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NDT Advance Access originally published online on March 22, 2006
Nephrology Dialysis Transplantation 2006 21(6):1721-1724; doi:10.1093/ndt/gfl124
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Teaching Point
(Section Editor: A. Meyrier)

Sudden collapse during haemodialysis due to immune-mediated heparin-induced thrombocytopaenia

Andrew Davenport

University College London Center for Nephrology, Royal Free Hospital, Pond Street, London NW3 2QG, UK

Correspondence and offprint requests to: Andrew Davenport. Email: Andrew.davenport{at}royalfree.nhs.uk

Keywords: cardiac arrest; haemodialysis complication; heparin; HIT; pseudo-pulmonary embolus; thrombocytopaenia



   Introduction
Top
 Introduction
Case
 Discussion
 Teaching points
 References
 
Heparin is the most commonly used extracorporeal anticoagulant for haemodialysis. Although it is well recognized that heparin can cause minor thrombocytopaenia when patients first start haemodialysis and are exposed to heparin, due to heparin binding to platelet factor 4 (PF4), there is a second type of heparin-induced thrombocytopaenia (HIT type II), which is immune-mediated. This is a relatively rare syndrome, with a reported prevalence varying from 0 to 5% in chronic haemodialysis patients [1–4]. It has been reported to occur more frequently with bovine, than porcine unfractionated heparin (UFH), and with UFH more than low molecular weight heparins and heparinoids [5]. Typically, IgG isotype antibodies develop after 5–10 days of exposure to heparin. These antibodies recognize an epitope on the heparin–PF4 complex, resulting in their binding to the Fc{gamma} RIIA receptors on the platelet surface and cross-linking of the receptors. This further leads to platelet activation and aggregation, with additional release of PF4, platelet-derived micro-particles and thrombin generation. In some cases, antibodies are IgA or IgM isotypes, and in certain others, the antibodies are directed against other antigens including IL-8 and leucocytes, that lead to platelet activation and aggregation. These activated platelets and platelet microthrombi are rapidly cleared by the reticulo-endothelial system, resulting in peripheral blood thrombocytopaenia.

With the development of readily available assays to detect circulating antibodies and heparin–PF4 complexes, the reported prevalence of positive assay results in stable chronic haemodialysis patients is much greater than that of clinical complications [4–6]. HIT type II is a procoagulant state, and such patients may present clinically with clots in the vascular access and the dialyser [7–8]. Occasionally, infrequently a systemic reaction occurs following a heparin bolus, such as at the start of haemodialysis, characterized by pyrexia, hypertension and tachycardia. Rarely do acute hypotensive emergencies occur shortly after the commencement of haemodialysis, which may be fatal. Once HIT type II is suspected, exposure to various kinds of heparins (including low molecular weight heparins) is mandatory. The following case typifies the so-called ‘pseudo-pulmonary embolus’ syndrome [9] and emphasizes the importance of excluding exposure to even small amounts of heparin in a patient with HIT type II.



   Case
Top
 Introduction
 Case
Discussion
 Teaching points
 References
 
A 73-year-old type II diabetic man with a history of a previous anterior myocardial infarction some 13 months earlier, was admitted with end-stage renal failure and commenced haemodialysis through a right internal jugular venous dual lumen catheter. He was anticoagulated with UFH (Multiparin, CP Pharmaceuticals, Wrexham, UK) during dialysis, with a loading dose of 500 IU and a maintenance dose varying between 500–1000 IU/h. The dialysis circuit was rinsed with 1.0 l of normal saline, and a polysulphone membrane dialyser was used (F6, Fresenius, Runcorn, UK). During the fifth haemodialysis session, the venous pressure increased from 80 to 280 mmHg (Table 1), despite a reduction in the blood pump speed to 180 ml/min. The dialysis catheter which had been locked with 2.0 ml of UFH (10 000 IU) in each lumen, was then locked with 2 mg of tPA, in view of the poor blood flow and high venous pressure. The peripheral platelet count, which had been 120 x 1012/l, had fallen to 44 x 1012/l (Figure 1), and HIT type II was suspected. He received UFH for 6 days.


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  		Table 1. Arterial (AP) and venous (VP) circuit pressures and measured blood pump speed (Qb) during haemodialysis sessions

 

Figure 1
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  		Fig. 1. Peripheral platelet count prior to and during admission. Arrows denote days on which patient had haemodialysis treatment.

 
The dialysis catheter was removed on the following day due to malfunction. A new dialysis catheter was inserted, and following insertion was capped off with UFH, and then the patient was sent for haemodialysis. Once again he was given both a loading dose and maintenance dose of UFH. Flow through the new dialysis catheter was poor, with an arterial pressure of –180 mmHg, and a venous pressure of 220 mmHg, which rose to 300 mmHg, and the blood flow was reduced from 300 to 250 ml/min. Post dialysis, the catheter was locked with UFH.

