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(Chest. 2002;122:37-42.)
© 2002 American College of Chest Physicians

Heparin-Induced Thrombocytopenia*

Temporal Pattern of Thrombocytopenia in Relation to Initial Use or Reexposure to Heparin

Norbert Lubenow, MD; Reiner Kempf, MD; Angelika Eichner, MD; Petra Eichler, MSc; Lena E. Carlsson, MSc and Andreas Greinacher, MD

* From the Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.

Correspondence to: Andreas Greinacher, MD, Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt-University, Sauerbruchstr., D-17487 Greifswald, Germany; e-mail: greinach{at}uni-greifswald.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction associated with a decrease of platelet counts that usually begins after at least 5 days of heparin treatment. Uncertainty exists about the risk of early onset of HIT (ie, < 5 days) in relation to previous heparin exposure. We therefore analyzed the temporal pattern of thrombocytopenia in patients with laboratory-confirmed HIT to assess whether patients with previous heparin exposure have an increased risk of early onset of HIT.

Design: Platelet count patterns in patients with a laboratory-confirmed diagnosis of HIT were examined in a retrospective chart review of a clinical study database. The onset of thrombocytopenia < 100 x 109/L associated with the current heparin treatment (mainly unfractionated heparin) was analyzed using nonparametric maximum likelihood estimation.

Results: A total of 119 patients with 125 treatment episodes were assessed: HIT developed in 79 patients during initial exposure to heparin, and in 46 patients during reexposure. Early onset (< 5 days) of thrombocytopenia was associated with very recent heparin exposure. Patients reexposed to heparin within 3 months had an earlier onset of thrombocytopenia as compared to patients reexposed to heparin after 3 months (4.9 ± 4.4 days vs 11.5 ± 5.5 days [mean ± SD], p = 0.001). There was no difference between onset on thrombocytopenia < 100 x 109/L in patients reexposed to heparin within 3 to 12 months and after 1 year (9.7 ± 6.4 days vs 12.3 ± 5.2 days, p = 0.41). Whether platelet counts were obtained daily or less regularly did not affect the analysis.

Conclusion: Early onset of thrombocytopenia in HIT is associated with recent heparin treatment (< 3 months). In contrast, for patients who did not receive heparin within the previous 3 months, HIT is an unlikely explanation for thrombocytopenia that occurs within the first 5 days.

Key Words: heparin • heparin-induced thrombocytopenia • platelets • temporal pattern


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Heparin-induced thrombocytopenia (HIT) is an important adverse effect of heparin treatment in either therapeutic or prophylactic doses. HIT occurs in up to 3% of patients treated with unfractionated heparin (UFH)1 for prophylaxis of thrombosis following orthopedic hip-replacement surgery. Affected patients are at increased risk of having new thromboembolic complications develop.2

There are great differences in the recommendations for optimal monitoring of patients during heparin treatment for early detection of HIT. The range extends from daily controls of platelet counts from day 0,3 measurements every 2 to 3 days,4 to measurements every day from day 5,2 5 or day 7.6

In patients receiving heparin for the first time, it is generally accepted that HIT typically occurs >= 5 days after starting heparin.2 7 However, as heparin is frequently used, many patients have a history of previous heparin exposure. These patients present an increasing problem because HIT can become clinically manifest in some patients much earlier than day 5.8 Many patients undergoing major surgery such as orthopedic hip-replacement or cardiac surgery typically show a decrease of platelet counts within the first 1 to 2 days following surgery due to reasons not related to HIT. With increasing awareness of HIT, the question is often raised whether a fall of platelet counts on the first or second postoperative day may be an anamnestic HIT response if the patients had received heparin during an earlier hospital stay.

We previously reported a large registry of HIT patients with clinically apparent HIT and HIT antibodies confirmed in our laboratory.9 In the current study, we retrospectively assessed the temporal pattern of platelet counts in this population to provide further evidence for an optimal strategy of monitoring patients for HIT during heparin treatment, with special emphasis on the relation of previous heparin exposure to the timing of onset of HIT.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
A patient registry, which already served as a historical control for two prospective trials,9 was used for the present retrospective analysis. This registry included inpatients from surgical departments (63%) and internal medicine and others such as neurology (37%). The data of this registry have been extensively controlled and audited by external experts, and led to the approval of lepirudin both in the European Union and the United States. This study was also approved by the ethical board of the university hospital of Greifswald, Germany.

The objectives of the study were to assess whether the timing of the onset of HIT depends on: (1) whether the patient was receiving heparin for the first time, or had undergone previous heparin treatment; (2) the time interval between the heparin exposure that resulted in HIT and the previous heparin exposure, if any; and (3) the route of heparin administration (IV or subcutaneous [sc]).

