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NDT Advance Access published online on March 19, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm055
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

National survey of heparin-induced thrombocytopenia in the haemodialysis population of the UK

Colin A. Hutchison2 and Indranil Dasgupta1

1Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, Warwickshire, UK and 2Division of Medical Sciences, University of Birmingham, Birmingham, UK

Correspondence and offprint requests to: Dr Colin A. Hutchison, Division of Medical Sciences, Medical School, University of Birmingham, Birmingham, B15 2TT. Email: CAH692{at}bham.ac.uk



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Background. Heparin-induced thrombocytopoenia (HIT) type II is an antibody-mediated, drug-induced thrombocytopenia which is associated with significant morbidity and mortality. Several case reports and small series have described the occurrence of HIT type II in the haemodialysis population and the challenges associated with it. Some of these reports raise the possibility of a recent increase in prevalence of this condition. But to date, there has never been a large study to estimate the prevalence, demography or treatment options for this syndrome in the haemodialysis population.

Methods. The renal units in the UK were surveyed to establish the prevalence of HIT type II syndrome in the haemodialysis population. Demographic data for haemodialysis patients with HIT type II syndrome were gathered and current treatments assessed.

Results. Fifty responses from the 81 UK renal units surveyed were received. The combined population for these units was 13 682 patients on dialysis of whom 10 564 were on maintenance haemodialysis. The prevalence and incidence of HIT type II syndrome in the UK haemodialysis population were 0.26 and 0.32 per 100 patients, respectively. The mean age of the patients with HIT type II syndrome was 62 years (range 22–86), 52% were females and 92% were Caucasians. Only 17% of patients have had complications of HIT syndrome. Thirty-six percent of renal units use danaparoid as anticoagulant of choice for patients on haemodialysis with HIT type II syndrome.

Conclusion. This is the largest survey of HIT type II in the haemodialysis population to date. The prevalence is considerably lower (0.26 per 100 patients) than previous estimates, with only a minority of patients developing complications of the condition. Haemodialysis patients with HIT type II in the UK are predominately treated with danaparoid.

Keywords: complications; haemodialysis; haemodialysis patients; heparin; heparin-induced thrombocytopenia; thrombocytopenia



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
Worldwide there is a continuing expansion in the number of patients with end-stage renal failure (ESRF). The majority are unsuitable for transplantation because of the demographics and comorbidities of this population. This results in increasing numbers of patients receiving long-term haemodialysis (HD). Currently, unfractionated or low-molecular weight heparins are used in the majority of renal units to prevent clotting in the extra-corporeal circuit.

Heparin-induced thrombocytopenia (HIT) is a relatively common side effect of heparin therapy and can cause substantial morbidity and mortality [1]. Two clinical entities of HIT can be distinguished—HIT type I and HIT type II. HIT type I is a harmless pharmacological phenomenon that is seen when the platelets fall in the first 24–48 h after starting heparin. It never leads to thrombosis and does not necessitate stopping heparin [2]. HIT type II is the most important and frequent drug-induced thrombocytopenia. It is mediated by antibodies against the heparin-platelet-factor-4 (PF4) complex [2,3]. Thrombocytopenia itself rarely causes significant complications, but the disorders associated with it are potentially life-threatening [4]. Venous thromboembolism occurs in up to 50% of patients with HIT type II [5]; other significant complications include skin reactions at the site of injection, disseminated intravascular coagulation, cerebral thrombosis, myocardial infarction and ischaemic limbs [1]. Diagnosis of HIT type II depends on the exclusion of other conditions associated with thrombocytopenia and on the demonstration of heparin-induced antibodies (HIA) in the plasma.

Although to date there have been single centre studies describing the prevalence of HIA and associated thrombosis in the HD population [6–8], there has been no evaluation of HIT type II in the HD population on a larger scale. The aim of this study was to determine the prevalence, demography and treatment patterns for HIT type II in the haemodialysis population of the UK.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
A survey of all renal units in the UK was undertaken; a questionnaire was sent to the clinical director of each unit. The renal units were given a month to complete the survey and then a reminder email was sent, followed by a new survey form at 6 weeks if still no return was received. The survey was designed to be straightforward for the respondent to fill in yet still provide essential information. The survey consisted of two sections: the first to determine the demographics and policies of the individual renal unit in relation to HIT type II. The second to provide clinical details of individual cases of HIT type II.

