Anticoagulation in chronic kidney disease patients
1. Anticoagulation in chronic kidney
disease patients—the practical
aspects
Stephen Hughes,1 Iren Szeki,1
Michael J. Nash,2 and Jecko
Thachil2
2. 1. Lutz J, Menke J, Sollinger D, et al. Haemostasis in chronic kidney
disease. Nephrol Dial Transplant. 2014;29:29–40. [PubMed]
2. Ronco C, McCullough P, Anker SD, et al. The clinical management
of the Cardio-Renal syndromes: work group statements from the 7th
ADQI consensus conference. Nephrol Dial Transplant.
2010;25:2077–2089. [PubMed]
3. Wattanakit K, Cushman M, Stehman-Breen C, et al. Chronic kidney
disease increases risk for venous thromboembolism. J Am Soc
Nephrol. 2008;19:135–140. [PMC free article] [PubMed]
4. Pavord S, Myers B. Bleeding and thrombotic complications of kidney
disease. Blood Rev. 2011;25:271–278. [PubMed]
5. Ocak G, Verduijn M, Vossen CY, et al. Chronic kidney disease
stages 1–3 increase the risk of venous thrombosis. J Thromb
Haemost. 2010;8:2428–2435. [PubMed]
3. 6. Barbano B, Gigante A, Amoroso A, et al. Thrombosis in nephrotic
syndrome. Semin Thromb Hemost. 2013;39:469–476. [PubMed]
7. Wattanakit K, Cushman M. Chronic kidney disease and venous
thromboembolism: epidemiology and mechanisms. Curr Opin Pulm
Med. 2009;15:408–412. [PMC free article] [PubMed]
8. Boccardo P, Remuzzi G, Galbusera M. Platelet dysfunction in renal
failure. Semin Thromb Hemost. 2004;30:579–589. [PubMed]
9. Palmer SC, Di Micco L, Razavian M, et al. Antiplatelet agents for
chronic kidney disease. Cochrane Database Syst Rev.
2013;2:CD008834. [PubMed]
10. Krüger T, Brandenburg V, Schlieper G, et al. Sailing between Scylla
and Charybdis: oral long-term anticoagulation in dialysis patients.
Nephrol Dial Transplant. 2013;28:534–541. [PubMed]
4. 11. Davenport A. What are the anticoagulation options for intermittent
hemodialysis? Nat Rev Nephrol. 2011;7:499–508. [PubMed]
12. Casu B, Oreste P, Torri G, et al. The structure of heparin
oligosaccharide fragments with high anti-(factor Xa) activity
containing the minimal antithrombin III-binding sequence. Chemical
and 13C nuclear-magnetic-resonance studies. Biochem J.
1981;197:599–609. [PMC free article] [PubMed]
13. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants.
Chest. 2012;141(Suppl 2):e24S–e43S. [PMC free article] [PubMed]
5. 14. Linkins L-A, Dans AL, Moores LK, et al. Treatment and prevention
of heparin-induced thrombocytopenia: antithrombotic therapy and
Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012;141(Suppl 2):e495S–e530S. [PMC free article] [PubMed]
15. Bjornsson TD, Wolfram KM, Kitchell BB. Heparin kinetics
determined by three assay methods. Clin Pharmacol Ther.
1982;31:104–113. [PubMed]
16. de Swart CA, Nijmeyer B, Roelofs JM, et al. Kinetics of
intravenously administered heparin in normal humans. Blood.
1982;60:1251–1258. [PubMed]
6. 17. Olsson P, Lagergren H, Ek S. The elimination from plasma of
intravenous heparin. An experimental study on dogs and humans.
Acta Med Scand. 1963;173:619–630. [PubMed]
18. Baglin T, Barrowcliffe TW, Cohen A, et al. Guidelines on the use
and monitoring of heparin. Br J Haematol. 2006;133:19–34.
www.bcshguidelines.com/ (29 January 2014, date last accessed)
[PubMed]
19. National Institute for Health and Clinical Excellence (NICE) Venous
thromboembolic diseases: the management of venous
thromboembolic diseases and the role of thrombophilia testing.
2012 NICE full clinical guideline 144 June www.nice.org.uk. (29
January 2014, date last accessed)
20. Braunwald E, Antman E, Beasley J, et al. ACC/AHA guidelines for
the management of patients with unstable angina and non-ST-
segment elevation myocardial infarction. A report of the American
College of Cardiology/American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol. 2000;36:970–1062.
