Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin
Theodore E. Warkentin, M.D., Mark N. Levine, M.D., Jack Hirsh, M.D., Peter Horsewood, Ph.D., Robin S. Roberts, M.Tech., Michael Gent, D.Sc., and John G. Kelton, M.D.
Background Heparin-induced thrombocytopenia, defined by thepresence of heparin-dependent IgG antibodies, typically occursfive or more days after the start of heparin therapy and canbe complicated by thrombotic events. The frequency of heparin-inducedthrombocytopenia and of heparin-dependent IgG antibodies, aswell as the relative risk of each in patients given low-molecular-weightheparin, is unknown.
Methods We obtained daily platelet counts in 665 patients ina randomized, double-blind clinical trial comparing unfractionatedheparin with low-molecular-weight heparin as prophylaxis afterhip surgery. Heparin-induced thrombocytopenia was defined asa decrease in the platelet count below 150,000 per cubic millimeterthat began five or more days after the start of heparin therapy,and a positive test for heparin-dependent IgG antibodies. Wealso tested a representative subgroup of 387 patients for heparin-dependentIgG antibodies regardless of their platelet counts.
Results Heparin-induced thrombocytopenia occurred in 9 of 332patients who received unfractionated heparin and in none of333 patients who received low-molecular-weight heparin (2.7percent vs. 0 percent; P = 0.0018). Eight of the 9 patientswith heparin-induced thrombocytopenia also had one or more thromboticevents (venous in 7 and arterial in 1), as compared with 117of 656 patients without heparin-induced thrombocytopenia (88.9percent vs. 17.8 percent; odds ratio, 36.9; 95 percent confidenceinterval, 4.8 to 1638; P<0.001). In the subgroup of 387 patients,the frequency of heparin-dependent IgG antibodies was higheramong patients who received unfractionated heparin (7.8 percent,vs. 2.2 percent among patients who received low-molecular-weightheparin; P = 0.02).
Conclusions Heparin-induced thrombocytopenia, associated thromboticevents, and heparin-dependent IgG antibodies are more commonin patients treated with unfractionated heparin than in thosetreated with low-molecular-weight heparin.
Thrombocytopenia induced by heparin typically appears five ormore days after the start of heparin therapy.1,2,3 The thrombocytopeniais caused by heparin-dependent IgG antibodies that activateplatelets through their Fc receptors.4,5,6 Recently, severallaboratories have shown that these antibodies recognize a complexof heparin with platelet factor 4.7,8,9,10 Paradoxically, thromboticcomplications develop in some patients with heparin-inducedthrombocytopenia,1,2,3 possibly because of in vivo plateletactivation.11
The frequency of heparin-induced thrombocytopenia and associatedthrombotic complications is uncertain. Previous prospectivestudies have not usually confirmed the diagnosis with appropriatelaboratory tests; other studies included patients with earlythrombocytopenia, even though this transient and reversibleevent is not related to heparin-induced antibodies.2,3
In this article, we report our analysis of platelet counts andheparin-dependent IgG antibodies in a randomized, double-blind,controlled trial of 665 patients who received prophylaxis againstvenous thrombosis with either unfractionated heparin or low-molecular-weightheparin. We used a sensitive and specific assay for heparin-dependentIgG antibodies (the platelet 14C-labeled serotonin-release assay12,13)to confirm the diagnosis of heparin-induced thrombocytopeniain all patients who had thrombocytopenia after receiving heparinfor at least five days. We also tested a representative subgroupof 387 patients, regardless of their platelet counts, to determinethe frequency of heparin-dependent IgG antibodies. We foundthat patients treated with unfractionated heparin had a higherfrequency of heparin-induced thrombocytopenia and formationof heparin-dependent IgG antibodies than patients treated withlow-molecular-weight heparin. We also found that heparin-inducedthrombocytopenia is a risk factor for thrombotic complications,including venous thrombosis.