Renal unit demographics and experience of HIT type II
The questionnaire asked the clinical directors to define the number of patients on haemodialysis and peritoneal dialysis (PD) and the number of prevalent cases of HIT type II in their unit on 1 April 2005. They were also asked to provide the number of new cases of HIT type II in the last year (April 2004–April 2005). Regarding the units’ current policy for managing HIT type II the questionnaire asked the following: which anticoagulant is used for ongoing anticoagulation for dialysis and would the clinicians consider changing the patient to PD%

Clinical details and management of individual haemodialysis patients with HIT type II
A clinical diagnosis of HIT type II should be made when thrombocytopenia occurs following exposure to heparin in the absence of any other causes, this should then be confirmed by the presence of HIA. Participants were asked to confirm if patients with the ‘clinical diagnosis’ of HIT type II had the presence of HIA confirmed. The following demographic details for each HD patient with HIT type II were requested: age, sex and ethnicity. The length of time on HD before the diagnosis of HIT type II was asked for each patient. The questionnaire then asked for the anticoagulation used for ongoing HD sessions for the patient. Finally clinicians were asked to provide details of any complications the patient had experienced associated with the HIT type II.

Data analysis
Responses from the individual renal units were analysed to allow calculation of both unit and national prevalence and incidence of HIT type II in UK dialysis population. The renal unit demographics and patient take on rates were taken from the UK Renal Registry [9]. Clinical details for patients with HIT type II were assessed to give mean age, sex and duration of dialysis to diagnosis. Complication rates of HIT type II and prevalence of anticoagulants used for ongoing HD used were determined.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Conclusion
 Acknowledgements
 References
 
The questionnaire was sent to all the renal units in the UK. Fifty responses were received from the 81 renal units (61.7%). This gave an ESRF population of 13 682 studied; 77% were on maintenance haemodialysis (10 564) and the remainder on peritoneal (3118). Table 1 presents sample size and ethnicity for the renal units surveyed by the UK Renal Registry [9] and those who responded to this survey.


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  		Table 1. Demographics for UK renal units, the study population and haemodialysis patients with HIT type II

 
Renal unit demographics and experience of HIT type II
The number of current patients in the population studied with HIT type II was 28, giving a prevalence of 0.26 per 100 haemodialysis patients. There were 17 new cases of HIT type II amongst the haemodialysis population giving an incidence of 0.32 per 100 haemodialysis patients. Only 14 of the 50 responding renal units had patients with HIT type II; Figure 1 presents the prevalence's for the responding units (range 0.22–1.74 per 100 patients). The incidence of HIT type II ranged from 0.58 to 4.3, in the units affected. There were no reported cases of HIT type II in patients on peritoneal dialysis. The policies of the renal units for ongoing anticoagulation, for HD, in patients with HIT type 2 are as follows: 36% use danaparoid; 6% an LMWH; 6% prostacyclin and 4% warfarin, lepirudin or hirudin. Four percent of renal units would seek the advice of their local haematologists and 34% of units do not have a policy. Twenty-six percent of renal units would consider changing the patient to PD when HIT type II is diagnosed.


Figure 1
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  		Fig. 1. The number of renal units with different prevalence rates of HIT type II in their haemodialysis populations, for the 14 UK renal units with cases.

 
Clinical details and management of individual haemodialysis patients with HIT type II
The mean age of the patients with HIT type II was 62.4 years (22–86). Forty-eight percent were males, 52% females. We received ethnicity details for 85% of the patients: 91.6% were Caucasians (22); 4% Indo-Asians (1); 4% Afro-Caribbeans (1). One hundred percent of the patients described as having HIT type II by the renal units were confirmed to have HIA. The mean time between starting haemodialysis and the development of HIT type II was 61 days (5–390 days). Only five patients (20%) were diagnosed with HIT type 2 between 5 and 10 days after starting haemodialysis and in five patients (20%) it was after 90 days or more (ure 2, time to diagnosis of HIT type II). Fourteen percent of patients with HIT type II had complications of the syndrome, with 4% having one of the following: petechial rash, pulmonary embolism, retroperitoneal haematoma; 8% had a deep vein thrombosis and 83% had no reported complications (Figure 3, complications of HIT type II in the HD population). The following anticoagulants are being used in patients with HIT type II for ongoing haemodialysis: danaparoid 36% (9), warfarin 12% (3), hirudin 12% (3), lepirudin 8% (2), lepirudin and argatroban 8% (2), tinzaparin 4% (1) and 12% (3) manage with saline flushes alone.


Figure 2
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  		Fig. 2. Time from commencement of haemodialysis to diagnosis of HIT type II. Dotted lines represent normal window of presentation of HIT type II of 5–10 days.

 

Figure 3
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  		Fig. 3. Complications of HIT type II syndrome in haemodialysis patients. Numbers represent percentages.

