A 55 year old with severe sepsis develops Heparin Induced Thrombotic Thrombocytopenia Syndrome (HITTS) while on continuous veno-venous haemodiafiltration (CVVHDF).

Outline the strategies available for prolonging the life of the CVVHDF circuit in this patient, mentioning the advantages and disadvantages of each strategy.

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College Answer

No Anticoagulant +/- Saline Flushes (50-100ml every hour)

* Ensure good wide bore access, high flow rates, consider predilution
Advantage: 
Minimizes bleeding risk, but consumption of platelets and factors by membrane
(theoretical)

Disadvantage: 
Shortened filter life / increased time off dialysis

Regional citrate 
Advantage: 
Provides good regional anticoagulation
Pre-mix solutions and protocols for use have simplified process
Disadvantage 
Labor intensive,
Requires diligent monitoring of serum sodium, ionized calcium, and bicarbonate
Requires infusion of calcium outside the circuit (access issues) Large sodium load occurs when trisodium citrate used
May cause alkalosis
Special diasylate required: hyponatraemic, without buffer, Ca free
Not appropriate in liver failure

Prostacycline and Analogues 
Advantages 
Reduced bleeding risk
Disadvantages 
Shorter filter life
Hypotension

Direct thrombin Inhibitors: Hirudin / Lepirudin / Argatroban

Advantages:

Linear relationship between levels and APTT (<100s) for Hirudin

Disadvantages 
Renal clearance, accumulation in renal failure (Hirudin, Lepirudin) Hepatic metabolism, accumulation in liver disease (Argatroban) No antagonist
Argatroban falsely raises INR / PT Expense

Other agents Danaparoid Limited availability
Risk of cross-reactivity with heparin-induced antibodies

Serine Protease inhibitors (nafamostat) 
limited experience, massive cost

Fondaparinux 
Not readily available
Limited evidence supporting its use

Warfarin  /NSAIDS

Discussion

Thus question would have benefited from a tabulated answer.

In the table below, I have included heparin, for completeness. However one would be well-advised to omit heparin from their answer in the exam.

If one were to review only one resource for this answer, one would be satisfied by this article from Tolwani and Wille.