Methods
Randomized Clinical Trial
Platelet counts were obtained daily during a randomized trialin which a preparation of low-molecular-weight heparin, enoxaparin(Lovenox, Rhône–Poulenc Rorer, Montreal), was comparedwith a preparation of unfractionated calcium heparin (Calciparine,Laboratoires Anglo-French, Dorval, Quebec, Canada; preparedfrom porcine intestinal mucosa), for the prevention of thrombosisafter elective hip surgery.14 The preparations of both unfractionatedand low-molecular-weight heparin were manufactured in France(Laboratoires Choay and Rhône–Poulenc Rorer, respectively).Low-molecular-weight heparin was given at a dose of 30 mg subcutaneouslytwice daily, and unfractionated heparin at 7500 units subcutaneouslytwice daily, beginning at 6 a.m. on the first day after theoperation (day 1). The study drug was given for a mean (±SD)period of 10±3 days (maximum, 14). Preoperative (base-line)and daily postoperative platelet counts were measured in allpatients for 14 postoperative days or until discharge, if thatoccurred sooner (total, 8164 platelet counts; mean, 12 per patient).
Definition of Thrombocytopenia and Heparin-Induced Thrombocytopenia
Thrombocytopenia was defined as at least two consecutive plateletcounts below 150,000 per cubic millimeter. Early thrombocytopeniawas defined as thrombocytopenia occurring on postoperative days1 through 5, inclusive, and late thrombocytopenia as that occurringon or after postoperative day 6 (that is, after five days ofreceiving the study drug). Heparin-induced thrombocytopeniawas defined as a decrease in the platelet count to below 150,000per cubic millimeter after five days of treatment with the studydrug (late thrombocytopenia) plus a positive test for heparin-dependentIgG antibodies.
Collection of Blood Samples to Test for Heparin-Dependent IgG Antibodies
Blood samples were obtained in one of two ways to test for heparin-dependentIgG antibodies. First, a test for heparin-dependent IgG antibodieswas requested by some physicians throughout the clinical trialfor eight patients who were thought to have heparin-inducedthrombocytopenia. The identity of the study drug received bythe patient was not known to any of the investigators at thetime of such testing. Second, we also tested a large subgroupof 387 patients (58.2 percent of all study patients) for heparin-dependentIgG antibodies to determine the frequency of seroconversionindependently of the platelet counts. These samples (total,4308; mean, 11 per patient) were not selected from patientswith thrombocytopenia, thrombosis, or other clinical eventsbut were selected only on the basis of availability. Sampleswere not available from all 665 patients to be tested for heparin-dependentIgG antibodies because the decision to test blood systematicallyfor these antibodies was made at the conclusion of the clinicaltrial. Because of the two methods of acquiring samples, testsfor heparin-dependent IgG antibodies were performed in all studypatients with late thrombocytopenia (12 patients, including1 patient with early and sustained thrombocytopenia).
Serologic Assay for Heparin-Dependent IgG Antibodies
We used the platelet 14C-labeled serotonin-release assay12,13to detect heparin-dependent IgG antibodies. At least two differentsamples, including the last sample obtained, were used for eachpatient in the subgroup of 387 patients. We also used storedserial samples to determine the date of seroconversion for patientswho tested positive for heparin-dependent IgG antibodies. Alllaboratory testing was performed by personnel who were unawareof the platelet counts, clinical outcomes, or the type of heparingiven.
Clinical Outcomes
Deep venous thrombosis, pulmonary embolism, and hemorrhage werediagnosed by objective tests and standard criteria.14 We includedall events that occurred before the patients' discharge fromthe hospital. Clinical events and radiologic studies were interpretedby a committee that was unaware of the assigned treatments.
Normal Range of Postoperative Platelet Counts
After orthopedic surgery, most patients have a transient decreasein the platelet count, followed by an increase above the preoperativecount. We calculated a reference range for the platelet countin our population of patients by determining the mean (±2SD) preoperative and postoperative platelet counts (with log-transformeddata) for the patients whose plasma tested negative for heparin-dependentIgG antibodies (367 patients).