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Conclusion
 Acknowledgements
 References
 
This is the largest reported survey of HIT type II syndrome in haemodialysis patients. Sixty-two percent of renal units in the UK responded to the survey. The ESRF population surveyed was 13 682 patients, of whom the majority were on haemodialysis (10 564); this population was representative of the UK haemodialysis population in terms of size and ethnicity.

In the general population, it has been demonstrated that the prevalence of HIT type II is less common in medical patients than surgical patients (0.7% vs 5%) [5] and has a lower incidence with low-molecular weight heparins than unfractionated heparin (UH) (0.5% vs 5%) [10,11]. Our finding of an incidence of 0.26% of HIT type II in the haemodialysis population in the UK is lower than that seen in the general medical population (0.7%), but higher than the obstetric population at 0.08%. This finding supports the suggestion by authors of a recent review that dialysis patients have a lower risk of HIT type II than the general population. Their suggestion is based on findings of a lower frequency of HIA in the dialysis population compared with the general population in the literature (1.1–6.8% vs 4.5–51%) [6]. There are several possible explanations for this lower frequency such as the impaired immunity of dialysis patients or the smaller quantities of heparin the HD patients are exposed to in the extra-corporeal circuit compared with the therapeutic heparin in general patients.

The review by Chang and Parikh [6] demonstrates in both the general and dialysis populations the frequency of HIT type II is always significantly lower than the presence of HIAs. This is supported by the work of Palomo et al. [12] who could find no significant relationship between the presence of HIA and either thrombocytopenia or thrombosis. Therefore, the finding that the prevalence of HIT type II in the HD population is significantly lower than the known prevalence of HIA in the HD population, is not surprising.

To our knowledge there has only been one study aimed at determining the incidence of HIT type II from clinical grounds in the HD population. Yamamoto et al. [7] found an incidence of 3.5% in 154 consecutive patients starting on HD at one centre. This increased incidence can be explained by the low threshold Yamamoto et al. had for screening for HIAs: with indications such as clots in the drip chambers or increased circuit pressures associated with a 20% drop in platelet count. From our own experience, HIT type II is generally only screened for in daily practice if there is a very significant drop in the patients’ platelets count following the commencement of heparin.

Interestingly, we found that only 28% of the responding UK renal units had cases of HIT type II, with prevalence rates ranging from 0.22 to 1.74%. This variation in prevalence between units raises the possibility of clustering of cases relating to local factors. Previously it has been shown that bovine heparin has a higher incidence of HIT type II than porcine and although all UK centres now use porcine there may well be other locally variable factors such as the quantity or type of heparin given (UH or LMWH) [8,13]. Another possible explanation for this clustering of cases is variability in clinician sensitivity for screening for HIT type II.

Haemodialysis patients with HIT type II had an average age of 62 years and no significant difference in gender. Ninety-two percent of patients were Caucasian with only 4% being Indo-Asian and 4% Afro-Caribbean, these are comparable to national ethnic variations in dialysis patients (Table 1) [9].

In the general population, HIT type II would normally develop after 5–10 days of treatment with heparin and only rarely after 15 days. In contrast to this, we found a mean time to diagnosis of 58 days (0–390 days), with only 20% of the population being diagnosed within the classical time frame of between 5 and 10 days. Interestingly, 20% were diagnosed with HIT type II 90 days or more after commencing haemodialysis. The most likely explanation for this is that HIA are being picked up incidentally when there is another cause of thrombocytopenia. This is possible because of the high background rate of HIAs not related to thrombocytopenia in the HD population [12]. Other possibilities are some patients may not have been exposed to heparin early in the course of their dialysis or the antibody-mediated reaction is delayed in some patients possibly because of small doses of heparin to which the patient is exposed.

Several groups have demonstrated that the presence of HIA in the HD population is associated with increased morbidity and mortality [14–16]. In contrast to this study, it was found that only the minority of patients diagnosed with HIT type II had reported complications (17%). It is possible that units are underreporting the possible complications of HIT type II, with a specific HD complication needing to be thought of such as: thrombosis of the arterial venous fistula.

Guidelines published in the British Journal of Haematology this year recommend treating HIT type II in the UK with danaparoid or lepirudin, but cautions against the use of lepirudin in patients with renal impairment [5]. A significant proportion of the UK renal units are following this advice using danaparoid as anticoagulation of choice. However, currently over a third of renal units in the UK do not have a policy for managing haemodialysis patients with HIT type II and a concerning fact is that 6% would use an LMWH.

