| | Incidence of Thrombocytopenia in Hospitalized Patients with Venous Thromboembolism published online 14 August 2009. Abstract PurposeTo determine the incidence of heparin-associated thrombocytopenia in patients receiving prophylaxis or treatment for venous thromboembolism. MethodsWe assessed the database of the National Hospital Discharge Survey from 1979 through 2005 and complemented this with a meta-analysis of published literature. ResultAmong 10,554,000 patients discharged from short-stay hospitals throughout the US with venous thromboembolism during the 27 years of study, secondary thrombocytopenia was coded in 38,000 patients (0.36%). From 1979 through 1992, secondary thrombocytopenia was coded in only 0.15% of hospitalized patients with venous thromboembolism. The frequency increased sharply to 0.54% from 1993 through 2005. Secondary thrombocytopenia was rarely diagnosed among 1,446,000 patients aged <40 years and among 77,000 women who had venous thromboembolism with deliveries. Meta-analysis of published literature showed a higher incidence among patients who received unfractionated heparin (UFH) for prophylaxis than those who received low-molecular-weight heparin (LMWH) for prophylaxis. Treatment resulted in smaller differences of the incidence between UFH and LMWH. ConclusionHeparin-associated thrombocytopenia is rare among patients aged <40 years and women following delivery. The risk of heparin-associated thrombocytopenia is more duration-related than dose-related, and higher with UFH when used for an extended duration. Our findings and those of the literature suggest that although heparin-associated thrombocytopenia is uncommon, the incidence can be minimized by use of LMWH, particularly if extended prophylaxis or extended treatment is required. The incidence of heparin-induced thrombocytopenia has remained uncertain because tests for heparin-dependent antiplatelet antibodies have not usually been performed in prospective studies, and the incidence of heparin-induced thrombocytopenia can be affected by such variables as the dose and duration of heparin treatment, type of patient population, definition of thrombocytopenia, and the heparin preparation used.1 An estimate of the incidence among all hospitalized patients with venous thromboembolism, based on the opinion of the attending physician as indicated on the hospital discharge code, would be useful. In this investigation, therefore, we assessed the database of the National Hospital Discharge Survey to determine the incidence of thrombocytopenia associated with the use of heparin in the treatment and prevention of venous thromboembolism, and we complemented this with a meta-analysis of the published literature. Clinical Significance•The incidence of heparin-associated thrombocytopenia is approximately 0.5%. •An increase in frequency of heparin-associated thrombocytopenia after 1993 might have resulted from a change in the manufacturing process of heparin. •Heparin-associated thrombocytopenia is rare among patients <40 years of age. •Heparin-associated thrombocytopenia is rare among women following delivery. •The risk of heparin-associated thrombocytopenia is more duration-related than dose-related and higher with unfractionated heparin when used for an extended duration. Methods  Data Sources The number of patients discharged from short-stay non-Federal hospitals throughout the US with a diagnostic code for pulmonary embolism, deep venous thrombosis, or the combination of pulmonary embolism and deep venous thrombosis, venous thromboembolism, from 1979 through 2005 was obtained from the National Hospital Discharge Survey.2 Among these patients, the number with secondary thrombocytopenia was determined. The National Hospital Discharge Survey consists of data obtained annually from approximately 270,000 sampled inpatient records from about 500 non-Federal short-stay hospitals (average length of stay <30 days) in 50 states and the District of Columbia.2 The Survey samples about 8% of short-stay non-Federal hospitals and about 1% of discharges. The ICD-9 (International Classification of Diseases, Ninth Revision) codes used for identification of patients with certain diseases and procedures are shown in Table 1. | | |  | Disease of Procedure | ICD-9 Codes | Comments | |
