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Uremic Bleed

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Dr Chow Yok Wai
Hospital Kuala Lumpur

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  • very good and imp , can you please send me a copy on drmithil@gmail.com,,
    so i can teach other student , thanks
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Uremic Bleed

  1. 1. Evidence-based treatment recommendations for uremic bleeding
  2. 2. Normal hemostatic mechanisms
  3. 3. Normal Hemostasis <ul><li>Primary hemostasis </li></ul><ul><ul><li>Platlet plug formation </li></ul></ul><ul><ul><li>Within seconds </li></ul></ul><ul><li>Secondary hemostasis </li></ul><ul><ul><li>Plasma coagulation system </li></ul></ul><ul><ul><li>Fibrin </li></ul></ul><ul><ul><li>Strengthen primary hemostatic plug </li></ul></ul><ul><ul><li>Minutes </li></ul></ul>
  4. 4. Primary hemostasis Secondary hemostasis <ul><li>Platlet (+) coagulation </li></ul><ul><li>Thrombin (+) platlet activation </li></ul>
  5. 5. Primary Hemostasis <ul><li>3 critical events:- </li></ul><ul><ul><li>Platlet adhesion </li></ul></ul><ul><ul><li>Granule release </li></ul></ul><ul><ul><li>Platlet aggregation </li></ul></ul>
  6. 7. Primary Hemostasis <ul><li>Platlet adhesion </li></ul><ul><ul><li>Platlets adhere to collagen fibrils in vascular subendothelium via GP Ia-IIa </li></ul></ul><ul><ul><ul><li>Interaction stabilized by VWF </li></ul></ul></ul><ul><ul><li>VWF forms a link between receptor site at GP Ib/IX and collagen fibrils </li></ul></ul>
  7. 9. Primary Hemostasis <ul><li>Granule release </li></ul><ul><ul><li>Dependant on level of cyclic nucleotides, Ca influx, hydrolysis of membrane phospholipids and phosphorylation of critical intracellular proteins </li></ul></ul><ul><ul><li>Binding of platlet agonist (NE, collagen, thrombin) to platlet surface receptors (+) phospholipase C and phospholipase A2  (+) arachidonic acid release from phosphatidylinositol and phosphatidylcholine </li></ul></ul>
  8. 10. Primary Hemostasis <ul><li>Diacylglycerol (DAG) and inositol triphosphate (IP3) </li></ul><ul><li>DAG (+) protein kinase C  phosphorylates myosin light chains kinase  platlet granule secretion </li></ul><ul><li>IP3 mediates Ca + movement into platlet cytosol, (+) phosphorylation of myosin light chains  interact with actin  granule movement and platlet shape change </li></ul>
  9. 12. <ul><li>Thromboxane A2 </li></ul><ul><ul><li>Platlet activation </li></ul></ul><ul><ul><li>Platlet secretion </li></ul></ul><ul><li>Prostacyclin </li></ul><ul><ul><li>Inhibits platlet activation (by increasing intraplatlet cyclic adenosine monophosphate(CAMP)) </li></ul></ul>
  10. 13. Platlet granule release <ul><li>Lysosomes </li></ul><ul><ul><li>Heparinase </li></ul></ul><ul><li>Dense granules </li></ul><ul><ul><li>ADP (adenosine diphosphate) </li></ul></ul><ul><ul><li>Serotonin </li></ul></ul><ul><ul><li>Calcium </li></ul></ul><ul><li>Alpha granules </li></ul><ul><ul><li>Fibronectin </li></ul></ul><ul><ul><li>VWF </li></ul></ul><ul><ul><li>Fibrinogen </li></ul></ul><ul><ul><li>Thromboxane A2 </li></ul></ul><ul><ul><li>Factor Va </li></ul></ul><ul><ul><li>Thrombospondin </li></ul></ul><ul><ul><li>Platlet Derived Growth Factor (PDGF) </li></ul></ul><ul><ul><li>Heparin neutralizing protein (platlet factor 4) </li></ul></ul>
