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Uremic Bleed
 

Uremic Bleed

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Dr Chow Yok Wai

Dr Chow Yok Wai
Hospital Kuala Lumpur

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    Uremic Bleed Uremic Bleed Presentation Transcript

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