|---|
| Pulmonary embolism | 415.1, 634.6, 635.6, 636.6, 637.6, 638.6, and 673.2 | | | | Deep venous thrombosis | 451.1, 451.2, 451.8, 451.9, 453.2, 453.8, 453.9, 671.3, 671.4, and 671.9. | Five-digit codes, such as 451.11 (included under the code 451.1), were not listed, as they were included under the corresponding 4-digit codes | | | Secondary thrombocytopenia | 287.4 | This includes platelet alloimmunization as well as post-transfusion purpura, thrombocytopenia due to dilution, drugs, extracorporeal circulation, and massive blood transfusion. Patients with cancer and those who had undergone extracorporeal circulation with cardiac surgery were eliminated in a sensitivity analysis | | | Cancer | | | | |  Lip, oral cavity, and pharynx | 140.0, 140.1, 140.3-140.6, 140.8, 140.9, 141.0-141.6, 141.8, 141.9, 144.0, 144.1, 144.8, 144.9, 145.0-145.6, 145.8, 145.9, 146.0-146.9, 147.0-147.3, 147.8, 147.9, 148.0-148.3, 148.8, 148.9, 149.0, 149.1, 149.8, and 149.9 | | | | Esophagus | 150.0-150.5, 150.8, and 150.9 | | | | Stomach | 151.0-151.6, 151.8, and 151.9 | | | | Colon | 153.0-153.9 | | | | Rectum, rectosigmoid junction, and anus | 154.0-154.3 and 154.8 | | | | Liver, gallbladder, intra- and extrahepatic bile ducts | 155.0-155.2, 156.0-156.2, 156.8, and 156.9 | | | | Pancreas | 157.0-157.4, 157.8, and 157.9 | | | | Trachea, bronchus, and lung | 162.0, 162.2-162.5, 162.8, 162.9 | | | | Female breast | 174.0-174.9 | | | | Uterus | 179, 182.0, 182.1, and 182.8 | | | | Cervix | 180.0, 180.1, 180.8, and 180.9; ovary 183.0 | | | | Prostate | 185 | | | | Bladder | 188.0-188.9 | | | | Kidney | 189,0, 189.1 | | | | Brain | 191.0-191.9 | | | | Lymphoma (includes lymphosarcoma and reticulosarcoma) | 200.0-200.2, 200.8, 201.0-201.7, 201.9, 202.0-202.6, 202.8, 202.9 | | | | Leukemia | 204.0-204.2, 204.8, 204.9, 205.0-205.3, 205.8, 205.9, 206.0-206.2, 206.8, 206.9, 207.0-207.2, 207.8, 208.0-208.2, 208.8, 208.9 | | | | ”Other” lymphatic and hematopoietic tissues (includes myeloproliferative disease) | 238.7 | | | | Extracorporeal circulation | 39.61 | | | | Vaginal deliveries | 650-659, 669.5, 669.6, V30.00-V30.07, V30.09, V30.10-V30.17, V30.19, 72, 73 | | | | Deliveries by caesarean section | 669.7, V30.01-V38.01, V39.01, 74.0-74.2, 74.4, 74.9 | | | | | |
Statistical Analysis and Methodological Considerations Data were analyzed using SPSS Version 11.5 for Windows (SPSS Inc., Chicago, Ill). Relative risk and 95% confidence intervals (CI) were calculated using calculator for confidence intervals of relative risk.3 To minimize the effect of confounding factors that might produce thrombocytopenia in addition to heparin, we performed a sensitivity analysis in which the most likely causes of non-heparin-associated thrombocytopenia were eliminated. In the sensitivity analysis, we eliminated patients with venous thromboembolism who had cancer, because they might have had chemotherapy, a common cause of thrombocytopenia.4 We also eliminated patients who underwent extracorporeal circulation. Approximately one fifth of patients undergoing cardiopulmonary bypass surgery have heparin-induced platelet antibodies detectable before the procedure as a result of prior heparin exposure.5 Many more develop antibodies after surgery.5 Meta-analyses were performed of the incidence of heparin-associated thrombocytopenia shown in prospective investigations in which unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) were compared for treatment of venous thromboembolism or prophylaxis against venous thromboembolism. Only investigations that included ≥100 patients in each arm were included. PubMed searches of heparin-induced thrombocytopenia matched with age, elderly, pediatrics, and demographics were made for all years and all languages. Review articles, guidelines, and prior meta-analyses also were searched for additional references. Meta-analysis was performed using the Metan procedure of Stata, release 8.0 (StataCorp LP, College Station, Tex). To assess the validity of combining results from individual studies, we used the Mantel-Haenszel test for statistical analyses to pool results across studies because of heterogeneity. Statistical tests detected heterogeneity between studies for prophylaxis. A random effects model using the method of DerSimonian & Laird was applied. The fixed effects model was used for treatment, and the combination of treatment and prophylaxis and heterogeneity was not detected. We considered a probability, P <.05, to be statistically significant for all statistical tests. Funnel plots were examined to evaluate interstudy variation in risk ratios in relation to sample size to assess the possibility that publication bias might be a contributing factor. The possibility of a publication bias exists for the studies of prophylaxis but not for the studies of treatment. Results Over the 27 years of study, among 10,554,000 patients discharged from short-stay hospitals with venous thromboembolism, secondary thrombocytopenia was coded in 38,000 patients (0.36%, 95% CI, 0.32-0.40%) (Table 2). During the 14-year interval from 1979 through 1992, secondary thrombocytopenia was rarely coded in patients with venous thromboembolism. During that time interval, only 7000 cases of secondary thrombocytopenia were recorded on discharge codes among 4,823,000 patients with venous thromboembolism (0.15%, 95% CI, 0.14-0.16%). A sharp increase was observed during the 13-year interval from 1993 through 2005 (Table 2). During that period, 31,000 cases of secondary thrombocytopenia were coded among 5,731,000 patients discharged with venous thromboembolism (0.54%, 95% CI, 0.52-0.56%). The relative risk, comparing 1993-2005 with 1979-1992, was 3.73 (95% CI, 3.63-3.82). | | | | | Patients with VTE | Thrombocytopenia (%) (95% CI) | |
|---|
| 1979-1992 | 4,823,000 | 7000(0.15)(0.14-0.16) | | | 1993-2005 | 5,731,000 | 31,000(0.54)(0.52-0.56) | | | All years | 10,554,000 | 38,000(0.36)(0.32-0.40) | | | Age (years) | | | | | 0-39 | 1,446,000 | Too low to calculate | | | 40-59 | 2,605,000 | 13,000(0.50)(0.49-0.51) | | | ≥60 | 6,504,000 | 23,000(0.35)(0.35-0.35) | | | Sex | | | | | Males | 4,447,000 | 17,000(0.38)(0.37-0.39) | | | Females | 6,107,000 | 21,000(0.34)(0.34-0.34) | | | Race | | | | | White | 7,602,000 | 25,000(0.33)(0.33-0.33) | | | Black | 1,170,000 | 5,000(0.43)(0.42-0.44) | | | | |
Secondary thrombocytopenia occurred primarily in patients aged 40 years or older, 36,000 of 9,109,000 (0.40%, 95% CI, 0.39-0.41%) (Table 2). It was rarely diagnosed among 1,446,000 younger patients with venous thromboembolism. The number of sampled cases of thrombocytopenia was too small to accurately calculate an incidence. Blacks had a higher incidence of secondary thrombocytopenia than Whites, 5000 of 1,170,000 (0.43%) versus 25,000 of 7,602,000 (0.33%) (relative risk 1.30, 95% CI, 1.26-1.34) (Table 2). Males had a slightly higher incidence than females, 17,000 of 4,447,000 (0.38%) versus 21,000 of 6,107,000 (0.34%) (relative risk 1.11, 95% CI, 1.09-1.13) (Table 2). From 1979 through 2005, among 112,712,000 women who had vaginal deliveries or caesarean sections, 77,000 (0.07%) were discharged with venous thromboembolism. Among these, the number of women with secondary