  11. 14. Platlet Aggregation <ul><li>ADP  change formation on GP IIb/IIIa complex  binds fibrinogen  linking adjacent platlets into hemostatic plug </li></ul><ul><li>PDGF  (+) growth and migration of fibroblast and smooth muscle cells within vessel wall </li></ul>
  12. 17. Coagulation cascade <ul><li>End result  fibronogen to fibrin conversion </li></ul><ul><li>4 reactions </li></ul><ul><ul><li>Reaction 1 </li></ul></ul><ul><ul><ul><li>intrinsic or contact phase of coagulation </li></ul></ul></ul><ul><ul><ul><li>Complex formation on subendothelial collagen: </li></ul></ul></ul><ul><ul><ul><ul><li>Factor XII (Hageman factor) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>HMW kiminogen (HMWK) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Prekallikrein (PK) </li></ul></ul></ul></ul><ul><ul><ul><li>FXII  XIIa after binding to HMWK </li></ul></ul></ul><ul><ul><ul><li>FXIIa (+) PK  kallikrein, FXI to FXIa </li></ul></ul></ul><ul><ul><ul><li>FIXa  subsequent coagulation actions </li></ul></ul></ul><ul><ul><ul><li>Kallikrein (+) FXII  FXIIa </li></ul></ul></ul>
  13. 18. Coagulation cascade <ul><li>Reaction 2 </li></ul><ul><ul><li>Extrinsic or tissue factor dependant pathway </li></ul></ul><ul><ul><li>Complex formation : </li></ul></ul><ul><ul><ul><li>FVII, calcium, tissue factor </li></ul></ul></ul><ul><ul><li>FX, FIX, FVII, FII  vit K and calcium dependent </li></ul></ul><ul><li>Reaction 3 </li></ul><ul><ul><li>Factor X activation via complex formation. </li></ul></ul><ul><ul><ul><li>FIX  FIXa, FX is activated by IXa in concert with FVIII </li></ul></ul></ul>
  14. 19. Coagulation cascade <ul><li>Reaction 4 </li></ul><ul><ul><li>Conversion of prothrombin (FII)  thrombin in presence of FV, Ca + , PL </li></ul></ul><ul><ul><li>Thrombin- function:- </li></ul></ul><ul><ul><ul><li>Activates FV, FVIII, FXIII </li></ul></ul></ul><ul><ul><ul><li>Stimulates platlet aggregation and secretion </li></ul></ul></ul><ul><ul><ul><li>Stimulates release of fibrinopeptidase A and B from alpha and beta chains of fibrinogen </li></ul></ul></ul><ul><ul><ul><li>Fibrin monomer  polymerisation by FXIII </li></ul></ul></ul>
  15. 21. Uremic Bleed <ul><li>VWF </li></ul><ul><ul><li>VWF-GPIb/IX </li></ul></ul><ul><ul><ul><li>(+) TxA2 production </li></ul></ul></ul><ul><ul><ul><li>Activate GPIIb/IIIa receptors  promote platlet aggregation </li></ul></ul></ul><ul><ul><li>Dysfunctional VWF </li></ul></ul><ul><ul><ul><li>Decrease binding </li></ul></ul></ul><ul><ul><ul><ul><li>Decreased binding affinity for GPIb/IX receptors </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Reduce expression of GPIb/IX receptors on platlets </li></ul></ul></ul></ul><ul><ul><li>These decrease interaction </li></ul></ul><ul><ul><ul><li>Impair phosphatidylinositol breakdown </li></ul></ul></ul><ul><ul><ul><li>Alteration of cytosolic calcium concentration </li></ul></ul></ul><ul><ul><ul><ul><li>Decrease TXA2 and ADP production </li></ul></ul></ul></ul>
  16. 22. <ul><li>Factor VII </li></ul><ul><ul><li>Functional defect </li></ul></ul><ul><li>Cyclic adenosine monophosphate (CAMP) </li></ul><ul><ul><li>Uremia  higher Prostacyclin </li></ul></ul><ul><ul><ul><li>Vasodilator </li></ul></ul></ul><ul><ul><ul><li>Inhibitor of platlet aggregation </li></ul></ul></ul><ul><ul><ul><li>(+)adenylyl cyclase  CAMP  disrupt breakdown of phosphatidylinositol and alter ca mobilisation  reduction of TXA2 and ADP </li></ul></ul></ul>
