Background Heparin-induced thrombocytopenia is a relativelycommon antibody-mediated drug reaction. We studied the temporalrelation between previous or current heparin therapy and theonset of heparin-induced thrombocytopenia.
Methods We examined the time between the start of heparin therapyand the onset of thrombocytopenia in 243 patients with serologicallyconfirmed heparin-induced thrombocytopenia. We also investigatedthe persistence of circulating heparin-dependent antibodiesby performing a platelet serotonin-release assay and an assayfor antibodies against platelet factor 4. The outcome in sevenpatients who had previously had an episode of heparin-inducedthrombocytopenia and were later treated again with heparin wasalso examined.
Results A fall in the platelet count beginning four or moredays after the start of heparin therapy occurred in 170 of the243 patients (70 percent); in these patients, a history of previousheparin treatment did not influence the timing of the onsetof thrombocytopenia. In the remaining 73 patients (30 percent),the onset of thrombocytopenia was rapid (median time of onset,10.5 hours after the start of heparin administration); all thesepatients had been treated with heparin within the previous 100days. During recovery from thrombocytopenia, heparin-dependentantibodies in the serum fell to undetectable levels at a medianof 50 to 85 days, depending on the assay performed. In the sevenpatients who were given heparin again after the disappearanceof heparin-dependent antibodies, a new episode of heparin-inducedthrombocytopenia did not occur.
Conclusions Heparin-induced thrombocytopenia can begin rapidlyin patients who have received heparin within the previous 100days. Heparin-dependent antibodies do not invariably reappearwith subsequent heparin use.
Heparin-induced thrombocytopenia is a syndrome of antibody-mediatedthrombocytopenia that paradoxically is often associated withthrombosis.1,2,3,4,5 Most patients with this disorder produceIgG antibodies6,7 against complexes of platelet factor 4 andheparin.8,9,10,11 Platelet factor 4, a small peptide storedwithin the alpha granules of platelets, binds to heparin andis released into the blood during treatment with heparin.12In vitro, IgG–platelet factor 4–heparin complexescan activate platelets,13,14 a finding that raises the possibilitythat platelet activation in vivo contributes to the thromboticcomplications of heparin-induced thrombocytopenia.15,16
Typically, heparin-induced thrombocytopenia begins with theappearance of thrombocytopenia about a week after the startof heparin therapy.4,5 Occasionally, a more rapid fall in theplatelet count occurs if the patient has previously been treatedwith heparin.2,5,17,18,19 We report here a study of the timingof the onset of thrombocytopenia in relation to heparin treatment,including previous treatment with heparin, in 243 patients withserologically confirmed heparin-induced thrombocytopenia.
Methods
Patients, Data Extraction, and Definitions
We reviewed the medical and laboratory records of all the patientsin Hamilton, Ontario, Canada, in whom a diagnosis of heparin-inducedthrombocytopenia was serologically confirmed during the 15-yearperiod ending June 30, 1998. We recorded the date and time thatheparin treatment was started, as well as the route of administrationand the dose administered; the date and time of the onset ofthrombocytopenia; and whether or not heparin treatment had beengiven previously.
Heparin-induced thrombocytopenia was considered present if bothof the following criteria were met: a decrease in the plateletcount to less than 150,000 per cubic millimeter (with a minimaldecrease of 30 percent of the platelet count) or a 50 percentor greater decrease in the platelet count; and a positive serologictest for heparin-induced thrombocytopenia.
We defined the first day of the course of heparin that resultedin heparin-induced thrombocytopenia as day 0. With that pointas a reference, the time when the platelet count began to fallwas identified (and rounded to the nearest day). We used thisday in our analyses because it corresponds closely with theday on which heparin-dependent antibodies become detectable.4In the case of 61 patients, daily platelet counts were not available,so we could not determine the day of onset of thrombocytopenia;for these patients, the range of possible days of onset (e.g.,days 10 to 12) was determined, and the mean value was used foranalysis.
We classified heparin-induced thrombocytopenia as having a typicalonset if the fall in the platelet count began four or more daysafter the start of heparin therapy.4,17 Heparin-induced thrombocytopeniawas classified as having a rapid onset if the fall in the plateletcount began less than four days after heparin therapy was started.We defined previous use of heparin as "definite" if it couldbe documented in the patient's medical records, as "possible"if there had been at least one previous hospitalization fora surgical procedure or illness during which treatment withheparin would have been likely, and as "unlikely" if there hadbeen no hospitalization or only a hospitalization during whichheparin therapy would have been unlikely. Previous treatmentwith heparin was considered recent if heparin had been givenduring the 100 days preceding the first day of the current courseof treatment.