thrombocytopenia was too small to accurately calculate an incidence. Sensitivity Analysis Among all patients with cancer, 240,000 of 52,678,000 (0.46%, 95% CI, 0.44-0.48%) had secondary thrombocytopenia. Among those with cancer and venous thromboembolism, 9000 of 1,135,000 (0.79%, 95% CI, 0.74-0.84%) had secondary thrombocytopenia. When patients with cancer were eliminated from the primary analysis, the incidence of secondary thrombocytopenia with venous thromboembolism from 1979-2005 was 29,000 of 9,419,000 (0.31%, 95% CI, 0.30-0.32%). From 1979 through 1992, secondary thrombocytopenia among patients with venous thromboembolism who did not have cancer occurred in 6000 of 4,402,000 (0.14%, 95% CI, 0.13-0.15%). From 1993 through 2005, among 5,017,000 patients discharged with venous thromboembolism who did not have cancer, 22,000 cases of secondary thrombocytopenia were diagnosed (0.44%, 95% CI, 0.42-0.46%). The relative risk, comparing 1979-1992 with 1993-2005, was 3.22 (95% CI, 3.13-3.31). Throughout the 27 years of study, 39,000 patients with venous thromboembolism had undergone extracorporeal circulation. Among these, the number of sampled cases of thrombocytopenia was too small to accurately calculate a proportion. In view of the extremely small number of patients with venous thromboembolism who underwent extracorporeal circulation and had secondary thrombocytopenia, such patients were not eliminated from the primary analysis. Meta-analyses are shown in Figure 1, Figure 2, Figure 3. These show the summary treatment effects for the outcomes that were calculated by using the fixed effects model (Figure 2, Figure 3) and the random effects model (Figure 1). Discussion We assumed that the vast majority of patients with pulmonary embolism or deep venous thrombosis would have been treated with heparin, and thrombocytopenia in such patients, therefore, was heparin-associated. The diagnosis of immune heparin-induced thrombocytopenia is usually based on a fall of the platelet count below 150×109/L,6 or either a decrease in platelet count of more than 50% from baseline or a platelet count <100×109/L7 or <150×109/L.8 We assume that these criteria were the basis for diagnosis of heparin-associated thrombocytopenia in included patients in this investigation. It has been recommended that heparin-dependent immunoglobulin G antibodies should be measured if available.9 For a diagnosis of heparin-induced thrombocytopenia, some required a positive laboratory assay for heparin-dependent antiplatelet antibodies in addition to a decreased or low platelet count.10 The term “heparin-associated thrombocytopenia” has been used when a laboratory assay for heparin-dependent antiplatelet antibodies was not obtained.11 The term “heparin-induced thrombocytopenia” was reserved for those with thrombocytopenia confirmed by laboratory testing for such antibodies.11 The incidence of heparin-associated thrombocytopenia that we found from 1993-2005 among patients hospitalized with venous thromboembolism was 0.5%. Many others found a similar or lower incidence during this time interval in prospective investigations of <2000 patients7, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 (Table 3). Prandoni et al,22 in a prospective investigation of LMWH that included prophylaxis and treatment of other conditions as well as venous thromboembolism, showed a similar incidence of heparin-associated thrombocytopenia (0.8%) (Table 3). Hull et al,23 in a systematic review, also found a similar incidence. Girolami et al24 observed no heparin-associated thrombocytopenia among patients treated with UFH, but an incidence of 1.4% among those who received UFH for prophylaxis (Table 3). Others with UFH for treatment of venous thromboembolism observed an incidence of 1.2%25 and 1.7%.26 Widely differing results have been reported, however, with some reporting an incidence of heparin-associated thrombocytopenia as high as 28% with UFH and 18% with LMWH8 (Table 3). | | | | First Author, Reference, Date | Dx Hep-Depend Antiplatelet Ab⁎ | Type of Study | Indication | UFH Ave or Median Duration, Days (Range) | UFH No. Pts | UFH HAT No (%) | LMWH Ave or Median Duration, Days (Range) | LMWH Number Patients | LMWH HAT No (%) | |