Statistical Analysis
The relevant outcomes in this study were all events that eitheroccurred or did not occur in each patient. We compared the proportionsof patients who had outcome events between groups by Fisher'sexact test15 and an associated method developed by Gart16 forcomputing confidence intervals around the odds ratio. Confidenceintervals for single binomial proportions were calculated bythe "exact" approach.17 The cumulative proportion of patientswho had an event over time was estimated by the Kaplan–Meiermethod18 to allow for variation in the length of time at risk.Cumulative-incidence curves were compared between groups bythe Mantel–Haenszel test.18 All P values are two-tailed.
Results
Late Thrombocytopenia
In the entire group of 665 patients, 12 patients had thrombocytopeniaafter receiving either unfractionated or low-molecular-weightheparin for five or more days. In 1 of these 12 patients thrombocytopeniadeveloped on postoperative day 1 and persisted beyond day 5.All 12 patients had tests for heparin-dependent IgG antibodies,8 because their physicians suspected that they had heparin-inducedthrombocytopenia. Eight of the 12 were included (by chance)within the subgroup of 387 patients. Thus, four patients weretested twice because they were included in both groups fromwhich samples were acquired.
Frequency of Heparin-Induced Thrombocytopenia
Nine of the 12 patients with thrombocytopenia had heparin-dependentIgG antibodies and therefore had heparin-induced thrombocytopenia.All of these nine had received unfractionated heparin (Table 1).Thus, of the 332 patients randomly assigned to receive unfractionatedheparin, 2.7 percent (95 percent confidence interval, 1.3 to5.1 percent) had heparin-induced thrombocytopenia. By contrast,none of the 333 patients who received low-molecular-weight heparin(0 percent, 95 percent confidence interval 0 to 1.1 percent)had heparin-induced thrombocytopenia (P = 0.0018). Because somepatients were discharged from the hospital before 14 days hadpassed, the cumulative proportion of patients who had heparin-inducedthrombocytopenia at day 14 was 3.3 percent (Figure 1). Noneof the nine patients with heparin-induced thrombocytopenia hadmajor or minor hemorrhagic events.
Figure 1. Cumulative Frequency of Heparin-Induced Thrombocytopenia in the Two Study Groups.
The postoperative day on which the platelet count fell below 150,000 per cubic millimeter is shown.
Two patients with late thrombocytopenia tested negative forheparin-dependent IgG antibodies. Both had received unfractionatedheparin. Alternative clinical factors could explain the thrombocytopeniain these two patients (multiple myeloma in one, and colon rupturewith peritonitis and septicemia in the other). In both, theplatelet count recovered to normal despite the continuationof heparin therapy. Neither patient had thrombosis.
A third patient who received low-molecular-weight heparin wasfound to have thrombocytopenia on postoperative day 1. It persisteduntil her death on postoperative day 29, despite the discontinuationof low-molecular-weight heparin on postoperative day 9. Thispatient had two negative tests for heparin-dependent IgG antibodies.She died with a leukoerythroblastic blood picture and metastaticadenocarcinoma in the bone marrow. No thrombotic event occurred.
Early Postoperative Thrombocytopenia
Thrombocytopenia occurred commonly (in 28.4 percent of patients)during the early postoperative period (postoperative days 1through 5). There was no significant difference in the frequencyof early thrombocytopenia between the group receiving unfractionatedheparin and the group receiving low-molecular-weight heparin;thrombocytopenia occurred in 93 of 332 patients (28.0 percent;95 percent confidence interval, 23.3 to 33.2 percent) receivingunfractionated heparin, as compared with 96 of 333 patients(28.8 percent; 95 percent confidence interval, 24.0 to 34.0percent; P = 0.86) receiving low-molecular-weight heparin. Furthermore,the platelet count recovered within three days to more than150,000 per cubic millimeter in 188 of 189 (99.5 percent) ofthese patients, despite the continuation of heparin. The onepatient who did not have an increase in the platelet count hadadenocarcinoma, as noted, and tested negative for heparin-dependentIgG antibodies. In the subgroup of 387 patients, tests for heparin-dependentIgG antibodies were negative in all 98 patients with early,reversible thrombocytopenia.