Criteria for diagnosis of HIT were a decrease of platelet counts to < 100 x 109/L, and confirmation of HIT antibodies using the heparin-induced platelet activation test. The heparin-induced platelet activation test was carried out using washed platelets of four healthy blood donors; a positive result consisted of activation occurring with patient serum at therapeutic levels, but not at high levels of heparin.10 11

Although a decrease of platelet counts by > 50% during heparin treatment is assumed to have the highest predictive value for HIT,7 platelet counts preceding the platelet count drop were often not available in this retrospective study, as platelet counts are not controlled regularly in clinical routine. We therefore used the absolute platelet count threshold of 100 x 109/L as a cutoff value, knowing that this might overestimate the interval between start of heparin treatment and onset of HIT; ie, a >= 50% fall in the platelet count could have occurred 1 to 2 days before the arbitrary threshold of 100 x 109/L had been reached.

Initial exposure to heparin was assumed if the medical history gave no evidence of former heparin treatment. However, undocumented exposure to heparin such as flushing of venous accesses might have been missed by this approach. Any documented interruption of heparin treatment for > 24 h was defined as reexposure.

Statistical Methods
For analysis of (1) the time periods between start of heparin therapy and decrease of platelet counts < 100 x 109/L, (2) the relation of the time interval to previous heparin exposure and onset of thrombocytopenia < 100 x 109/L, and (3) the comparison of the different modes of heparin administration, two groups were defined. In the first group, all patients with daily platelet counts were analyzed. The second group included these patients and additional patients with nondaily platelet count measurements.

The nonparametric Mann-Whitney test (Wilcoxon rank-sum test)12 was applied for analysis of the relation of the interval between initial exposure and reexposure to heparin and the day of onset of thrombocytopenia < 100 x 109/L and comparison of the different modes of heparin administration. The patients were grouped according to their previous heparin exposure: <= 1 month, from 1 to 3 months, from 3 months to 1 year, and > 1 year, and for a second analysis according to the mode of heparin administration: sc UFH vs IV UFH. For all calculations, the first day of heparin administration was defined as day 1. The nonparametric maximum likelihood estimation was applied in patients without daily platelet count measurements by means of interval censoring type II.13


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Altogether, 119 patients with 125 treatment episodes were assessed: 79 episodes with initial exposure and 46 episodes with reexposure to heparin. Of these, 29 patients with 30 treatment episodes had daily platelet counts (14 initial exposures and 16 reexposures to heparin). Four patients received two heparin courses, and one patient received three heparin courses. Four treatment episodes have been excluded from the analysis of the relation between exposure time and onset of thrombocytopenia (initial treatment [n = 3], reexposure [n = 1]). Two reexposure treatment episodes have been excluded from the analysis of the relation between the heparin-free interval and onset of thrombocytopenia.

Sixty-nine percent of patients had a thrombotic complication when HIT was diagnosed. The patient characteristics are given in Table 1 .


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  		Table 1.. Patient Characteristics*

 
Relation Between Exposure Time and Thrombocytopenia
Thrombocytopenia < 100 x 109/L occurred on average on day 10.8 ± 5.1 (mean ± SD) [n = 121; range, 1 to 33 days; Fig 1 ], and in the subgroup with daily platelet counts on day 8.9 ± 7.2 (n = 30; range, 2 to 33 days). The overall likelihood of thrombocytopenia < 100 x 109/L developing by day 5 was 25%, by day 8 was 38%, and by day 15 was 95%; in patients with daily platelet counts, it was 40% by day 5, 47% by day 8, and 90% by day 15, respectively. To assess whether the biphasic distribution (Fig 1) of platelet count decrease was associated with first exposure or reexposure to heparin, patients were grouped accordingly.



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  		Figure 1.. Day of onset of thrombocytopenia < 100 x 109/L in 121 heparin treatment episodes of patients with laboratory-confirmed HIT; episodes of initial exposure (n = 76, white bars) and reexposure (n = 45, black bars) are shown in stacked columns. The range of onset of thrombocytopenia extended from 1 to 33 days. In initially exposed patients, thrombocytopenia < 100 x 109/L occurred on average on day 11. In the group of reexposed patients, two subgroups are recognizable with peaks on day 2 and day 11.

 
Relation Between Initial Exposure and Reexposure to Heparin and Onset of Thrombocytopenia < 100 x 109/L
Initial Exposure to Heparin: In the 76 evaluable patients who were initially exposed to heparin, platelet counts fell to < 100 x 109/L on average on day 11.9 ± 4.6 (mean ± SD) [range, 2 to 33 days]; the likelihood of thrombocytopenia < 100 x 109/L developing by day 5 was 12%, by day 8 was 27%, and by day 15 was 98%. In patients with daily platelet counts (n = 14), thrombocytopenia < 100 x 109/L occurred on average on day 11.1 ± 7.1 (range, 2 to 33 days). The likelihood of thrombocytopenia < 100 x 109/L developing by day 5 was 14%, by day 8 was 21%, and by day 15 was 93% (Fig 2 ).