The result of the ELISA for HIT type II that became available (Quest laboratories, Surrey, UK), was strongly positive, and followed the correction for both heparin and enoxaparin at 93%. Thereafter, all subsequent dialysis prescription charts were marked HIT to avoid heparin. The next two dialysis sessions were heparin free, using predialyser saline boluses. Blood pump speeds varied between 200 and 250 ml/min, with the arterial and venous pressures increasing during the two sessions from –100 to –200 mmHg, and 100–240 mmHg, respectively. The patient's general condition was improving and he was due for discharge following his next dialysis treatment. At the start of the third heparin-free haemodialysis, the initial pressures were high—arterial, –240 mmHg and venous, 200 mmHg—with a blood flow of 150 ml/min, and within a few minutes of starting the dialysis session he felt light headed, became profoundly hypotensive, with an unrecordable blood pressure and suffered a cardiac arrest. He was found to be very hypoxic PaO2 of 2.24 kPa (17 mmHg in asystole, profound hypoxia with an arterial PaCO2 of 6.34 kPa (48 mmHg), and could not be resuscitated.



   Discussion
Top
 Introduction
 Case
 Discussion
Teaching points
 References
 
In this case, the peripheral platelet count fell slightly following initial exposure to heparin, and then started to fall precipitously some 6 days later (Figure 1). In addition to thrombocytopaenia, there were also mechanical problems with the central venous access catheter, typified by high arterial and venous pressures at relatively low blood pump speeds, such that tPA was administered to try and lyse catheter-associated thrombus, and as this was unsuccessful, the catheter was removed. Clinically, HIT type II was suspected and all subsequent haemodialysis treatments prescribed were heparin free, with no heparin added to the extracorporeal priming fluid, and no heparin used to flush the central venous catheter prior to connection to the dialysis machine. Typically, following heparin withdrawl, the platelet count usually recovers within 5–10 days. In this case, although HIT type II was suspected, the platelet count had still not recovered even 10 days after the clinical diagnosis. This was because the patient received a heparin lock when the second central venous access catheter was inserted, as the clinical diagnosis had not been communicated, and similarly the patient inadvertently received UFH during the first haemodialysis post-catheter insertion. Thereafter, the patient continued to have UFH locks placed in the venous catheter post-dialysis treatments. Heparin locks do lead to the leaking of heparin from the catheter tip into the systemic circulation, especially if the catheter is over-filled [10]. In addition, at the start of the next dialysis, the patient inadvertently receives a bolus of heparin due to flushing of the catheter. The amount of heparin retained in the catheter between dialyses, depends not only on the concentration of the heparin solution used to cap off the catheter, but also the catheter design [14]. This highlights both the difficulty in and the importance of avoiding all heparin exposure.

HIT type II is essentially a clinical diagnosis combined with laboratory confirmation. However, Warkentin and Greinacher have suggested that a pre-test probability score can be used to assess the likelihood of HIT type II in patients, based upon the severity of the thrombocytopaenia, the timing of the onset of the fall in peripheral platelet count, the occurrence of thrombosis, or an acute systemic reaction and the exclusion of other causes of thrombocytopaenia (Table 2). This patient had a pre-laboratory antibody test probability score of 7, and therefore was highly likely to have HIT type II. This was confirmed in the laboratory with an ELISA using a correction step to exclude false positive results. The gold-standard laboratory test for HIT antibodies is the serotonin release assay (SRA), where the antibodies in the patient's serum activate platelets in vitro, releasing serotonin. Unfortunately, the SRA is very time consuming and expensive, and although it is very specific, has a low sensitivity [12]. Thus, a negative test does not necessarily exclude the diagnosis. In general, the functional tests (SRA and particle gel immunoassay, which agglutinates in the presence of heparin-PF4 antibody) are better at detecting clinically significant HIT antibodies, whereas immunoassays though are technically easier and more sensitive, give more false positive results, and therefore require additional correction steps [11–12].


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  		Table 2. Clinical and laboratory criteria to determine likelihood of immune-mediated HIT [11]. Pre-test probability score: ≤3 = low, 4–5 intermediate, ≥6 = high

 
The differential diagnosis of sudden hypotensive collapse at the start of haemodialysis before any ultrafiltration is wide, range from acute myocardial dysfunction (infarction, arrhythmia and/or tamponade), pulmonary embolus, sepsis or air embolus to anaphylactoid reactions. HIT type II can cause acute dyspnoea and cardiovascular collapse [9,13]. In this case, the dialysis catheter was flushed with n-saline prior to connecting the patient to the dialysis circuit, thus flushing the remaining UFH in the dialysis catheter into the patient [14]. On connecting the patient to the dialysis circuit, and starting with a modest blood pump speed, very high arterial and venous pressures were recorded. The clinical scenario of collapse, shortly after an intravenous heparin bolus, was most likely to be one of HIT type II ‘pseudo-pulmonary embolus’ [9]. This is not due to a major pulmonary embolus, but is thought to be due to an endothelial injury, with sudden augmented release of IL-6, von Willebrand factor, and other adhesion molecules, resulting in an acute adult-type respiratory distress syndrome as a result of sudden vascular leak with hypoxia and hypotension [15,16]. Other possible explanations include an anaphlyactoid-like reaction due to mast-cell activation [17].