|---|
| Simmoneau,12 1997 | No | | | 7.0±2.4 | 308 | 1(0.3) | 7.3±2.3 | 304 | 0(0) | | | Fiessinger,51 1996 | No | | | 5-10 | 133 | 2(1.5) | 5-10 | 120 | 1(0.8) | | | Koopman,52 1996 | No | | | 6.1±1.8 | 198 | 5(2.5) | 6.5±2.2 | 202 | 3(1.5) | | | Merli,13 2001 | Yes | | | ≥5 | 290 | 0(0) | ≥5 | 610 | 1(0.2) | | | Harenberg,53 2000 | No | | | 10.7±2.7 | 273 | 4(1.5) | 11.8±2.8 | 265 | 3(1.1) | | | Lindhoff-Last,7 2002 | Yes | | | 5-7 | 375 | 2(0.5) | | | 0(0) 2(0.5) | | | MATISSE,25 2003 | No | | | 6.9±2.2 | 1110 | 13(1.2) | | | | | | Powers,26 1979 | No | Prospective | | ≥5 | 117 | 2(1.7) | | | | | | Prandoni,14 2004 | Yes | | | 6.5(5-12) | 360 | 1(0.3) | 6.5(5-17) | 360 | 1(0.3) | | | Levine,54 1996 | No | | | ≥5 | 253 | 3(1.2) | ≥5 | 247 | 5(2.0) | | | Kirchmaier,55 1998 | No | | | 14-16 | 131 | 4(3.1) | 14-16 | 256 | 2(0.8) | | | Prandoni,22 2005 | Yes | Prospective | Prophylaxis Treatment CV, AF, CAD, other | | | | 8(2-30) | 1754 | 14(0.8) | | | Hillbom,43 2002 | No | | | 10±2 | 106 | 6(5.7) | 10±2 | 106 | 6(5.7) | | | Nurmohamed,15 1995 | No | | | 10 or to discharge | 709 | 1(0.1) | 10 or to discharge | 718 | 0(0) | | | Colwell,44 1994 | No | | | ≤7 | 209 | 5(2.4) | ≤7 | 398 | 10(2.5) | | | GHAT,16 1992 | No | | | 16±1 | 168 | 0(0) | 16±1 | 167 | 0(0) | | | Heilmann,17 1989 | No | | | 10 | 150 | 0(0) | 10 | 150 | 0(0) | | | Forette,19 1995 | No | | | 28 | 149 | 1(0.7) | 28 | 146 | 0(0) | | | Ganzer,45 1999 | Yes | Prospective | Prophylaxis DVT Ortho/Trauma | 5 | 307 | 10(3.3) | 5 | 325 | 0(0) | | | Greinacher,46 2005 | Yes | Prospective | | ? | 231 | 12(5.2) | ? | 271 | 0(0) | | | McLeod,47 2001 | No | | Prophylaxis VTE Colon Surg | ≤10 | 675 | 6(0.9) | ≤10 | 674 | 6(0.9) | | | Rao,20 1989 | No | Prospective | | ≥5 | 193 | 0(0) | | | | | | Leyvraz,48 1991 | Yes | | | 5-7 | 175 | 2(1.1) | 5-7 | 174 | 0(0) | | | Mahlfeld,49 2002 | Yes | Prospective | | 9 | 252 | 5(2.0) | 9 | 252 | 1(0.4) | | | Samama,18 1999 | No | | | | | | 6-14 | 731 | 6(0.8) | | | Warkentin,50 1995 | Yes | | | 10±3 | 332 | 9(2.7) | 10±3 | 333 | 0(0) | | | Leizorovicz,21 2004 | No | | | | | | 14 | 1848 | 10(0.5) | | | Girolami,24 2003 | Yes if possible | Prospective | Prophylaxis VTE-Med Or Treatment VTE | 14(5-45) 10(5-32) | | 5(1.4) 0(0) | | | | | | Oliveira,8 2008 | No | Registry | VTE Proph 70% VTE Treat 5% AF 6% ACS 13% | <7 | 513 | 145(28.3) | <7 | 366 | 70(18.3) | | | Hull,23 2001 | No | | | | | | In-hosp 6-14 Out-of-hosp Out-of-hosp 18-28 | | 3(0.3) 5(0.5) | | | Martel,10 2005 | | Meta-analysis Prospective trials | Prophylaxis VTE-Med or Surg | | 3529 | (2.6)⁎ | | 3758 | (0.2)† | | | Morris,11 2007 | No (Yes in 20 analysis) | | | | 2399 | 36(1.5) | | 2876 | 34(1.2) | | | | |
| ⁎ Diagnosis requires heparin-dependent antiplatelet antibodies. †Inverse variance-weighted average. |
During the 1980s, several prospective comparisons, most of which were randomized, compared bovine lung UFH with porcine intestinal mucosal UFH27, 28, 29, 30, 31, 32, 33 (Table 4). These investigations had ≤111 patients in each arm. The incidence of heparin-associated thrombocytopenia with porcine UFH was often higher than observed in recent years (Table 4). The incidence with bovine UFH, on average, was even higher (Table 4). This would seem contrary to our observation of a lower incidence of heparin-associated thrombocytopenia during that period. Larger studies usually result in more precise estimates.34 | | | | First Author, Reference, Date | Dx Hep-Depend Antiplate Ab⁎ | Type of Study | Indication | Bovine Lung UFH Ave or Median Duration, Days (Range) | Bovine Lung UFH Number Patients | Bovine Lung UFH HAT No (%) | Porcine UFH Ave or Median Duration, Days (Range) | Porcine UFH Number Patients | Porcine UFH HAT No (%) | |
