such as desmopressin or estrogens are being implemented.

ReferencesReferences

1.1. Uremic Bleeding: Pathogenesis and Uremic Bleeding: Pathogenesis and Therapy. Therapy. The American Journal of the The American Journal of the Medical Sciences. Volume 316(2) August Medical Sciences. Volume 316(2) August 1998 p 94-1041)1998 p 94-1041)

2.2. Management of Bleeding with Uremia and Management of Bleeding with Uremia and Liver Disease.Liver Disease. Current Opinion in Current Opinion in Hematology.Volume6(5) Sep.1999 P 329-333Hematology.Volume6(5) Sep.1999 P 329-333

3.3. Estrogen for Uremic Bleeding.Estrogen for Uremic Bleeding. Hospital Hospital Pharmacy.Volume 33(8) Aug.1998 P 999-Pharmacy.Volume 33(8) Aug.1998 P 999-10051005

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