There are several limitations to this study. Predominately, these relate to the design of a survey to determine the incidence of a rare disease opposed to the preferential prospective multi-centre study. As with any survey there is the danger of a bias in the units who respond, however this is likely to have been overcome by the large numbers studied here. Specific to this study, the main concern is the limitation of ensuring uniformity in the diagnosis of HIT type II between centres. As a recently published manuscript has suggested: ‘the diagnosis of this condition can be difficult’ [17]. Therefore, it is likely that clinicians have different thresholds for considering a diagnosis of HIT type II and, as discussed above, the presence of HIAs is not always significant.



   Conclusion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
Acknowledgements
 References
 
This is the largest survey of HIT type II in the haemodialysis population to date. The prevalence is considerably lower (0.26 per 100 patients) than previous estimates have suggested. We found that the haemodialysis patients do not present in classical patterns with HIT type II, a significant proportion have delayed onset and only a minority developed complications (17%). There is diversity of anticoagulants being used for these patients in the UK, but danaparoid predominates.



   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 Acknowledgements
References
 
We would like to thank the clinicians who took the time to respond to our survey and made this report possible.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 

  1. Aster RH. (1995) Heparin-Induced Thrombocytopenia and Thrombosis. N Engl J Med 332:1374–1376.[Free Full Text]
  2. Haase M, Bellomo R, Rocktaeschel T, et al. (2005) Use of fondaparinux (ARIXTRA(R)) in a dialysis patient with symptomatic heparin-induced thrombocytopaenia type II. Nephrol Dial Transplant 20:444–446.[Free Full Text]
  3. Aster RH. (2005) Drug-induced immune thrombocytopenia: an overview of pathogenesis. Semin Hematol 36:1 Suppl 1, 2–6.
  4. Mattioli A. (2004) Prevalence of anti-PF4/heparin antibodies and the HIT syndrome in cardiovascular medicine. Semin Thromb Hemost 30:291–295.[CrossRef][Web of Science][Medline]
  5. Keeling D, Davidson S, Watson H. (2006) Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The management of heparin-induced thrombocytopenia. Br J Haematol 133:259–269.[CrossRef][Web of Science][Medline]
  6. Chang JJL and Parikh CR. (2006) When heparin causes thrombosis: significance, recognition and management of heparin induced thrombocytopenia in dialysis patients. Semin Dialysis 19:297–304.[Web of Science][Medline]
  7. Yamamoto S. (1996) Heparin-Induced Thrombocytopenia in Haemodialysis Patients. Am J Kidney Dis 28:82–85.[Web of Science][Medline]
  8. Samuelsson O, Amiral J, Attman PO, et al. (2005) Heparin-induced thrombocytopenia during continuous haemofiltration. Nephrol Dial Transplant 10:1768–1771.
  9. Ansell D, Feest T, Rao R, Williams A, Winearls C. ( December 2005) The Eighth Annual Report. UK Renal Registry.
  10. Warkentin TE, Levine MN, Hirsh J, et al. (1995) Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin. N Engl J Med 332:1330–1336.[Abstract/Free Full Text]
  11. Martel N, Lee J, Wells PS. (2005) Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 106:2710–2715.[Abstract/Free Full Text]
  12. Palomo I, Pereira J, Alarcon M, et al. (2005) Prevalence of heparin-induced antibodies in patients with chronic renal failure undergoing hemodialysis. J Clin Lab Anal 19:189–195.[CrossRef][Web of Science][Medline]
  13. Ward D. (1997) The approach to anticoagulation in patients treated with extracorpeal therapy in the intensive care unit. Adv Ren Replace Ther 4:160–173.[Medline]
  14. Pena de la Vega L, Miller RS, Benda MM. (2005) Association of heparin-dependent antibodies and adverse outcomes in hemodialysis patients: a population-based study. Mayo Clin Proc 80:995–1000.[Web of Science][Medline]
  15. Nakamoto H, Shimada Y, Kanno T, et al. (2005) Role of platelet factor 4-heparin complex antibody (HIT antibody) in the pathogenesis of thrombotic episodes in patients on hemodialysis. Hemodial Int 9:Suppl 1, S2–S7.
  16. Mureebe L, Coats RD, Silliman WR, Shuster TA, Nichols WK, Silver D. (2004) Heparin-associated antiplatelet antibodies increase morbidity and mortality in hemodialysis patients. Surgery 136:848–853.[CrossRef][Web of Science][Medline]
  17. Arepally GM and Ortel TL. (2006) Heparin induced thrombocytopenia. N Engl J Med 355:809–817.[Free Full Text]
Received for publication: 24. 8.06
Accepted in revised form: 18. 1.07


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