|---|
| Ansell,27 1980 | No | | Treatment | 9.5±2.0 | 21 | 4(19.0) | 10.2±2.3 | 22 | 1(4.5) | | | Ansell,28 1985 | No | | Treatment or prophylaxis Venous or arterial emboli | 8.5±3.2 | 54 | 1(1.9) | 9.5±4.3 | 50 | 2(4.0) | | | Bailey,29 1986 | No | | Treatment Venous or arterial emboli | 9.0±1.4 | 22 | 1(4.5) | 7.2±0.5 | 21 | 0(0) | | | Bell,30 1980 | No | | Treatment | ≥4 | 50 | 13(26.0) | ≥4 | 99† | 8(8.1) | | | Cipolle,31 1983 | No | Prospective | Treatment VTE Ischemic cerebrovascular disease, Myocardial infarction, Prophylaxis dysrhythmia | 2-26 | 100 | 10(10.0) | 2-26 | 111 | 1(0.9) | | | Green,32 1984 | | | Treatment Venous or cerebrovascular disease | ≥6 | 45 | 10(22.2) | ≥6 | 44 | 3(6.8) | | | Powers,33 1984 | No | | Treatment | ≥10 | 65 | 5(7.7) | ≥10 | 66 | 0(0) | | | | |
| ⁎ Diagnosis requires heparin-dependent antiplatelet antibodies. †45 intestinal mucosa A and 54 intestinal mucosa O. |
We speculate that there may have been a difference in the characteristics of porcine UFH since 1993. Pharmaceutical companies in the United States started dealing with China as early as 1978, but large amounts of porcine mucosal heparin for UFH and LMWH began to be imported after the introduction of LMWH in the 1990s (personal communication Fareed Jawed, PhD, DSc Loyola University, Maywood, Ill, November 19, 2008). Whether there is an association is undetermined. An important issue is the sensitivity and specificity of the coded discharge diagnoses in the National Hospital Discharge Survey. The specificity of ICD-9-CM (ICD-9, Clinical Modification) coding is high. Thus, the vast majority of diagnoses of heparin-associated thrombocytopenia that were coded in discharge abstracts actually occurred. The incidences, however, are underreported because of the imperfect sensitivity of coding for capturing diagnoses.35 Relative changes, such as the increased incidence of heparin-associated thrombocytopenia in 1993-2005, however, are likely to be correct. Regarding the robustness of discharge codes for deep venous thrombosis, White and associates36 showed that 92% of 198 coded cases of idiopathic deep venous thrombosis were valid. Regarding pulmonary embolism, review and reabstraction of a sample of Medicare hospitalizations from late 1986 and early 1989 showed that 92% of codable cases for pulmonary embolism were on the abstract.37 A 0.4% prevalence of pulmonary embolism in hospitalized Whites and Blacks ≥20 years of age throughout the US, based on the National Hospital Discharge Survey's use of ICD-9 codes,38 was remarkably close to the incidences of pulmonary embolism in a university hospital (0.4%), a nonuniversity tertiary care center (excluding estimates of undiagnosed pulmonary embolism in patients who died; 0.4%), and a community/teaching hospital (0.3%).39, 40, 41 These incidences were based on review of multiple data sources, including radiographic reports and autopsies (but not including estimates of unsuspected deaths from pulmonary embolism when no autopsy was performed).39, 40, 41 Two phenomena have been described, which potentially could introduce variability into the sensitivity of coding: diagnosis-related group “creep” and changes over time of the ICD-9-CM coding system. Diagnosis-related group “creep” is an artifact of coding that might have increased the sensitivity when reimbursement became directly linked to the extent of coding.42 It is unlikely that this explained the increased incidence of heparin-associated thrombocytopenia that we observed beginning in 1993, because this was 10 years after