   Teaching points
Top
 Introduction
 Case
 Discussion
 Teaching points
References
 
Immune-mediated HIT is more common following the initiation of haemodialysis, and/or when chronic haemodialysis patients are exposed to heparin for other medical/surgical conditions.

  1. Once clinically suspected, all heparins must be totally avoided, including heparin priming of the circuit, and heparin locking of dialysis venous access catheters.
  2. Patients have increased risk of access thrombosis, both central venous access catheters and A–V fistulae and grafts.
  3. Immune-mediated HIT may cause acute cardiovascular collapse within a few minutes of the initiation of dialysis following a heparin bolus, due to ‘pseudo-pulmonary embolus’ syndrome.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Case
 Discussion
 Teaching points
 References
 

  1. Yamamoto S, Koide M, Matsuo M et al. Heparin induced thrombocytopenia in haemodialysis patients. Am J Kidney Dis 1996; 28: 82–85[Web of Science][Medline]
  2. Greinacher A, Zinn S, Wizemann, Birk UW. Heparin induced antibodies as a risk factor for thromboembolism and haemorrhage in patients undergoing chronic haemodialysis. Lancet 1996; 348: 764[Medline]
  3. Davenport A. The management of heparin induced thrombocytopenia during renal replacement therapy. Hemodial Int 2001; 5: 81–85
  4. Boon DM, van Vliet HH, Zietse R, Kappers-Klunne MC. The presence of antibodies against a PF4-heparin complex in patients on haemodialysis. Thromb Haemostat 1996; 76: 480[Medline]
  5. Reilly RF. The pathophysiology of immune mediated heparin induced thrombocytopenia. Seminars Dialysis 2003; 16: 54–60[CrossRef]
  6. Sitter T, Spannagl M, Banas B, Schiffl H. Prevalence of heparin-induced antibodies in haemodialysis patients. Nephron 1998; 79: 245–246[Medline]
  7. O'Shea SI, Sands JJ, Nudo SA, Ortel TL. Frequency of antiheparin platelet factor 4 antibodies in haemodialysis patients and correlation with recurrent vascular access thrombosis. Am J Haematol 2002; 69: 72–73[CrossRef][Web of Science][Medline]
  8. Davenport A. Management of heparin-induced thrombocytopenia during continuous renal replacement therapy. Am J Kid Dis 1998; 32: E3[Medline]
  9. Popov D, Zarrabi MH, Foda H, Graber M. Pseudopulmonary embolism: acute respiratory distress in syndrome of heparin-induced thrombocytopenia. Am J Kidney Dis 1997; 29: 449–452[Web of Science][Medline]
  10. Agharazii M, Plamondon I, Lebel M, Douville P, Desmeules S. Estimation of heparin leak into the systemic circulation after central venous catheter heparin lock. Nephrol Dial Transplant 2005; 20: 1238–1240[Abstract/Free Full Text]
  11. Warkentin TE, Greinacher A. eds. Heparin induced thrombocytopenia. 3rd edn. Marcel Dekker, New York: 2004
  12. Warkentin TE, Heddle NM. Laboratory diagnosis of immune heparin-induced thrombocytopenia. Curr Hematol Rep 2003; 2: 148–157[Medline]
  13. Perkins RM, Lee JD, Rutberg S, McCune DE, Cooper RH. Thrombocytopenia and acute respiratory distress associated with intravenous bolus heparin exposure. Hosp Phys 2003; 39: 59–61[Medline]
  14. Davenport A. Central venous catheters for haemodialysis: how to overcome the problems. Haemodial Int 2000; 4: 78–82
  15. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581–589[Abstract]
  16. Blank M, Shoenfeld Y, Tavor S et al. Anti-platelet factor 4/heparin antibodies from patients with heparin induced thrombocytopenia provoke direct activation of microvascular endothelial cells. Int Immunol 2002; 14: 121–129[Abstract/Free Full Text]
  17. Tejedor Alonso MA, Lopez Revuelta K, Garcia Bueno MJ et al. Thrombocytopenia and anaphylaxis secondary to heparin in a haemodialysis patient. Clin Nephrol 2005; 63: 236–240[Medline]
Received for publication: 22. 2.06
Accepted in revised form: 27. 2.06


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