7. 21. Spinler SA, Inverso SM, Cohen M, et al. Safety and efficacy of
unfractionated heparin versus enoxaparin in patients who are obese
and patients with severe renal impairment: analysis from the
ESSENCE and TIMI 11B studies. Am Heart J. 2003;146:33–41.
[PubMed]
22. Thorevska N, Amoateng-Adjepong Y, Sabahi R, et al.
Anticoagulation in hospitalized patients with renal insufficiency: a
comparison of bleeding rates with unfractionated heparin vs
enoxaparin. Chest. 2004;125:856–863. [PubMed]
23. Anderson DR, O'Brien BJ, Levine MN, et al. Efficacy and cost of
low-molecular-weight heparin compared with standard heparin for
the prevention of deep vein thrombosis after total hip arthroplasty.
Ann Intern Med. 1993;119:1105–1112. [PubMed]
24. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced
thrombocytopenia in patients treated with low-molecular-weight
heparin or unfractionated heparin. N Engl J Med. 1995;332:1330–
1335. [PubMed]
8. 25. Handeland GF, Abildgaard U, Holm HA, et al. Dose adjusted
heparin treatment of deep venous thrombosis: a comparison of
unfractionated and low molecular weight heparin. Eur J Clin
Pharmacol. 1990;39:107–112. [PubMed]
26. Pfizer Ltd; Summary of Product Characteristics—Fragmin
(dalteparin) 10,000 IU/0.4 ml solution for injection.
http://www.medicines.org.uk/emc/medicine/26901/SPC/ (4
December 2014, date last accessed) [date of revision of the text
October 2012]
27. Sanofi Aventis; Summary of Product Characteristics—Clexane
(enoxaparin) Forte Syringes.
http://www.medicines.org.uk/emc/medicine/10054/SPC/ (4
December 2014, date last accessed) [date of revision of the text 19
February 2014]
9. 28. Leo Laboratories Ltd; Summary of Product Characteristics—
Innohep (tinzaparin) 20,000 IU/ml and Innohep syringe 20,000
IU/ml. https://www.medicines.org.uk/emc/medicine/2623/SPC. (4
December 2014, date last accessed) [date of revision of the text 24
February 2014]
29. Palm M, Mattsson C. Pharmacokinetics of heparin and low
molecular weight heparin fragment (Fragmin) in rabbits with
impaired renal or metabolic clearance. Thromb Res. 1985;40:129–
133. [PubMed]
30. Collet JP, Montalescot G, Fine E, et al. Enoxaparin in unstable
angina patients who would have been excluded from randomized
pivotal trials. J Am Coll Cardiol. 2003;41:8–14. [PubMed]
10. 31. Fox KA, Antman EM, Montalescot G, et al. The impact of renal
dysfunction on outcomes in the ExTRACT-TIMI 25 trial. J Am Coll
Cardiol. 2007;49:2249–2255. [PubMed]
32. Chow SL, Zammit K, West K, et al. Correlation of antifactor Xa
concentrations with renal function in patients on enoxaparin. J Clin
Pharmacol. 2003;43:586–590. [PubMed]
33. Bazinet A, Almanric K, Brunet C, et al. Dosage of enoxaparin
among obese and renal impairment patients. Thromb Res.
2005;116:41–50. [PubMed]
34. Shprecher AR, Cheng-Lai A, Madsen EM, et al. Peak antifactor Xa
activity produced by dalteparin treatment in patients with renal
impairment compared with controls. Pharmacotherapy.
2005;25:817–822. [PubMed]
11. 35. Schmid P, Brodmann D, Odermatt Y, et al. Study of
bioaccumulation of dalteparin at a therapeutic dose in patients with
renal insufficiency. J Thromb Haemost. 2009;7:1629–1632.
[PubMed]
36. Siguret V, Pautas E, Fevrier M, et al. Elderly patients treated with
tinzaparin (Innohep®) administered once daily (175 anti-Xa IU/kg):
anti-Xa and anti-IIa activities over 10 days. Thromb Haemost.
2000;84:800–804. [PubMed]
37. Pautas E, Gouin I, Bellot O, et al. Safety profile of tinzaparin
administered once daily at a standard curative dose in two hundred
very elderly patients. Drug Safety. 2002;25:725–733. [PubMed]
38. Montalescot G, Collet JP, Tanguy ML, et al. Anti-Xa activity relates
to survival and efficacy in unselected acute coronary syndrome
patients treated with enoxaparin. Circulation. 2004;110:392–398.