Assays for Heparin-Dependent Antibodies
We used the platelet serotonin-release assay (hereafter referredto as the activation assay)20,21 to confirm the diagnosis ofheparin-induced thrombocytopenia and to study changes in thelevels of heparin-dependent antibodies in serum over time. Wealso used an assay that detects IgG, IgA, and IgM antibodiesagainst platelet factor 4 bound to polyvinylsulfonate22 (hereafterreferred to as the antigen assay; GTI-PF4, Genetic Testing Institute,Brookfield, Wis.).
Both the activation assay and the antigen assay were used totest blood samples that were obtained within 180 days afterthe initial positive serologic test. The date midway betweenthe date of the last positive sample and the date of the firstsubsequent negative sample was arbitrarily defined as the datethe test result became negative.
Use of Heparin in Patients with Previous Heparin-Induced Thrombocytopenia
We identified three patients with serologically confirmed heparin-inducedthrombocytopenia who had inadvertently received a course ofheparin that was started more than 100 days after an initialepisode of heparin-induced thrombocytopenia. Platelet countsand the results of repeated heparin-dependent antibody tests(available in two of the three patients) were reviewed to determinewhether heparin-induced thrombocytopenia had recurred. We alsoreviewed the records of four patients with a previous episodeof serologically confirmed heparin-induced thrombocytopeniawho later required anticoagulation for cardiac or vascular surgery,at a time when heparin-dependent antibodies were undetectablein their serum. After written informed consent was obtained,heparin was used during the surgery as an anticoagulant. Bloodsamples obtained daily until discharge were tested for heparin-dependentantibodies with use of both the activation assay and the antigenassay. In these four patients, heparin was used only duringthe surgical procedure.
Statistical Analysis
The distribution of the data corresponding to the day of onsetof heparin-induced thrombocytopenia and to the nadir of theplatelet count was skewed to the right. Accordingly, we analyzedlog-transformed data with use of the t-test to compare the groupsof patients. The groups were compared with respect to binaryvariables with use of Fisher's exact test.
The time to the disappearance of detectable heparin-dependentantibodies was analyzed by means of techniques used for survivalanalysis to allow for the varying duration of follow-up. TheKaplan–Meier method23 was used to estimate the cumulativeproportion of assays remaining positive over time; after logtransformation, 95 percent confidence intervals were computedby means of Greenwood's method for calculating standard errors.23A sign test24 was used to compare the activation and antigenassays with respect to the time to negative results in the patientswhose serum was analyzed with both assays. This test was usedbecause of the discrepancy in the number of patients for whomthe results of the activation assay became negative more quicklythan did the results of the antigen assay, as compared withthe number of patients for whom the reverse was true.
Results
We identified 243 patients with serologically confirmed heparin-inducedthrombocytopenia. Of these patients, 170 (70 percent) had heparin-inducedthrombocytopenia with a typical onset (i.e., the fall in theplatelet count began four or more days after the start of heparintherapy). In the remaining 73 patients (30 percent), the onsetwas rapid (i.e., the decrease began less than four days afterthe start of heparin therapy). Table 1 shows the characteristicsof the patients with typical-onset heparin-induced thrombocytopeniaand of those with rapid-onset heparin-induced thrombocytopenia.The two groups were similar with respect to sex, age, the severityof thrombocytopenia, the incidence of new thrombotic complications,the incidence of fatal hemorrhage, and 30-day mortality.
Table 1. Characteristics of the Patients According to the Time of Onset of Heparin-Induced Thrombocytopenia.
Of the 170 patients with typical-onset heparin-induced thrombocytopenia,47 (28 percent) had definitely received previous treatment withheparin, 49 (29 percent) had possible previous treatment withheparin, and 74 (44 percent) were unlikely to have previouslyreceived heparin. Thrombocytopenia usually began 5 to 10 daysafter the start of heparin treatment (Figure 1A) and did notbegin more quickly in patients who had definitely received aprevious course of heparin (Table 2).
Figure 1. Temporal Patterns of Heparin-Induced Thrombocytopenia in Relation to Previous Treatment with Heparin.