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  		Figure 2.. Temporal pattern of thrombocytopenia in 28 HIT patients with daily platelet counts: initially exposed patients (bold line), reexposed patients < 3 months (fine line), and reexposed patients > 3 months (dotted line). Patients reexposed < 3 months have an earlier occurrence of thrombocytopenia than reexposed patients > 3 months (p = 0.028) and initially exposed patients (p = 0.007). The temporal pattern of initially exposed and reexposed patients > 3 months does not differ significantly (p = 0.708). Statistical analysis is by Mann-Whitney test. A similar pattern is seen when all treatment episodes of daily and nondaily platelet counts are analyzed (n = 125) [not shown].

 
Reexposure to Heparin: In 45 evaluable patients reexposed to heparin, the interval between heparin treatments ranged from 1 day (one patient) to 21 years. Thrombocytopenia < 100 x 109/L occurred on day 8.9 ± 5.5 (mean ± SD) [range, 1 to 24 days; Fig 1 ). The likelihood of thrombocytopenia < 100 x 109/L developing by day 5 was 45%, by day 8 was 54%, and by day 15 was 91%. In the 16 patients with daily platelet counts, the interval between heparin treatments ranged from 4 days to 12 years. Thrombocytopenia < 100 x 109/L occurred on day 7.0 ± 7.0 of heparin treatment (range, 2 to 24 days). The likelihood of thrombocytopenia < 100 x 109/L developing by day 5 was 63%, by day 8 was 68%, and by day 15 was 88%.

Relation Between Heparin-Free Interval and Onset of Thrombocytopenia < 100 x 109/L Following Reexposure
As indicated in Figure 1 , there are two groups of patients with reexposure to heparin. In the one group, platelet counts decreased < 100 x 109/L in <= 5 days and in the other group after day 5. There was a strong correlation between the day of onset of thrombocytopenia and the length of the heparin-free interval. In patients with recent heparin treatment (ie, within the last 3 months), the platelet count decrease to < 100 x 109/L occurred significantly earlier than in patients who were reexposed to heparin after a longer time interval (4.9 ± 4.4 days vs 11.5 ± 5.5 days [mean ± SD], p = 0.002). In contrast, there was no difference in onset of thrombocytopenia < 100 x 109/L in patients with intervals to previous heparin exposure of 3 to 12 months, as compared to intervals of > 12 months (9.7 ± 6.4 days vs 12.3 ± 5.2 days, p = 0.41). This pattern did not change if only patients with daily platelet counts were assessed. In these patients, those with heparin treatment within the last 3 months had thrombocytopenia develop at 3.4 ± 3.8 days, as compared to 11.6 ± 8.1 days in patients who were exposed to heparin after a longer time interval (p = 0.028; Fig 2 ).

Relation Between Mode of Heparin Administration and Onset of Thrombocytopenia < 100 x 109/L
There were no significant differences between sc and IV administration of UFH with regard to the time period until platelet counts decreased to < 100 x 109/L. In initially exposed patients, it was 12.5 ± 4.7 days in the sc group (n = 50) and 11.4 ± 4.4 days in the IV group (mean ± SD; p = 0.92). In heparin reexposed patients, it was 8.4 ± 5.1 days in the sc group (n = 14) and 8.5 ± 6.0 days (n = 22) in the IV group (p = 0.90).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Two time patterns of onset of HIT were identified: a group of patients with early (<= 5 days) and a group of patients with late onset of thrombocytopenia (> 5 days; Fig 1 ). In the group of patients with early onset of HIT, those being reexposed to heparin were clearly overrepresented. This is not an unexpected finding, given that a rapid fall in the platelet count for an immune-mediated disorder such as HIT might be expected to be related to previous heparin exposure. However, an important and unexpected finding of this study is that the early onset of HIT occurred primarily in patients with recent previous heparin exposure, ie, within the past 3 months. Patients with a previous exposure to heparin that occurred > 3 months earlier had a time pattern of onset of thrombocytopenia indistinguishable from patients having had their initial exposure to heparin. The data were similar regardless whether heparin was administered IV or sc. As only few of the study objects received low-molecular-weight heparin, the findings mainly apply to UFH.

It is widely accepted that in patients with initial heparin treatment, a platelet count decrease > 50% from day 5 on is an early symptom of HIT.14 This is corroborated by the present study. In heparin-naïve patients with documented daily platelet count monitoring, the mean day of a HIT-related decrease of platelet counts < 100 x 109/L was day 9. Platelet count monitoring beginning after day 5 would have detected approximately 86% of these patients (Fig 2) . The early platelet count decrease in some of these patients might not have been the first symptom of HIT, but may have been caused by a comorbid condition or, if it was really HIT related, by unreported previous heparin exposure.