Methods of Prolonging the CVVHDF Filter Lifespan
Strategy Advantages Disadvantages
Nothing whatsoever 
(+/- regular saline flushes)
  • Circuit lifespan may still be acceptable for patients at high risk of bleeding (i.e. those who have "anticoagulated" themselves)
  • This will not benefit patients with HIT who are actually prothrombotic; another systemic anticoagulant will be required.
  • May not be suitable for patients with a normal or mildly impaired clotting function
High flow rate
  • Easy and cheap
  • Safe - no added pharmacological complications
  • Relies on a good vas cath position and a calm compliant patient.
  • The vas cath has to be reasonably widebore, which can increase the risk of vascular complications
  • The higher flow rate may not be tolerated by hemodynamically unstable patients
Filtration fraction under 25%
  • Maintains post-filter haematocrit <45% to keep the circuit from clotting
  • Allows use of post-dilution, maintains small solute clearance efficiency
  • May not be an option if fluid removal is required
  • Decreases efficiency of middle molecule clearance
Pre-dilution 
  • Routine and well-rehearsed modality
  • Reasonably safe in most patient groups
  • Cheap
  • Reasonable convective clearance of middle molecules
Unfractionated heparin
  • Routine and well-rehearsed modality
  • Reasonably safe in most patient groups
  • Cheap
  • Anticoagulation is easily reversible
  • Anticoagulation is short-term
  • Does not rely on renal clearance
  • Unsuitable for HIT patients
  • May cause HIT
  • May be unsuitable for patients at high risk of bleeding
Regional anticoagulation with heparin and protamine
  • Advantageous for patients at high risk of bleeding in whom filter lifespan is still reduced due to clotting
  • Reversal of anticoagulation at the end of the circuit decreases the risk of bleeding complications
  • Unsuitable for HIT patients
  • Cumbersome protocols, greatly increased workload
  • The heparin–protamine complex is taken up
    by the reticuloendothelial system and broken down, but
    then heparin and protamine are released back into the
    circulation.
  • Protamine has known disadvantages:
    • Protamine can act as an anticoagulant
    • Protamine causes pulmonary hypertension
Low molecular weight heparin
  • More convenient (boluses vs. infusion)
  • Identical filter life to unfractionated heparin
  • May be safer in terms of bleeding risk.
  • Lower incidence of HIT
  • No need for monitoring (or, rather, monitoring is too difficult and we give up)
  •  
  • More expensive compared to unfractionated heparin
  • Clearance is renal; there is the potential for accumulation
  • May be unsafe in patients at high risk of bleeding
Warfarin
  • Cheap
  • The patient may already be warfarinised
  • No evidence for benefit in preventing catheter thrombosis
  • Difficult to initiate
  • Slow to reverse
  • Metabolism affected by numerous factors
Platelet function inhibitors:
NSAIDs, aspirin, etc
  • Difficult to monitor
  • No reversal agent - irreversible inhibition
  • Long term effects
  • Many of these drugs rely on renal clearance
Citrate
  • Reversible
  • Effective
  • Pre-mix solutions have simplified this process; protocols exist to guide the inexperienced
  • Cumbersome protocol; greatly increased workload
  • Requires frequent monitoring:
    • Sodium
    • Calcium
    • Bicarbonate (or pH)
  • If you are using trisodium citrate, you end up giving a massive amount of sodium
  • Acidosis may result due to excess citrate
  • Alkalosis may result when that citrate is metabolised
  • In hepatic failure, this is contraindicated (as citrate is metabolised mainly by the liver)
  • Special calcium-free hyponatraemic and bufferless dialysate is required
  • If the patient has HITTS, they will still require some sort of systemic anticoagulation
  • Risk of toxicity
    • High anion gap metabolic acidosis
    • Ionised hypocalcemia
Direct thrombin inhibitors:
Hirudin / Lepirudin 
Bivalirudin / Argatroban
  • Alternative to heparin in HIT
  • Argatroban has a short halflife and is metabolised by the liver
  • There is a predictable near-linear relationship between hirudin levels and APTT
  • Expensive
  • Hirudin, lepirudin and bivalirudin are renally excreted; halflife will be prolonged
  • Argobatran is metabolised by the liver - halflife will be prolonged in liver failure
  • Argatroban falsely raises PT and INR.
  • All these molecules are too large to be removed by CRRT membranes, and will accumulate.
  • No reversal agent
Heparinoids (Danaparoid)
  • Expensive
  • Cross-reactivity with heparin/platelet antibodies (in 5%)
  • Long half life (48 hrs)
  • No reversal agent
  • Higher risk of bleeding than with heparin
Xa inhibitors: Fondaparinux
  • Renally cleared; may accumulate in high doses
  • Long halflife (15-20hrs)
  • No reversal agent
Serine protease inhibitors: Nafamostat
  • Suppresses neutrophil activity and may cause agranulocytosis
  • May cause increased bilirubin levels
  • Clearance relies on serum esterases, which may be decreased in chronic liver disease
  • May decrease protein C activity, leading to paradoxically increased circuit clotting
  • May cause anaphylaxis
  • May cause hyperkalemia
Prostacyclin (PGI2)
  • Very short half life (90 seconds)
  • Probably safe
  • Decreases platelet consumption in the circuit
  • Can be used together with heparin for a combined effect, as a "heparin-sparing" agent.
  • Hypotension from vasodilation
  • Ridicuously expensive
  • If the patient has HITTS, they will still require some sort of systemic anticoagulation

This table is reproduced with minimal changes in the Required Reading section on this topic.

References

Lewis, P. J., and C. T. Dollery. "Clinical pharmacology and potential of prostacyclin." British medical bulletin 39.3 (1983): 281-284.