Panel A shows data for the 202 patients in whom the day of onset of thrombocytopenia could be determined within a three-day period. Within the subgroup of patients who definitely had previously undergone treatment with heparin, two temporal patterns of thrombocytopenia (rapid onset and typical onset) were observed (Panel A). Within this subgroup, an analysis of the time elapsed since the previous heparin treatment revealed that patients with rapid-onset heparin-induced thrombocytopenia were more likely to have received heparin within the past 100 days than patients with typical-onset heparin-induced thrombocytopenia (73 of 73 vs. 16 of 47, respectively; P<0.001) (Panel B). None of the patients whose prior heparin treatment had occurred more than 100 days earlier had rapid-onset thrombocytopenia.
Table 2. Day of Onset of Thrombocytopenia in Relation to Previous Heparin Use among Patients with Typical-Onset Heparin-Induced Thrombocytopenia.
Heparin-induced thrombocytopenia of rapid onset occurred soonafter the initiation of heparin use (median, 10.5 hours afterthe start of therapy; interquartile range, 2.1 to 18.1 hours).All 73 patients in this category had definitely received heparinwithin the previous 100 days, whereas only 16 of the 47 patientswith a typical onset (34 percent) had recently received heparin(P<0.001) (Figure 1B). Blood samples obtained within twodays before the start of the current course of heparin wereavailable from eight of the patients with rapid-onset heparin-inducedthrombocytopenia. Heparin-dependent antibodies were detectedin all eight samples.
Figure 2 shows the proportion of patients over time in whomheparin-dependent antibodies remained detectable. The antigenassay tended to become negative more slowly than did the activationassay. The difference was statistically significant accordingto a comparison of the two curves by the sign test (P=0.007).The median time to a negative test according to the Kaplan–Meieranalysis was 50 days (95 percent confidence interval, 32 to64) in the case of the activation assays and 85 days (95 percentconfidence interval, 64 to 124) in the case of the antigen assays.
Figure 2. Kaplan–Meier Analysis of the Proportion of Patients with Heparin-Dependent Antibodies after an Episode of Heparin-Induced Thrombocytopenia.
The time (in days) to a negative test by the activation assay (144 patients) or the antigen assay (93 of the 144 patients) is shown. All 144 patients initially had positive tests for heparin-dependent antibodies and underwent subsequent testing within 180 days. The date the test result became negative was estimated to be the date midway between the date of the last positive test and the date of the first negative test. The antigen assay tended to become negative more slowly than did the activation assay (P=0.007 by the sign test). The bars indicate 95 percent confidence intervals.
Five patients had a typical onset of thrombocytopenia in associationwith an initial course of heparin but a rapid onset when heparinwas given again within the next 100 days. Figure 3 shows a representativecase of this kind of dual pattern of heparin-induced thrombocytopenia.
Figure 3. Representative Case of Typical-Onset Heparin-Induced Thrombocytopenia, Followed by a Rapid-Onset Episode.
The patient initially received a 10-day course of heparin (10,000 U per day by subcutaneous injection). Typical-onset heparin-induced thrombocytopenia developed on day 6, according to a positive test for heparin-dependent antibodies. On day 30, the patient received heparin again (5000 U as a bolus injection followed by intravenous infusion), and rapid-onset thrombocytopenia developed.
Table 3 lists outcomes in seven patients with a history of serologicallyconfirmed heparin-induced thrombocytopenia who received a subsequentcourse of heparin. Three of these patients were inadvertentlygiven heparin for 8 to 19 days between 10 months and 13.5 yearsafter an initial episode of heparin-induced thrombocytopenia.In none of these three patients did thrombocytopenia recur,and heparin-dependent antibodies could not be detected in thetwo patients whose serum was tested. Thrombocytopenia or thromboticcomplications did not occur in any of the four patients whoreceived an elective, brief course of heparin in preparationfor cardiopulmonary-bypass surgery (two patients) or vascularsurgery (two patients). Heparin-dependent antibodies were foundin the serum of one of these four patients beginning on postoperativeday 6.
Table 3. Outcome in Seven Patients with a History of Heparin-Induced Thrombocytopenia Who Received a Subsequent Course of Heparin after the Loss of Heparin-Dependent Antibodies.