Table 1 shows the thrombotic events that occurred in the ninepatients with heparin-induced thrombocytopenia. Seven patientshad deep venous thrombosis, including five with proximal-veinthrombosis. Two patients had pulmonary embolism. One other patienthad an arterial thrombosis (of the mesenteric artery). Heparin-inducedthrombocytopenia was strongly associated with thrombotic events(odds ratio, 36.9; 95 percent confidence interval, 4.8 to 1638;P<0.001), in particular proximal deep venous thrombosis andpulmonary embolism (Table 2 and Figure 2).
Figure 2. Cumulative Frequency of Thrombosis in Patients with and Patients without Heparin-Induced Thrombocytopenia.
All patients were followed to postoperative day 14 in this analysis.
In five of the eight patients with thrombosis that complicatedheparin-induced thrombocytopenia, the thrombosis began afterthe platelet count had fallen below 150,000 per cubic millimeter(Table 1 and Figure 3). In three patients, however, the initialthrombotic event occurred when the platelet count was above150,000 per cubic millimeter. However, in all these patients,seroconversion to heparin-dependent IgG antibodies had occurred,and the platelet count had begun to fall, before the onset ofthrombosis or at the same time.
Figure 3. Serial Platelet Counts of Nine Patients with Heparin-Induced Thrombocytopenia.
The bold line and shaded area indicate the mean (±2 SD) platelet count in the reference population (367 patients negative for heparin-dependent IgG antibodies). In the reference population there was a uniform early postoperative decrease in the platelet count (with a maximal decrease at postoperative days 1 to 3), followed by a return to the base-line values (at approximately day 5), followed by platelet counts higher than those at base line (with maximal values at days 11 to 14). Asterisks indicate the occurrence of thrombotic complications in the patients with heparin-induced thrombocytopenia. A dotted line is shown for one patient because the platelet count was not available on the day that thrombosis developed.
Laboratory and Clinical Analysis of Outcomes in the Subgroup of 387 Patients
Serial plasma samples from 387 patients were available to betested for heparin-dependent IgG antibodies. By chance, thissubgroup of patients included 8 of the 12 patients in the entirestudy population who had late thrombocytopenia (P = 0.77) and4 of the 8 patients who were tested because their physicianssuspected heparin-induced thrombocytopenia (P = 0.73).
Twenty of the 387 patients tested positive for heparin-dependentIgG antibodies. In all 20 samples, the tests were positive withboth unfractionated heparin and low-molecular-weight heparin.Not all 20 patients had late thrombocytopenia, but a positivetest for heparin-dependent IgG antibodies was strongly associatedwith its development: 6 of the 20 patients had late thrombocytopeniaas compared with 2 of the other 367 patients in the subgroup(odds ratio, 78.2; 95 percent confidence interval, 12.0 to 818.8;P<0.001).
We found a higher frequency of heparin-dependent IgG antibodiesin patients who received unfractionated heparin than in thosewho received low-molecular-weight heparin: 16 of 205 patients(7.8 percent) as compared with 4 of 182 (2.2 percent), respectively(P = 0.02). Tests of serial samples indicated that seroconversionhad occurred in all 20 patients between postoperative days 5and 10.
One or more thrombotic events occurred in 5 of the 6 patients(83.3 percent) in the 387-patient subgroup in whom heparin-inducedthrombocytopenia developed. In contrast, thrombotic events occurredin 3 of 14 patients (21.4 percent) in whom heparin-dependentIgG antibodies formed without the development of thrombocytopenia,and in 63 of 367 patients (17.2 percent) who tested negativefor heparin-dependent IgG antibodies. Heparin-induced thrombocytopeniawas therefore associated with an increased risk of thrombosis,as compared with the risk in either the patients who had heparin-dependentIgG antibodies without thrombocytopenia (odds ratio, 18.3; 95percent confidence interval, 1.1 to 943; P = 0.02) or the patientswho tested negative for heparin-dependent IgG antibodies (oddsratio, 24.1; 95 percent confidence interval, 2.6 to 1145; P<0.001).Patients in whom heparin-dependent IgG antibodies formed butwho did not have thrombocytopenia were not more likely to havethrombosis than patients who did not form heparin-dependentIgG antibodies (odds ratio, 1.3; 95 percent confidence interval,0.23 to 5.2; P = 0.72).