 

Fiaccadori, Enrico, et al. "Continuous haemofiltration in acute renal failure with prostacyclin as the sole anti-haemostatic agent." Intensive care medicine 28.5 (2002): 586-593.

 

Han, Sang Jin, et al. "Use of nafamostat mesilate as an anticoagulant during extracorporeal membrane oxygenation." Journal of Korean medical science26.7 (2011): 945-950.

 

Hu, Z. J., et al. "Time course of activated coagulation time at various sites during continuous haemodiafiltration using nafamostat mesilate." Intensive care medicine 25.5 (1999): 524-527.

 

Akizawa, T., et al. "Nafamostat mesilate: a regional anticoagulant for hemodialysis in patients at high risk for bleeding." Nephron 64.3 (1993): 376-381.

 

Wester, J. P., et al. "Low-dose fondaparinux in suspected heparin-induced thrombocytopenia in the critically ill." Neth J Med 65.3 (2007): 101-108.

 

Mahieu, Elien, et al. "Anticoagulation With Fondaparinux for Hemodiafiltration in Patients With Heparin‐Induced Thrombocytopenia: Dose‐Finding Study and Safety Evaluation." Artificial organs 37.5 (2013): 482-487.

 

Morabito, Santo, et al. "Continuous renal replacement therapies: anticoagulation in the critically ill at high risk of bleeding." Journal of nephrology16.4 (2003): 566-571.

 

Tan, H. K., I. Baldwin, and R. Bellomo. "Continuous veno-venous hemofiltration without anticoagulation in high-risk patients." Intensive care medicine 26.11 (2000): 1652-1657.

 

Tolwani, Ashita J., and Keith M. Wille. "THE CLINICAL APPLICATION OF CRRT—CURRENT STATUS: Anticoagulation for Continuous Renal Replacement Therapy." Seminars in dialysis. Vol. 22. No. 2. Blackwell Publishing Ltd, 2009.

 

Davies, H. T., et al. "A randomized comparative crossover study to assess the affect on circuit life of varying pre-dilution volume associated with CVVH and CVVHDF." The International journal of artificial organs 31.3 (2008): 221-227.

 

Davenport, Andrew. "Pre-dilution or post-dilution fluid replacement for continuous veno-venous hemofiltration: that is the question." Nephron Clinical Practice 94.4 (2004): c83-c84.

 

Davies, Hugh, and Gavin Leslie. "Maintaining the CRRT circuit: non-anticoagulant alternatives." Australian Critical Care 19.4 (2006): 133-138.

 

Reeves, John H., et al. "A controlled trial of low-molecular-weight heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous venovenous hemodialysis with filtration." Critical care medicine 27.10 (1999): 2224-2228.

 

Jeffrey, R. F., et al. "Anticoagulation with low molecular weight heparin (Fragmin) during continuous hemodialysis in the intensive care unit." Artificial organs 17.8 (1993): 717-720.

 

Wilkieson, Trevor J., et al. "Low-intensity adjusted-dose warfarin for the prevention of hemodialysis catheter failure: a randomized, controlled trial."Clinical Journal of the American Society of Nephrology 6.5 (2011): 1018-1024.

 

Teraoka, Satoshi, et al. "Heparin-free hemodialysis with an oral anti-platelet agent." ASAIO journal 38.3 (1992): M560-M563.

 

De Pont, Anne-Cornelie JM, et al. "Pharmacokinetics and pharmacodynamics of danaparoid during continuous venovenous hemofiltration: a pilot study."Critical Care 11.5 (2007): R102.

 

Haase, Michael, et al. "Use of fondaparinux (ARIXTRA®) in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II." Nephrology Dialysis Transplantation 20.2 (2005): 444-446.

 

Ho, Grace, et al. "Use of fondaparinux for circuit patency in hemodialysis patients." American Journal of Kidney Diseases 61.3 (2013): 525-526.