[PubMed]
12. 39. van Dongen CJ, van den Belt AG, Prins MH, et al. Fixed dose
subcutaneous low molecular weight heparins versus adjusted dose
unfractionated heparin for venous thromboembolism. Cochrane
Database Syst Rev. 2004;4 CD001100. [PubMed]
40. Summary of Product Characteristics—Exembol (Argatroban)
Mitsubishi Pharma Europe.
https://www.medicines.org.uk/emc/medicine/26622/SPC. (4
December 2014, date last accessed) [date of revision of the text 28
June 2012]
41. A Summary of Product Characteristics—Orgaran (Danaparoid)
Merck Sharp and Dohme LTD.
https://www.medicines.org.uk/emc/medicine/1386/SPC. (4
December 2014, date last accessed) [date of revision of the text 31
August 2013]
42. UK: GlaxoSmithKline; Summary of Product Characteristics—Arixtra
(fondaparinux) 5 mg, 7.5 mg, 10 mg pre-filled syringe.
https://www.medicines.org.uk/emc/medicine/15937/SPC. (4
13. 43. Limdi NA, Limdi MA, Cavallari L, et al. Warfarin dosing in patients
with impaired kidney function. Am J Kidney Dis. 2010;56:823–831.
[PMC free article] [PubMed]
44. Chan KE, Lazarus JM, Thadhani R, et al. Warfarin use associates
with increased risk for stroke in hemodialysis patients with atrial
fibrillation. J Am Soc Nephrol. 2009;20:2223–2233. [PMC free
article] [PubMed]
45. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney
dysfunction, and outcomes following acute myocardial infarction in
patients with atrial fibrillation. JAMA. 2014;311:919–28. [PubMed]
46. El-Abbadi M, Giachelli CM. Mechanisms of vascular calcification.
Adv Chronic Kidney Dis. 2007;14:54–66. [PubMed]
14. 47. Brodsky SV, Nadasdy T, Rovin BH, et al. Warfarin-related
nephropathy occurs in patients with and without chronic kidney
disease and is associated with an increased mortality rate. Kidney
Int. 2011;80:181–189. [PMC free article] [PubMed]
48. Bayer PLC; Summary of Product Characteristics—Xarelto
(Rivaroxaban)
https://www.medicines.org.uk/emc/medicine/21265/SPC. (4
December 2014, date last accessed) [date of revision of the text 6
January 2014]
49. Bristol-Myers Squibb-Pfizer; Summary of Product Characteristics—
Eliquis (Apixiban)
https://www.medicines.org.uk/emc/medicine/27220/SPC. (4
December 2014, date last accessed) [date of revision of the text 1
October 2013]
50. Boehringer Ingelheim Limited; Summary of Product Characteristics
—Pradaxa (Dagibatran)
https://www.medicines.org.uk/emc/medicine/20760/SPC. (4
15. 51. MHRA. Drug safety update. Dabigatran (Pradaxa): risk of serious
haemorrhage—contraindications clarified and reminder to monitor renal
function. Med Healthc Prod Regul Agency. 2012;5
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON175429.
(4 December 2014, date last accessed) [date of revision of the text 21 july
2014]
52. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail
elderly. N Engl J Med. 2012;366:864–866. [PubMed]
53. Granger CB, Chertow GM. A pint of sweat will save a gallon of blood: a call
for randomized trials of anticoagulation in end stage renal disease.
Circulation. 2014;129:1190–1192. [PubMed]
16. referencia 7
• 1. Cushman M. Epidemiology and risk factors for venous
thrombosis. Semin Hematol. 2007;44:62–69. [PMC free article]
[PubMed]
• 2. Silverstein RL, Bauer KA, Cushman M, et al. Venous thrombosis
in the elderly: more questions than answers. Blood. 2007;110:3097–
3101. [PubMed]
• 3. Phlogose Virchow R, Thrombose im Gefä βsystem . Gesammelte
Abhandlungen zur Wissenschaftlichen Medizin. Frankfurt, Germany:
1856.
• 4. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic
kidney disease in the United States. J Am Med Assoc.
2007;298:2038–2047. [PubMed]
• 5. US Renal Data Systems. USRDS 2006 Annual Data Report: Atlas
of end-stage renal disease in the United States. Bethesda, MD:
National Institutes of Health, National Institute of Diabetes and
Digestive and Kidney Diseases; 2007.
