Daniel C. Marko, MD Hematopathology/Transfusion Medicine Diagnostic Services of Manitoba

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3 Daniel C. Marko, MD Hematopathology/Transfusion Medicine Diagnostic Services of Manitoba

4 Disclosure of Potential Conflict of Interest I have no direct or indirect financial (or other) interests with companies whose products and/or services will be mentioned in this presentation. The material presented is for educational purposes only.

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8 Objectives Define uremia Clinical manifestations of uremia Normal platelet function Pathogenesis of platelet dysfunction in uremia Role of uremic toxins Role of nitric oxide Treatment

9 What is uremia?

10 Azotemia refers to high levels of urea or nitrogen (can be measured chemically, but no symptoms). Uremia Clinicopathological manifestations of severe azotemia

11 What is urea? Review of the urea cycle

12 Arginase Arginosuccinate Lyase Arginosuccinate Synthetase Ornithine Transcarbamylase Carbamoyl Phosphate Synthetase I NH CO 2 + 2ATP The urea cycle takes place primarily in the liver, and to a lesser extent in the kidney.

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14 Clinical Manifestations of Uremia

15 Clinical features of uremia Neural and muscular Fatigue, peripheral neuropathy, seizures, anorexia, nausea, decreased taste and smell, cramps, restless legs, sleep disturbance, daytime sleepiness, hiccups, coma, encephalopathy Cardiovascular Hypertension, atherosclerosis, coronary artery disease, pericarditis, uremic fetor, peripheral and pulmonary edema Skin Itching, skin dryness, uremic frost (excretion of urea through the skin) Hematological Anemia, granulocyte and lymphocyte dysfunction, platelet dysfunction Gastrointestinal Endocrine and metabolic Amenorrhea, altered levels of amino acids, bone disease by hyperphosphatemia, hyperparathyroidism, and vitamin D deficiency, reduced basal metabolic rate, insulin resistance, oxidative stress.. Azotemia is another word that refers to high levels of urea or a build up of azoles groups or nitrogen, but is used primarily when the abnormality can be measured chemically but is not yet so severe as to produce symptoms. Uremia is the pathological manifestations of severe azotemia

16 Clinical Manifestations of Bleeding Disorders Variable Platelet-type bleeding Coagulation-type bleeding Onset Spontaneous Following trauma, immediate Spontaneous Following trauma, delayed Location Skin, mucous membranes (epistaxis, gingival hemorrhage, menorrhagia) Deep soft tissue, joints (hemarthroses) Cutaneous findings Petechiae, purpura Hematomas

17 Azotemia is another word that refers to high levels of urea, but is used primarily when the abnormality can be measured chemically but is not yet so severe as to produce symptoms. Uremia is the pathological manifestations of severe azotemia Clinical/Lab Manifestations of Platelet Dysfunction in Uremia Most WHO Grade= 0 Most common w/bleeding: Grade 1 If Grade 3 occurs injury or surgery Degree of azotemia doesn t correlate w/ bleeding risk.

18 Lab Manifestations In vitro coagulation tests normal +/- thrombocytopenia Platelet function tests abnormal

19 Normal Platelet Function Urea indirectly disrupts platelet adherence, platelet activation, and platelet aggregation. So, it is important to know how platelets are normally activated

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21 Dense or alpha granules DG = diacylglycerol; IP 3 = inositol trisphosphate; P2Y 1, P2Y 12 = G-protein-coupled ADP receptors; PIP 2 = phosphatidylinositol bisphosphate; PKC= Protein kinase C

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23 Alpha Granules Fibrinogen Dense Bodies ADP Fibronectin Calcium Factor V & vwf Histamine Platelet factor 4 Serotonin Platelet-derived growth factor (PDGF) Epinephrine P-selectin Beta-thromboglobulin Thrombospondin

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25 Urea indirectly: Causes platelet dysfunction Inhibits platelet activation

26 Pathogenesis of Platelet Dysfunction in Uremia

27 Uremic Toxins* Abnormal plt adhesion/aggregation Abnormal expression of glycoproteins vwf abnormalities Defective scramblase activity Abnormal production of nitric oxide* Defective scramblase activity Platelet activation issues: Abnormal dense granule release & contents (esp. ADP & serotonin) Abnormal a-granule release Defective cyclooxygenase activity/arachidonic acid Anemia Erythropoietin deficiency Platelet function issues * Alternative pathways to detox ammonia

28 Uremic Toxins

29 Urea does not cause uremic platelet dysfunction No predictable correlation between the urea concentration (or BUN) & bleeding time Guanidinosuccinic acid & methylguanidine suggested toxins

30 H20 + Urea Arginine Guanidine Methylguanidine Methylamine

31 Abnormal expression of glycoproteins

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35 Abnormal expression of Scramblase

36 Toxins directly interfere Lack of calcium influx due to NO

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38 X

39 Stevic et al, Blood. 2011; 118 (21): 1179

40 Nitric Oxide

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44 NO Soluble guanylyl cyclase adenylyl cyclase GTP cgmp cgmp cyclic guanosine monophosphate phosphodiesterase 3 camp ATP cgmp-dependent protein kinases AMP IRAG Insoitol 1,4,5 triphosphate receptorassociated protein Protein Kinase C Inositol trisphosphate (IP 3 ) Ca ++ Pleckstrin Pleckstrin-P

45 Increase camp Defective cyclooxygenase activity X

46 Anemia & Platelet Dysfunction

47 Renal Disease: Decr. renal EPO production Oxygen Sensor Model X +/- in uremia

48 Hematocrit >.30 L/L rbc occupy center of vessel & plts skim at the endothelial surface Anemia plts are dispersed impairing adherence to endothelial surface Correction of anemia w/ transfusions or erythropoietic stimulating agents gives the plts a fighting chance

49 Treatment

50 Uremia + active bleeding Raising the hgb >100 g/l Desmopressin (ddavp) Cryoprecipitate Dialysis: 1] Prevents uremia 2] Corrects bleeding time in 2/3 pts w/ uremic bleeding Hemodialysis or peritoneal Long-term: Estrogens Dialysis Incr. hgb (if low) ddavp No response cryoprecipitate.

51 Desmopressin (ddavp) Increases release of FVIII:vWF multimers from endothelial cells May enhance glycoprotein expression Dose: 0.30 mcg/kg [IV (w/ 50 ml saline over minutes) or intranasally] Effects begins w/n 1hr Last 4-24 hrs Desmopressin: analog of antidiuretic hormone w/ little vasopressor activity

52 Correction of Anemia Goal Hgb > 100 g/l or hct >30% Acute: RBC transfusions * Chronic: Erythropoietic stimulating agents (ESAs) Darbepoetin alfa and epoetin Platelet Function Improvement??? ESA may incr. the # of GP IIb/IIIa Enhancement of Gq protein Enhancement of Ca++ uptake *No prospective randomized studies that directly compared outcomes with erythropoietic agents versus red blood cell transfusions in patients with anemia and CKD

53 Conjugated Estrogens 17-b estradiol thought to act by influx of Ca++ May decrease generation of NO Controls chronic bleeds Dose: IV (0.6 mg/kg q1dx5); Oral ( mg/day); Transdermal (100 mcg) Peak 5-7 days; Effects 1 weeks after discontinued. Limited safety data for use in men

54 Cryoprecipitate 6 units Improvement seen w/n 1 hr; last 4-24 hrs.

55 Role of Platelets

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58 References

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