  17. 23. <ul><li>Uremia </li></ul><ul><ul><li>Increase NO generation </li></ul></ul><ul><ul><ul><li>Increase Cyclic Guanosine Monophosphate (CGMP) </li></ul></ul></ul><ul><ul><li>Elevation of TNF-alpha and IL 1beta </li></ul></ul><ul><ul><ul><li>Induce NO synthase  increase NO  increase CGMP  reduce TxA2 and ADP </li></ul></ul></ul><ul><li>Uremic Toxins </li></ul><ul><ul><li>92 known uremic retention solutes </li></ul></ul><ul><ul><li>Mediators a/w uremic bleed </li></ul></ul><ul><ul><ul><li>Urea </li></ul></ul></ul><ul><ul><ul><li>Creatinine </li></ul></ul></ul><ul><ul><ul><li>Guanidinosuccinic acid (GSA) </li></ul></ul></ul><ul><ul><ul><li>Phonolic acids </li></ul></ul></ul><ul><ul><ul><li>Methylguanidine </li></ul></ul></ul>
  18. 24. <ul><li>Urea </li></ul><ul><ul><li>Excess causes shunting of L arginine from urea cycle </li></ul></ul><ul><ul><li>Then transfers an amidine group to aspartic acid  formation of GSA (guanidinosuccinic acid) </li></ul></ul><ul><ul><li>L arginine (+) NO synthesis  (+) guanylyl cyclase  (-) ADP induced platlet aggregation </li></ul></ul>
  19. 25. Anemia <ul><li>RBC reduction </li></ul><ul><ul><li>Platlets assumes more midstream position </li></ul></ul><ul><ul><ul><li>Less likely platlets will react to damaged vasculature </li></ul></ul></ul><ul><ul><li>RBC (+) ADP and TxA2 </li></ul></ul><ul><ul><li>Hb had high affinity for NO (NO scavenger) </li></ul></ul><ul><ul><li> decrease TxA2 production </li></ul></ul><ul><ul><li> less ADP mediated aggregation </li></ul></ul><ul><ul><li> reduce release of adhesive proteins </li></ul></ul><ul><ul><li> reduce release of growth modulators </li></ul></ul><ul><ul><li> reduce release of coagulation factors from alpha granules </li></ul></ul><ul><ul><li> reduce fewer changes in platlet morphology </li></ul></ul>
  20. 26. Assessment <ul><li>Typical presentation </li></ul><ul><ul><li>Eccymoses </li></ul></ul><ul><ul><li>Purpura </li></ul></ul><ul><ul><li>Epistaxis </li></ul></ul><ul><ul><li>Bleeding from venepuncture sites </li></ul></ul><ul><ul><li>GI bleed </li></ul></ul><ul><ul><li>Intraranial bleed </li></ul></ul><ul><li>Evaluation </li></ul><ul><ul><li>Bleeding time (1-7 minutes) </li></ul></ul><ul><ul><li>Mild thrombocytopenia (rarely < 80,000) </li></ul></ul><ul><ul><li>Normal PT, PTT </li></ul></ul>
  21. 28. Erythropoietin <ul><li>Prevents uremic bleeding by:- </li></ul><ul><ul><li>inducing erythropoiesis  increase in the number of circulating rbc  displaces platelets closer to the vascular endothelium  decreasing response time to vascular damage </li></ul></ul><ul><ul><ul><ul><li>Vigano G et al . (1991) Recombinant human erythropoietin to correct uremic bleeding. Am J Kidney Dis 18: 44–49 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Zwaginga JJ et al . (1991) Treatment of uremic anemia with recombinant erythropoietin also reduces the defects in platelet adhesion and aggregation caused by uremic plasma. Thromb Haemost 66: 638–647  </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cases A et al . (1992) Recombinant human erythropoietin treatment improves platelet function in uremic patients. Kidney Int 42: 668–672 </li></ul></ul></ul></ul><ul><ul><li>Increases reticulated platelets-metabolically active </li></ul></ul><ul><ul><ul><ul><li>Tassies D et al . (1998) Effect of recombinant human erythropoietin treatment on circulating reticulated platelets