diagnosis-related groups were introduced. Regarding the stability of the ICD-9-CM codes, there were no changes over time in the codes we used. Because the diagnosis of heparin-induced thrombocytopenia is usually based on clinical criteria,9 the development of newer immunological techniques would not have affected the frequency of diagnosis. Pooled data from prospective comparisons of treatment or prophylaxis of venous thromboembolism that included >100 patients in each arm, showed a higher incidence of heparin-associated thrombocytopenia with UFH (1.4%) than with LMWH (0.6%)7, 12, 13, 14, 15, 16, 17, 19, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 (Table 5, Figure 3). The incidence of heparin-associated thrombocytopenia depended on whether the patients received treatment for venous thromboembolism or prophylaxis. A previously published meta-analysis of heparin-associated thrombocytopenia among patients who received prophylaxis showed a higher incidence among those who received UFH (2.6% vs 0.2%)10 (Table 3). A previous meta-analysis of comparisons among patients who received treatment for venous thromboembolism did not show a difference in the incidence of heparin-associated thrombocytopenia comparing UFH with LMWH (1.5% vs 1.2%)11 (Table 3). Our review of the literature supported these observations. Prospective comparisons of investigations of patients who received prophylaxis showed a higher incidence of heparin-associated thrombocytopenia in those receiving UFH than in those receiving LMWH, 1.6% versus 0.6%15, 16, 17, 19, 43, 44, 45, 46, 47, 48, 49, 50 (Table 5, Figure 1). Treatment, however, resulted in a smaller difference in the incidence of heparin-associated thrombocytopenia between UFH and LMWH, 0.9% versus 0.6%12, 13, 14, 51, 52, 53, 54, 55 (Table 5, Figure 2). Treatment with LMWH and prophylaxis with LMWH resulted in the same incidences of heparin-associated thrombocytopenia, 0.6% versus 0.6%7, 12, 13, 14, 15, 16, 17, 19, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 (Table 5). Unfractionated heparin, when used for prophylaxis, was associated with a higher incidence of heparin-associated thrombocytopenia than when used for treatment, 1.6% vs 0.9%7, 12, 13, 14, 15, 16, 17, 19, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 (Table 5). These observations suggest that the risk of heparin-associated thrombocytopenia is more duration-related than dose-related. With the relatively longer administration of heparin for prophylaxis, the incidence of heparin-associated thrombocytopenia is higher with UFH than with LMWH. | | | | | UFH Heparin-Associated Thrombocytopenia | LMWH Heparin-Associated Thrombocytopenia | References | |
|---|
| | n/N | (%) | (95% CI) | n/N | (%) | (95% CI) | |
|---|
| VTE prophylaxis | 57/3463 | (1.6) | (1.2-2.1) | 23/3714 | (0.6) | (0.4-0.9) | 15, 16, 17, 19, 43, 44, 45, 46, 47, 48, 49, 50 | | | VTE treatment | 22/2321 | (0.9) | (0.6-1.3) | 18/3126 | (0.6) | (0.3-0.9) | 7, 12, 13, 14, 51, 52, 53, 54, 55 | | | All patients prophylaxis or treatment | 79/5784 | (1.4) | (1.1-1.7) | 41/6840 | (0.6) | (0.4-0.8) | 7, 12, 13, 14, 15, 16, 17, 19, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 | | | | |
| ⁎ All included investigations included ≥100 patients in each arm and are outlined in Table 2. |