The 387-patient subgroup was representative of the entire studypopulation. There were no significant differences between thisgroup and the remaining 278 study patients with respect to thestudy drug received (P = 0.07), the frequency of heparin-inducedthrombocytopenia (P = 0.74), the occurrence of thrombotic eventsassociated with heparin-induced thrombocytopenia (P = 1.0),or the occurrence of any thrombotic event (P = 0.53).
Discussion
In this study, we report the frequency of heparin-induced thrombocytopeniain 665 patients who received either unfractionated or low-molecular-weightheparin for antithrombotic prophylaxis after elective hip surgery.Daily platelet counts were obtained in all patients, and everypatient who had thrombocytopenia after five days of heparinprophylaxis was tested for heparin-dependent IgG antibodies.We also tested a large, representative subgroup of 387 patientsfor heparin-dependent IgG antibodies regardless of their plateletcounts.
We defined heparin-induced thrombocytopenia as a decrease inthe platelet count to below 150,000 per cubic millimeter, beginningfive or more days after the start of heparin therapy, and apositive test for heparin-dependent IgG antibodies. Our investigationwas designed to avoid overestimating the frequency of heparin-inducedthrombocytopenia, by excluding patients with early thrombocytopeniarelated to surgery or other factors.
We found heparin-induced thrombocytopenia in 2.7 percent ofpatients who received unfractionated heparin. By postoperativeday 14, the cumulative risk of heparin-induced thrombocytopeniain this group reached 3.3 percent (Figure 1). In contrast, nopatient treated with low-molecular-weight heparin had heparin-inducedthrombocytopenia. In eight of nine patients with heparin-inducedthrombocytopenia, a thrombotic event occurred, giving an overallfrequency of heparin-induced thrombocytopenia associated withthrombosis of 2.4 percent (95 percent confidence interval, 1.1to 4.7 percent) among the patients who received unfractionatedheparin.
Tests of plasma samples from the subgroup of 387 patients allowedus to estimate the frequency of heparin-dependent IgG antibodiesin patients receiving unfractionated or low-molecular-weightheparin. There was a significantly higher frequency of theseantibodies in patients who received unfractionated heparin thanin those who received low-molecular-weight heparin. Althougha positive test for heparin-dependent IgG antibodies was stronglyassociated with thrombocytopenia, some patients did not havethrombocytopenia despite the presence of the antibodies in theirplasma. This phenomenon may relate to the marked variabilityin the reactivity of platelets to heparin-dependent IgG antibodies.13,19,20,21
Heparin-induced thrombocytopenia was a strong risk factor forthrombotic events, particularly venous thrombosis (Table 2).Analysis of the 387-patient subgroup also showed a strong associationbetween heparin-induced thrombocytopenia and thrombosis. Theplasma samples from this subgroup were studied on the basisof availability alone; thus, bias in referral for laboratorytesting does not explain the association between heparin-inducedthrombocytopenia and thrombosis.
Previous reports of heparin-induced thrombocytopenia have emphasizedits association with arterial thrombosis.2,3 Although therewas one patient in our series with arterial thrombosis (mesenteric-arterythrombosis resulting in bowel infarction), seven other patientswith heparin-induced thrombocytopenia had venous thrombosis,including two with pulmonary embolism and five with proximaldeep venous thrombosis. These observations are probably relatedto the high base-line risk of venous thrombosis in patientsundergoing orthopedic surgery and to the systematic investigationfor venous thrombosis we performed in all patients. Our previousretrospective study22 indicated that the type of thromboticcomplication (arterial or venous) is influenced by the clinicalsituation. We have recently postulated that the venous thromboticcomplications that occur in some patients with heparin-inducedthrombocytopenia might be related to the formation of procoagulantplatelet-derived microparticles.11
Platelet counts have also been monitored in several large clinicaltrials that compared unfractionated with low-molecular-weightheparin as antithrombotic prophylaxis after hip surgery23,24,25,26,27or for the treatment of deep venous thrombosis.28,29,30,31,32,33,34,35However, in only one of these studies were tests for heparin-dependentIgG antibodies performed.26 These investigators found heparin-inducedthrombocytopenia in 2 of 199 patients (1.0 percent) who receivedunfractionated heparin after hip-replacement surgery, as comparedwith none of 198 patients who received low-molecular-weightheparin26; both patients with thrombocytopenia also had proximaldeep venous thrombosis. In four other studies,27,28,29,30 fiveadditional patients had thrombocytopenia associated with thromboticevents (venous in four and arterial in one) that were thoughtto have been caused by heparin-induced thrombocytopenia, althoughconfirmatory tests for heparin-dependent IgG antibodies werenot reported; these five patients had also received unfractionatedheparin.