17. • 6. Kottgen A, Selvin E, Stevens LA, et al. Serum cystatin C in the
United States: the Third National Health and Nutrition Examination
Survey (NHANES III) Am J Kidney Dis. 2008;51:385–394. [PubMed]
• 7. Levey AS, Stevens LA, Schmid CH, et al. A new equation to
estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–
612. [PMC free article] [PubMed]
• 8. Guntupalli K, Soffer O, Baciewicz P. Pulmonary embolism in end
stage renal disease. Intensive Care Med. 1990;16:405–407.
[PubMed]
• 9. Mossey RT, Kasabian AA, Wilkes BM, et al. Pulmonary
embolism: low incidence in chronic renal failure. Arch Intern Med.
1982;142:1646–1648. [PubMed]
• 10. Rotter W, Roettger P. Comparative pathologic-anatomic study of
cases of chronic global renal insufficiency with and without
preceding hemodialysis. Clin Nephrol. 1973;1:257–265. [PubMed]
18. • 11. Wiesholzer M, Kitzwogerer M, Harm F, et al. Prevalence of
preterminal pulmonary thromboembolism among patients on
maintenance hemodialysis treatment before and after introduction of
recombinant erythropoietin. Am J Kidney Dis. 1999;33:702–708.
[PubMed]
• 12. Tveit DP, Hypolite IO, Hshieh P, et al. Chronic dialysis patients
have high risk for pulmonary embolism. Am J Kidney Dis.
2002;39:1011–1017. [PubMed]
• 13••. Wattanakit K, Cushman M, Stehman-Breen C, et al. Chronic
kidney disease increases risk for venous thromboembolism. J Am
Soc Nephrol. 2008;19:135–140. [PMC free article]
[PubMed]Describes the association of CKD with risk of VTE in a
prospective study of the general population.
• 14••. Mahmoodi BK, Gansevoort RT, Veeger NJ, et al.
Microalbuminuria and risk of venous thromboembolism. J Am Med
Assoc. 2009;301:1790–1797. [PubMed]Describes the association of
microalbuminuria, the earliest form of CKD, with risk of VTE in a
prospective study of the general population; however, individuals
with kidney damage were not excluded from analysis.
19. • 15. Llach F, Papper S, Massry SG. The clinical spectrum of renal
vein thrombosis: acute and chronic. Am J Med. 1980;69:819–827.
[PubMed]
• 16. Lilova MI, Velkovski IG, Topalov IB. Thromboembolic
complications in children with nephrotic syndrome in Bulgaria
(1974–1996) Pediatr Nephrol. 2000;15:74–78. [PubMed]
• 17•. Mahmoodi BK, ten Kate MK, Waanders F, et al. High absolute
risks and predictors of venous and arterial thromboembolic events in
patients with nephrotic syndrome: results from a large retrospective
cohort study. Circulation. 2008;117:224–230. [PubMed]Describes
the association of nephrotic syndrome with risk of VTE.
• 18. Velasquez Forero F, Garcia Prugue N, Ruiz Morales N.
Idiopathic nephrotic syndrome of the adult with asymptomatic
thrombosis of the renal vein. Am J Nephrol. 1988;8:457–462.
[PubMed]
20. • 19•. Kayali F, Najjar R, Aswad F, et al. Venous thromboembolism in
patients hospitalized with nephrotic syndrome. Am J Med.
2008;121:226–230. [PubMed]Describes the association of nephrotic
syndrome with risk of VTE.
• 20. Abbott KC, Cruess DF, Agodoa LY, et al. Early renal
insufficiency and late venous thromboembolism after renal
transplantation in the United States. Am J Kidney Dis. 2004;43:120–
130. [PubMed
• 21. Poli D, Zanazzi M, Antonucci E, et al. High rate of recurrence in
renal transplant recipients after a first episode of venous
thromboembolism. Transplantation. 2005;80:789–793. [PubMed]
• 22•. Keller C, Katz R, Cushman M, et al. Association of kidney
function with inflammatory and procoagulant markers in a diverse
cohort: a cross-sectional analysis from the Multi-Ethnic Study of
Atherosclerosis (MESA) BMC Nephrol. 2008;9:9. [PMC free article]
[PubMed]Describes differences in levels of hemostasis biomarkers
with CKD.
• 23. Vaziri ND, Branson HE, Ness R. Changes of coagulation factors
IX, VIII, VII, X, and V in nephrotic syndrome. Am J Med Sci.