in uremic patients: association with early improvement in platelet function. Am J Hematol 59: 105–109  </li></ul></ul></ul></ul><ul><ul><li>enhances platelet aggregation and interaction between platelets and the subendothelium </li></ul></ul><ul><ul><li>improve platelet signaling through tyrosine phosphorylation  enhances the response of platelets to activating stimuli </li></ul></ul><ul><ul><ul><ul><li>Diaz-Ricart M et al . (1999) Erythropoietin improves signaling through tyrosine phosphorylation in platelets from uremic platelets. Thromb Haemost 82: 1312–1317  </li></ul></ul></ul></ul><ul><ul><li>scavenger of NO </li></ul></ul><ul><ul><ul><ul><li>  </li></ul></ul></ul></ul>
  22. 29. Erythropoietin <ul><li>Epo regimes:- 40-150u/kg IV 3X/week </li></ul><ul><li>Prevention and treatment </li></ul><ul><li>Goal: Hct >30% </li></ul><ul><ul><li>Takes up to 9 weeks </li></ul></ul><ul><ul><li>Beneficial effects on platlets  7 days </li></ul></ul>
  23. 31. Cryoprecipitate <ul><li>rich in factor VIII, vWF and fibrinogen </li></ul><ul><li>increase the proportion of functional clotting factors </li></ul><ul><li>beneficial effect on bleeding time within the first 4–12 h </li></ul><ul><li>Dosing is 10 bags of American-Red-Cross-prepared cryoprecipitate </li></ul><ul><li>fast onset of action (approximately 1 h) </li></ul><ul><li>Disadvantages </li></ul><ul><li>post-transfusion hepatitis, HIV, fever, and allergic reaction </li></ul><ul><li>Beneficial in patients who have received DDAVP </li></ul>
  24. 33. Desmopressin [DDAVP] (1-deamino-8-D-arginine vasopressin) <ul><li>most common agent used in uremic patients with active bleeding </li></ul><ul><li>predominately used to treat </li></ul><ul><ul><li>diabetes insipidus, </li></ul></ul><ul><ul><li>mild type I von Willebrand's disease, </li></ul></ul><ul><ul><li>and bleeding associated with hemophilia A </li></ul></ul>
  25. 34. Desmopressin [DDAVP] <ul><li>releasing factor VIII from storage sites </li></ul><ul><ul><li>increasing the concentration of factor VIII </li></ul></ul><ul><ul><li>minimizing the effects of dysfunctional vWF </li></ul></ul><ul><ul><li>larger vWF–factor-VIII multimers </li></ul></ul><ul><ul><li>strong association between their presence and shortening of bleeding time </li></ul></ul><ul><ul><li>doses for uremic bleeding are approximately 10-fold higher than doses used for diabetes insipidus </li></ul></ul>
  26. 35. Desmopressin [DDAVP] <ul><li>0.3 ug/kg to 0.4 ug/kg </li></ul><ul><li>intravenously or subcutaneously </li></ul><ul><li>single injection </li></ul><ul><li>Advantages:- </li></ul><ul><ul><li>decreases bleeding time within approximately 1 h after infusion or injection </li></ul></ul><ul><ul><li>bleeding time tended to return towards baseline within 24 h </li></ul></ul><ul><ul><li>avoidance of risk of exposure to various blood-borne pathogens </li></ul></ul>
  27. 36. Desmopressin [DDAVP] <ul><li>Disadvantages :- </li></ul><ul><ul><li>tachyphylaxis after one dose, </li></ul></ul><ul><ul><ul><li>caused by depletion of vWF from endothelial stores </li></ul></ul></ul><ul><ul><li>headache, </li></ul></ul><ul><ul><li>facial flushing, </li></ul></ul><ul><ul><li>rare thrombotic events. </li></ul></ul><ul><ul><ul><ul><li>Kohler M et al . (1989) Subcutaneous injection of desmopressin (DDAVP): evaluation of a new, more concentrated preparation. Hemostasis 1: 38–44 </li></ul></ul></ul></ul>