It is also well known that in patients reexposed to heparin, HIT can occur rapidly.8 Indeed, in patients with previous exposure to heparin, starting platelet count monitoring after day 5 was too late for early recognition of HIT in up to 63% of patients in the present study (Fig 2) . Monitoring of platelet counts beginning on day 1 of heparin treatment would detect these patients early. However, considering the wide use of heparin, the number of patients with a history of heparin exposure is increasing. It would cause substantial confusion, if in all patients reexposed to heparin an early (<= day 5) decrease of platelet counts would be attributed to potential HIT, especially in postsurgical patients. Many of these patients develop a transient decrease of platelet counts in the first days following major surgery, eg, cardiopulmonary bypass or orthopedic hip replacement. Switching antithrombotic treatment in all these patients to the new anticoagulants such as danaparoid, lepirudin, or argatroban, as it is recommended if HIT is clinically suspected,15 may enhance the frequency of adverse effects such as bleeding16 17 and would be expensive.

The present study provides a rationale to manage this dilemma. If the patient history indicates heparin use within the last 3 months, platelet counts should be monitored carefully from day 1 of heparin treatment. In all other patients, monitoring of platelet counts from day 5 seems to be sufficient to detect the majority of patients with HIT in time. However, as also shown in the present study, the history might be incomplete or the onset of HIT is exceptionally early in some patients. Therefore, HIT should be considered a relevant differential diagnosis if additional clinical signs of HIT such as skin necrosis or otherwise unexplained thromboembolic complications occur during the first days of heparin treatment.

The findings of this analysis are in accordance with a study of 260 patients by Warkentin and Kelton,18 who analyzed the timing of onset of HIT in relation to a recent (<= 100 days) or remote (> 100 days) prior heparin use. The minor differences in time patterns between the two studies can be explained by different criteria defining onset of HIT. Whereas in the study of Warkentin and Kelton18 a decrease in platelet count of > 30% (if < 150 x 109/L) or > 50% was used, we used the day the threshold of 100 x 109/L was reached. Furthermore, the start of heparin treatment was defined as day 0 in their study and day 1 in our study.

The most evident explanation for the rapid onset of HIT in patients recently exposed to heparin (< 3 months) are HIT antibodies remaining in the circulation, which can cause abrupt activation of platelets. HIT antibodies are transient and hardly detectable even by sensitive laboratory assays several months after cessation of heparin treatment.2 18 Warkentin and Kelton18 found that the mean time to a negative anti-platelet factor 4/heparin antibody status in HIT patients was 85 days when antigen assays were used. After disappearance of HIT antibodies from the circulation, B-cell–dependent HIT antibody synthesis will require several days. Based on these considerations, our study provides a rationale for the renewal of an old treatment strategy in elective heart surgery in HIT patients. Before lepirudin,17 danaparoid sodium,19 or argatroban20 became widely available, cardiac surgeons had to operate on patients with a history of HIT using heparin for cardiopulmonary bypass. After waiting for at least 3 months after diagnosis of HIT, they performed surgery using heparin for a restricted time period.21 22 In our experience, if HIT antibodies are no longer detectable by sensitive assays, short-term reexposure to heparin seems to be feasible and might be less risky for anticoagulation during heart-lung machine treatment than high-dose treatment with alternative anticoagulants such as danaparoid or lepirudin for which no antidote is available. We have been using this strategy for approximately 2 years without major complications but only in a limited number of patients.23 24 The feasibility of this concept has recently also been confirmed by others.18 25 However, any heparin exposure before or after surgery must be strictly avoided in such a setting.

In conclusion, a recent exposure to heparin within the past 3 months was identified as the most important factor to explain an early occurrence of HIT. Thus, for patients who have had such a recent exposure to heparin, and for whom a further course of heparin is administered, it appears appropriate to begin platelet count monitoring soon after starting heparin. In patients who did not receive heparin within the last 3 months, HIT is an unlikely explanation for isolated thrombocytopenia that occurs within the first days of heparin administration.


   Acknowledgements
 
The advice of Professor Dr. P. Groeneboom is highly appreciated. Data were obtained in part for the doctoral thesis of Mrs. A. Eichner.


   Footnotes
 
Abbreviations: HIT = heparin-induced thrombocytopenia; sc = subcutaneous; UFH = unfractionated heparin

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) Gr 1096/2–3. It is part of the Community Medicine Program of the Ernst-Moritz-Arndt University Greifswald, Germany.

Received for publication April 30, 2001. Accepted for publication November 29, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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