We observed a very low incidence of heparin-associated thrombocytopenia among pregnant women with venous thromboembolism who were hospitalized for deliveries. Others reported no heparin-associated thrombocytopenia in 244 pregnant women who received UFH56 and none among 486 who received LMWH.57 Some, however, reported an incidence of 1 of 604 (0.17%) in pregnant patients who received LMWH for treatment or prophylaxis during pregnancy.58 Heparin-induced thrombocytopenia is rare in pediatric patients. In 1999, a review of the literature showed only 9 pediatric patients aged 3 months to 15 years plus 14 newborns with heparin-induced thrombocytopenia.59 By 2004, 71 children had been reported in the literature with heparin-induced thrombocytopenia, and 12 new cases were added by Klenner et al.60 Our data showed that heparin-associated thrombocytopenia was rarely diagnosed in patients younger than age 40 years. In the data we present, males had a somewhat higher incidence of heparin-associated thrombocytopenia than females (relative risk 1.11). Oliveira et al also showed a higher incidence among men,8 but Warkentin et al showed that females were at greater risk of heparin-associated thrombocytopenia based on an analysis of 7 prospective investigations and their own in addition (common odds ratio 2.37).61 Weaknesses of this investigation were an inability to determine the method of diagnosis of heparin-associated thrombocytopenia, duration of prophylaxis or treatment, indication for prophylaxis or treatment, dose, and whether UFH or LMWH were used. In most investigations, the diagnosis of heparin-associated thrombocytopenia was based on platelet counts without testing for heparin-dependent antiplatelet antibodies (Table 3, Table 4), and it would be safe to assume that most clinical diagnoses were made without testing for such antibodies. It might not have been essential to know if UFH or LMWH was used, because it was only in patients who received UFH for prophylaxis that the incidence of heparin-associated thrombocytopenia was higher than in patients who received LMWH for prophylaxis (Table 5, Figure 1). The strength of this investigation lies in the huge number of patients, which gives information in low-incidence groups such as children and pregnant women, and permits evaluation of sex differences and age differences. Other information derived from the National Hospital Discharge Survey, which was impossible to identify from the published literature, is the increased incidence of heparin-associated thrombocytopenia after 1992. This identifies a need for further investigation. In conclusion, our findings and those of the literature suggest that although heparin-associated thrombocytopenia is uncommon, the incidence can be minimized by use of LMWH, particularly if extended prophylaxis or extended treatment is required. Low-molecular-weight heparin was shown from meta-analysis to be particularly useful for reducing the incidence of heparin-associated thrombocytopenia in patients receiving prophylaxis (prolonged duration with low doses). Differences in the incidence of heparin-associated thrombocytopenia, comparing LMWH with unfractionated heparin, were not shown, however, with treatment (high doses for a short duration). References 1. 1Hirsh J, Warkentin TE, Raschke R, et al. considerations, monitoring, efficacy, and safety. Chest. 1998;114(5 Suppl):489S–510S. MEDLINE |
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a Research and Advanced Studies Program, Michigan State University, College of Osteopathic Medicine, Detroit Medical Center Campus, Detroit, Mich b Department of Medicine, University of Calgary, Alberta, Canada c Department of Internal Medicine, St. Joseph Mercy Oakland Hospital, Pontiac, Mich  Requests for reprints should be addressed to Paul D. Stein, MD, 44405 Woodward Avenue, Pontiac, MI 48341-5023
Conflict of Interest: Russell Hull has received research support from Sanofi-Aventis and Leo-pharma. He has been on advisory boards for Sanofi-Aventis, Boehringer Ingelheim, Bayer, and Pfizer. None of the authors have any conflict of interest with the content of this article. Authorship: All authors had access to the data and a role in writing the manuscript. PII: S0002-9343(09)00437-9 doi:10.1016/j.amjmed.2009.03.026 © 2009 Elsevier Inc. All rights reserved. | |
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