  28. 38. Estrogens <ul><li>Unsure mechanism of action:- </li></ul><ul><ul><li>Decrease L arginine production (precursor of NO)  decrease NO concentrations  Less guanylyl cyclase stimulation  less cGMP production  </li></ul></ul><ul><ul><ul><li>increase TxA2 and ADP production </li></ul></ul></ul><ul><ul><ul><li>Decrease antithrombin III </li></ul></ul></ul><ul><ul><ul><li>Decrease protein S levels </li></ul></ul></ul><ul><ul><ul><li>Increase FVII concentration </li></ul></ul></ul><ul><li>Conjugated estrogens  improve bleeding time and clinical bleeding (males and females) </li></ul>
  29. 39. Estrogens <ul><li>0.6mg/kg IV over 30 min daily </li></ul><ul><ul><li>X 5 days </li></ul></ul><ul><li>Onset of action- 6 hours </li></ul><ul><li>Max effect 5-7 days </li></ul><ul><li>Duration of action- 14-21 days </li></ul><ul><li>More data on IV </li></ul><ul><li>Also could use oral/transdermal </li></ul><ul><li>Imp for pt for EL surgeries </li></ul><ul><li>Successfully used in pt with GI bleed </li></ul><ul><ul><ul><li>Bronner MH et al . (1986) Estrogen–progesterone therapy for bleeding gastrointestinal telangiectasias in chronic renal failure. Ann Int Med 105: 371–374  </li></ul></ul></ul><ul><ul><ul><li>Sloand JA and Schiff MJ (1995) Beneficial effect of low-dose transdermal estrogen on bleeding time and clinical bleeding in uremia. Am J Kidney Dis 26: 22–26  </li></ul></ul></ul><ul><ul><ul><li>Heunisch C et al . (1998) Conjugated estrogens for the management of gastrointestinal bleeding secondary to uremia of acute renal failure. Pharmacotherapy 18: 210–217  </li></ul></ul></ul>
  30. 40. Estrogens <ul><li>Oral conjugated estrogens </li></ul><ul><ul><li>50mg dly for 7 days </li></ul></ul><ul><li>Transdermal estrogens </li></ul><ul><ul><li>50-100ug/d </li></ul></ul><ul><li>Estrogen-progesterone combination? </li></ul><ul><ul><li>Effective as well </li></ul></ul><ul><ul><ul><ul><li>Bronner MH et al . (1986) Estrogen–progesterone therapy for bleeding gastrointestinal telangiectasias in chronic renal failure. Ann Int Med 105: 371–374  </li></ul></ul></ul></ul>
  31. 44. Omega-3 fatty acids <ul><li>Can partially replace omega-6 fatty acids in cell membranes </li></ul><ul><ul><li>RBC </li></ul></ul><ul><ul><li>Platlets </li></ul></ul><ul><ul><li>Endothelial cells </li></ul></ul><ul><ul><li>Lymphocytes </li></ul></ul><ul><ul><li>Monocytes </li></ul></ul><ul><ul><li>Granulocytes </li></ul></ul><ul><ul><li>Fibroblast </li></ul></ul><ul><li>Competes with Omega-6 (involve in cyclooxygenase and lipoxygenase pathway  Pg and leucotriene production) </li></ul><ul><ul><li>Decrease TxA2 </li></ul></ul><ul><ul><li>Increase Prostacyclin </li></ul></ul><ul><ul><ul><li>Decrease chance of bleeding </li></ul></ul></ul>
  32. 45. Conclusion <ul><li>Uremic bleeding is extremely complex </li></ul><ul><li>Mechanism underlying uremic bleed is not fully understood </li></ul><ul><li>Treatment focus on few aspects of pathophysiology </li></ul><ul><ul><li>EPO </li></ul></ul><ul><ul><ul><li>Increase RBC  platlets get closer to endothelium </li></ul></ul></ul><ul><ul><li>Cryo/DDAVP </li></ul></ul><ul><ul><ul><li>Increase proportion of normal/functional clotting factors </li></ul></ul></ul><ul><ul><li>Estrogens </li></ul></ul><ul><ul><ul><li>Decreasing NO levels  increasing TxA2, ADP </li></ul></ul></ul>

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