1980;280:167–171. [PubMed]
21. • 24. Shlipak MG, Fried LF, Crump C, et al. Elevations of
inflammatory and procoagulant biomarkers in elderly persons with
renal insufficiency. Circulation. 2003;107:87–92. [PubMed]
• 25. Kraaijenhagen RA, in't Anker PS, Koopman MM, et al. High
plasma concentration of factor VIIIc is a major risk factor for venous
thromboembolism. Thromb Haemost. 2000;83:5–9. [PubMed]
• 26. Koster T, Blann AD, Briet E, et al. Role of clotting factor VIII in
effect of von Willebrand factor on occurrence of deep-vein
thrombosis. Lancet. 1995;345:152–155. [PubMed]
• 27. van Hylckama Vlieg A, van der Linden IK, Bertina RM,
Rosendaal FR. High levels of factor IX increase the risk of venous
thrombosis. Blood. 2000;95:3678–3682. [PubMed]
• 28. Meijers JC, Tekelenburg WL, Bouma BN, et al. High levels of
coagulation factor XI as a risk factor for venous thrombosis. N Engl
J Med. 2000;342:696–701. [PubMed]
22. • 29. van Hylckama Vlieg A, Rosendaal FR. High levels of fibrinogen
are associated with the risk of deep venous thrombosis mainly in the
elderly. J Thromb Haemost. 2003;1:2677–2678. [PubMed]
• 30. Cushman M, Folsom AR, Wang L, et al. Fibrin fragment D-dimer
and the risk of future venous thrombosis. Blood. 2003;101:1243–
1248. [PubMed]
• 31. Vaziri ND, Paule P, Toohey J, et al. Acquired deficiency and
urinary excretion of antithrombin III in nephrotic syndrome. Arch
Intern Med. 1984;144:1802–1803. [PubMed]
• 32. Marciniak E, Farley CH, DeSimone PA. Familial thrombosis due
to antithrombin 3 deficiency. Blood. 1974;43:219–231. [PubMed]
• 33. Robert A, Olmer M, Sampol J, et al. Clinical correlation between
hypercoagulability and thromboembolic phenomena. Kidney Int.
1987;31:830–835. [PubMed]
23. • 34. Cosio FG, Batard MA, Brandt JT, Griffin JH. Plasma
concentrations of the natural anticoagulants protein C and protein S
in patients with proteinuria. J Lab Clin Med. 1985;106:218–222.
[PubMed]
• 35. Allon M, Soffer O, Evatt BL, et al. C antigen levels in proteinuric
patients: dependence on type of glomerular pathology. Am J
Hematol. 1989;31:96–101. [PubMed]
• 36. Sirolli V, Ballone E, Garofalo D, et al. Platelet activation markers
in patients with nephrotic syndrome. A comparative study of different
platelet function tests. Nephron. 2002;91:424–430. [PubMed]
• 37. Tkaczyk M, Baj Z. Surface markers of platelet function in
idiopathic nephrotic syndrome in children. Pediatr Nephrol.
2002;17:673–677. [PubMed]
• 38. Jackson CA, Greaves M, Patterson AD, et al. Relationship
between platelet aggregation, thromboxane synthesis and albumin
concentration in nephrotic syndrome. Br J Haematol. 1982;52:69–
77. [PubMed]
24. • 39. Schieppati A, Dodesini P, Benigni A, et al. The metabolism of
arachidonic acid by platelets in nephrotic syndrome. Kidney Int.
1984;25:671–676. [PubMed]
• 40. Ay C, Simanek R, Vormittag R, et al. High plasma levels of
soluble P-selectin are predictive of venous thromboembolism in
cancer patients: results from the Vienna Cancer and Thrombosis
Study (CATS) Blood. 2008;112:2703–2708. [PubMed]
• 41. Kyrle PA, Hron G, Eichinger S, Wagner O. Circulating P-selectin
and the risk of recurrent venous thromboembolism. Thromb
Haemost. 2007;97:880–883. [PubMed]
• 42. Folsom AR, Cushman M, Heckbert SR, et al. Prospective study
of fibrinolytic markers and venous thromboembolism. J Clin
Epidemiol. 2003;56:598–603. [PubMed]
• 43. Lisman T, de Groot PG, Meijers JC, Rosendaal FR. Reduced
plasma fibrinolytic potential is a risk factor for venous thrombosis.
Blood. 2005;105:1102–1105. [PubMed]
• 44. Lau SO, Tkachuck JY, Hasegawa DK, Edson JR. Plasminogen
and antithrombin III deficiencies in the childhood nephrotic
syndrome associated with plasminogenuria and antithrombinuria. J
Pediatr. 1980;96:390–392. [PubMed]