R4 서미선 Bleeding in uremia

Introduction  main determinants of uremic bleeding → impaired platelet function  multifactorial  defects intrinsic to the platelet  abnormal platelet-endothelial interaction  uremic toxins, anemia

Clinical manifestations  typically cutaneous : easy bruising, mucosal bleeding  response to injury or invasive procedures  epistaxis, gingival bleeding, hematuria : less frequent  spontaneous gastrointestinal bleeding  difficult to estimate  modern dialysis techniques → uncommon very little justification

 bleeding time prolongation & uremic bleeding  very little justification, no large, prospective studies  degree of azotemia (elevation of BUN or creatinine) → not correlate with bleeding risk  main determinants of uremic bleeding → impaired platelet function  other coagulation parameters : intact  platelet count : usually normal or only slightly reduced  no prolongation of PT or aPTT

Pathogenesis  Intrinsic factors  abnormal expression of platelet glycoproteins  altered release of ADP & serotonin from platelet alpha-granules  faulty arachidonic acid  depressed prostaglandin metabolism  decreased platelet thromboxane A2 generation  abnormal platelet cytoskeletal assembly

 intrinsic dysfunction of GP IIb/IIIa → impairment in platelet aggregation  glycoprotein (GP)IIb/IIIa  platelet membrane glycoprotein  platelet aggregation : by interaction with fibrinogen & von Willebrand factor  platelet dysfunction → increased sensitivity to aspirin d/t transient, cyclooxygenase-independent prolongation of the bleeding time

 Extrinsic factors  uremic toxins, anemia, increased nitric oxide (NO) production  von Willebrand factor abnormalities  decreased platelet production  abnormal interactions between the platelet and the endothelium of the vessel wall

1)Uremic toxins  plasma factors  uremic platelets mixed with normal plasma  uremic plasma mixed with normal platelets → impairs platelet function  urea  not major platelet toxin  no correlation between BUN & bleeding time  adding urea, guanidinoacetic acid, creatinine to the plasma → adverse effect not replicated  high levels of guanidinosuccinic acid, methylguanidine → abnormal platelet function (NO production)

2) Anemia  hematocrit > 30 → red cells : occupy the center of the vessel platelets : skimming layer at the endothelial surface => close proximity → allows the platelets to adhere to the endothelium & form a platelet plug when endothelial injury  anemia → platelets : more dispersed → impairing adherence to the endothelium

3) Nitric oxide  endothelium-derived relaxing factor  produced by endothelial cells & platelets  inhibitor of platelet aggregation  studies in uremic patients  platelet NO synthesis ↑  uremic plasma stimulates NO production by cultured endothelial cells  guanidinosuccinic acid ↑(uremic toxin) → NO synthesis ↑  NO synthesis inhibitor administration → normalizes the bleeding time in uremic rats  beneficial effect of estrogens on platelet function : d/t reduction of NO synthesis

TREATMENT  asymptomatic : no specific therapy  actively bleeding or surgical procedure (eg, renal biopsy) → correction of platelet dysfunction

1)Correction of anemia  ↑hematocrit 25 ~ 30 % → bleeding time ↓ : enhanced platelet aggregation & increased platelet adhesion to endothelial cells  acutely : red cell transfusions  chronically : administration of recombinant human erythropoietin  improvement in platelet function will persist for as long as the hematocrit remains elevated

2) Erythropoietin  direct beneficial effect on platelet function  mechanisms  number of GPIIb/IIIa molecules on the platelet membrane↑  improving the defect in thrombin-induced phosphorylation of platelet proteins  improving platelet calcium signaling direct beneficial effect on platelet function

3) Desmopressin (dDAVP)  simplest & least toxic acute treatment  analog of antidiuretic hormone with little vasopressor activity  effective in at least one-half of patients  act by increasing the release of factor VIII:von Willebrand factor multimers from endothelial storage sites

 IV  preferred route  0.3 microg/kg in 50 mL of saline (15 to 30 minutes)  SC : same dose  Intranasal  3 microg/kg  begins within one hour & lasts 4 to 24 hours  most useful for acute bleeding or preparation for renal biopsy  Tachyphylaxis  develops after the second dose  due to depletion of endothelial multimer stores

3) Dialysis  hemodialysis or peritoneal dialysis  partially correct the bleeding time in two-thirds of uremic patients  peritoneal dialysis : preferable in active bleeding, (heparin administration is not required)  maintenance hemodialysis  minimal or regional heparin  avoidance of all anticoagulants  dialysis using prostacyclin or regional citrate administration as anticoagulants

4) Estrogen  more prolonged control of bleeding  administration of conjugated estrogens  0.6 mg/kg IV, daily for five days  2.5 to 25 mg of Premarin orally  50 to 100 microg of transdermal estradiol twice weekly  begin to act on the first day, with peak control reached over 5-7 days  duration of action : 1 week or more after therapy has been discontinued

 effect : dose-dependent  primarily mediated by estradiol, acting via the estrogen receptors  long-term use : limited by estrogen-related side effects  mechanism  reducing the production of L-arginine (precursor of nitric oxide) → decreased generation of NO

5) Cryoprecipitate  10 units IV q 12 to 24 hrs  begins within one hour & lasts 4 to 24 hours  factor VIII:von Willebrand factor multimers → enhances platelet aggregation  potential risk of infectious complications → limited use : life threatening bleeding (resistant to treatment with dDAVP & blood transfusions)