Discussion
In this study of serologically confirmed heparin-induced thrombocytopeniawe examined the time of onset of the disorder in relation toprevious treatment with heparin. We also investigated the persistenceof heparin-dependent antibodies after an episode of heparin-inducedthrombocytopenia. In 70 percent of the 243 patients we studied,the platelet count began to fall four or more days after thestart of heparin therapy (typically between days 5 and 10).In the remaining 30 percent the thrombocytopenia began a medianof 10.5 hours after the initiation of heparin therapy. All ofthe latter patients had recently been exposed to heparin, usuallywithin the previous 3 weeks and invariably within the previous100 days. In addition, we found that the presence of heparin-dependentantibodies in the blood was usually transient and did not alwaysrecur with subsequent heparin therapy.
The transience of heparin-dependent antibodies may explain thesecontrasting patterns of heparin-induced thrombocytopenia. Usingan activation assay, Cines and colleagues25 observed a rapiddecline (over a period of a few weeks) in the levels of heparin-dependentantibodies in two patients. We confirmed such observations andalso showed a rapid decline in the levels of antibodies againstplatelet factor 4 (Figure 2). The median time to a negativeactivation assay was 50 days, and the median time to a negativeantigen assay was 85 days. This difference is consistent withthe relatively high sensitivity of the antigen assay as comparedwith the activation assay10,22 (although the activation assayhas superior operating characteristics for diagnosis26).
In contrast to heparin-dependent antibodies, antibodies inducedby exposure to quinine, quinidine, or sulfonamides can persistfor years after an episode of drug-dependent thrombocytopenia.27,28In these cases, the onset of thrombocytopenia on reexposureto one of these drugs is abrupt, even many years after its previoususe.29,30,31
Our study suggests that patients in whom thrombocytopenia developswithin hours after exposure to heparin already have circulatingheparin-dependent antibodies that arose during a recent treatmentwith heparin. Several of our observations support this interpretation.First, rapid-onset thrombocytopenia occurred in the patientswho had received heparin within 100 days before the currenttreatment, an interval consistent with the persistence of heparin-dependentantibodies. Second, each of the eight patients from whom bloodsamples were available before the initiation of the heparintreatment that caused rapid-onset thrombocytopenia had positivetests for heparin-dependent antibodies. Third, among the patientswith rapid-onset heparin-induced thrombocytopenia, the intervalbetween the initiation of heparin administration and the fallin the platelet count was very short (median, 10.5 hours). Thisdecrease seems too rapid to be a secondary (anamnestic) immuneresponse, which generally would not begin until at least threedays after reexposure to the antigen.32
Seven patients with a history of serologically confirmed heparin-inducedthrombocytopenia received heparin again after the disappearanceof heparin-induced antibodies. Heparin-induced thrombocytopeniadid not recur in any of these seven patients, and heparin-dependentantibodies were found in only one, six days after brief, intraoperativeuse of heparin. These findings are consistent with the descriptionby Pötzsch and colleagues33 of 10 patients with a previousepisode of serologically confirmed heparin-induced thrombocytopeniawho briefly received heparin again in preparation for heartsurgery at a time when heparin-dependent antibodies were nolonger detectable. In none of these 10 patients did heparin-dependentantibodies reappear (according to the results of the antigenassay). These observations suggest that in the absence of heparin-dependentantibodies, the risk of a recurrence of heparin-induced thrombocytopeniaafter another brief exposure to heparin is low.
We believe that the use of heparin in patients with a historyof heparin-induced thrombocytopenia should be restricted topatients with a compelling indication for its use, such as cardiacor vascular surgery, and that it should be considered only ifheparin-dependent antibodies cannot be detected by a sensitiveassay. Because the risk of a recurrence of heparin-induced thrombocytopeniain such patients is unknown, it would be prudent to limit theuse of heparin to the surgical procedure itself and to use analternative anticoagulant for postoperative antithrombotic prophylaxisor therapy.
Supported by grants (B-3763 and T-4502, to Dr. Warkentin, andT-4404, to Dr. Kelton) from the Heart and Stroke Foundationof Ontario.
We are indebted to Robin S. Roberts for assistance with statisticalanalysis and to Jo-Ann I. Sheppard for technical assistance.
Source Information
From the Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences Corporation; and the Department of Pathology and Molecular Medicine and Department of Medicine, Faculty of Health Sciences, McMaster University — both in Hamilton, Ont., Canada.
Address reprint requests to Dr. Warkentin at the Hamilton Regional Laboratory Medicine Program, Hamilton Health Sciences Corp., General Site, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada.
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