Our study suggests that heparin-induced thrombocytopenia andassociated thrombotic complications are relatively common adverseeffects of heparin therapy. Moreover, heparin-induced thrombocytopeniais a strong risk factor for thrombotic events, including venousthromboembolism. We found that these complications were lesslikely to occur with low-molecular-weight heparin than withunfractionated heparin.
Low-molecular-weight heparin has certain advantages over unfractionatedheparin, including the absence of a requirement for anticoagulantmonitoring and a greater therapeutic index (less risk of bleedingfor a given antithrombotic effect).36,37 A disadvantage is therelatively high cost. In the United States, the preparationof low-molecular-weight heparin that we studied is about 10times as expensive as unfractionated heparin when it is givenas prophylaxis (approximately $20 per day vs. $2 per day). However,as more commercial preparations are approved for use, it islikely that the price difference will narrow, as it has in Europe.
It is important to emphasize that low-molecular-weight heparinis not indicated for the treatment of heparin-induced thrombocytopenia,because of the extensive cross-reactivity of the two forms ofheparin.2,3,38 However, the lower risk of immune sensitizationand the correspondingly lower risk of heparin-induced thrombocytopeniaand associated thrombotic events are important advantages oflow-molecular-weight heparin over unfractionated heparin.
Supported by grants from the Heart and Stroke Foundation ofOntario and Rhône–Poulenc Rorer. Dr. Warkentin isa Research Scholar of the Heart and Stroke Foundation of Canada.Dr. Levine is a Scientist of the Medical Research Council ofCanada. Dr. Hirsh is a Distinguished Research Professor of theHeart and Stroke Foundation of Ontario. Dr. Kelton is a CareerInvestigator for the Heart and Stroke Foundation of Ontario.
We are indebted to C.A. Smith and R.K. Sinha for assistancewith laboratory studies and to Dr. J. Leclerc, Dr. J. Neemeh,Dr. P.J. Powers, Dr. R.M. Jay, Dr. A.G. Turpie, Ms. B. St. Jacques,Ms. L. Boulet, Ms. L.N. Klama, Mr. H. Nelson, and Dr. G. Fosterfor additional assistance with this study.
Source Information
From the Departments of Pathology (T.E.W., P.H., J.G.K.), Clinical Epidemiology and Biostatistics (M.N.L., J.H., R.S.R., M.G.), and Medicine (T.E.W., M.N.L., J.H., J.G.K.), McMaster University; the Hamilton Civic Hospitals (T.E.W., M.N.L., J.H.); the Hamilton Civic Hospital Research Centre (M.N.L., J.H., R.S.R., M.G.); and the McMaster University Medical Centre (P.H., J.G.K.) — all in Hamilton, Ontario, Canada.
Address reprint requests to Dr. Warkentin at the Department of Laboratory Medicine, Hamilton Civic Hospitals (General Division), 237 Barton St. E., Hamilton, ON L8L 2X2, Canada.
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Heparin-Induced Thrombocytopenia
Berkowitz N., Beckman J., Shumate M. J., Hougardy N., Machiels J.-P., Ravoet C., Warkentin T. E., Hirsh J., Kelton J. G.
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N Engl J Med 1995;
333:1006-1007, Oct 12, 1995.
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