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Original Research: Critical Care |

Heparin-Induced Thrombocytopenia in Medical Surgical Critical IllnessHeparin-Induced Thrombocytopenia in the ICU FREE TO VIEW

Theodore E. Warkentin, MD; Jo-Ann I. Sheppard, BSc; Diane Heels-Ansdell, MSc; John C. Marshall, MD; Lauralyn McIntyre, MD; Marcelo G. Rocha, MD; Sangeeta Mehta, MD; Andrew R. Davies, MD; Andrew D. Bersten, MD; Tim M. Crozier, MD; David Ernest, MD; Nicholas E. Vlahakis, MD, FCCP; Richard I. Hall, MD, FCCP; Gordon G. Wood, MD; Germain Poirier, MD; Mark A. Crowther, MD; Deborah J. Cook, MD; for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group*
Author and Funding Information

From the Department of Pathology and Molecular Medicine (Dr Warkentin and Ms Sheppard) and the Department of Clinical Epidemiology and Biostatistics (Ms Heels-Ansdell), McMaster University, Hamilton, ON, Canada; St. Joseph’s Healthcare (Drs Crowther and Cook), Hamilton, ON, Canada; St. Michael’s Hospital and the University of Toronto (Dr Marshall), Toronto, ON, Canada; Mount Sinai Hospital and the University of Toronto (Dr Mehta), Toronto, ON, Canada; Ottawa Hospital General Campus and University of Ottawa (Dr McIntyre), Ottawa, ON, Canada; Capital Health Queen Elizabeth II Health Science Center and Dalhousie University (Dr Hall), Halifax, NS, Canada; Vancouver Island Health Authority (Dr Wood), Victoria, BC, Canada; Charles LeMoyne Hospital (Dr Poirier), Longueuil, QC, Canada; Pavilhão Pereira Filho (Dr Rocha), Santa Casa de Porto Alegre, Brazil; Monash Medical Centre (Dr Crozier), Melbourne, VIC, Australia; Box Hill Hospital and Monash University (Dr Ernest), Melbourne, VIC, Australia; Alfred Hospital (Dr Davies), Melbourne, Melbourne, VIC, Australia; Flinders Medical Centre and Flinders University (Dr Bersten), Adelaide, SA, Australia; and Mayo Clinic (Dr Vlahakis), Rochester, MN.

Correspondence to: Theodore E. Warkentin, MD, Room 1-270B, Hamilton Regional Laboratory Medicine Program, Hamilton General Hospital, Hamilton Health Sciences, 237 Barton St E, Hamilton, ON L8L 2X2, Canada; e-mail: twarken@mcmaster.ca


* A complete list of study participants is located in e-Appendix 1.

Funding/Support: PROTECT was funded by the Canadian Institutes of Health Research and the Australian and New Zealand College of Anesthetists Research Foundation. We also acknowledge the support of the Heart and Stroke Foundation of Ontario to Dr Warkentin [Grant T6950].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;144(3):848-858. doi:10.1378/chest.13-0057
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Background:  In a recent multicenter randomized trial comparing unfractionated heparin (UFH) with low-molecular-weight heparin (dalteparin) for thromboprophylaxis in 3,746 critically ill patients, 17 patients (0.5%) developed heparin-induced thrombocytopenia (HIT) based on serotonin-release assay-positive (SRA+) status. A trend to a lower frequency of HIT with dalteparin vs UFH was observed in the intention-to-treat analysis (five vs 12 patients, P = .14), which was statistically significant (three vs 12 patients, P = .046) in a prespecified per-protocol analysis that excluded patients with DVT at study entry. We sought to characterize HIT outcomes and to determine how dalteparin thromboprophylaxis may reduce HIT frequency in patients in the ICU.

Methods:  In 17 patients with HIT, we analyzed platelet counts and thrombotic events in relation to the study drug and other open-label heparin, to determine whether the study drug plausibly explained seroconversion to SRA+ status and/or breakthrough of thrombocytopenia/thrombosis. We also compared antibody frequencies (dalteparin vs UFH) in 409 patients serologically investigated for HIT.

Results:  HIT-associated thrombosis occurred in 10 of 17 patients (58.8%) (8:1:1 venous:arterial:both). Dalteparin was associated with fewer study drug-attributable HIT-related events (P = .020), including less seroconversion (P = .058) and less breakthrough of thrombocytopenia/thrombosis (P = .032). Antiplatelet factor 4/heparin IgG antibodies by enzyme-linked immunosorbent assay were less frequent among patients receiving dalteparin vs UFH (13.5% vs 27.3%, P < .001). One patient with HIT-associated DVT died after UFH bolus (anaphylactoid reaction), whereas platelet counts recovered in two others with HIT-associated VTE despite continuation of therapeutic-dose UFH.

Conclusions:  The lower risk of HIT in patients in the ICU receiving dalteparin appears related to both decreased antibody formation and decreased clinical breakthrough of HIT among patients forming antibodies.

Figures in this Article

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating IgG that recognizes multimolecular platelet factor 4 (PF4)/heparin complexes.1 The frequency of HIT is higher with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH) based on two meta-analyses2,3 that analyzed randomized trials and prospective observational studies of postoperative thromboprophylaxis. The PROTECT (The Prophylaxis for Thromboembolism in Critical Care Trial) randomized trial,4 which compared UFH with the LMWH, dalteparin, for thromboprophylaxis in mixed surgical-medical critically ill patients, used the serotonin-release assay (SRA) to classify patients as having HIT among those who underwent serologic investigations because of thrombocytopenia or thrombosis.5 Seventeen patients had HIT based on SRA-positive (SRA+) status: five in the dalteparin group and 12 in the UFH group, a nonsignificant difference in the intention-to-treat analysis (five of 1,873 [0.3%] vs 12 of 1,873 [0.6%]; hazard ratio, 0.47; 95% CI, 0.16-1.35; P = .16; Fisher exact test, P = .14). However, the difference in HIT was statistically significant in a prespecified per-protocol analysis that excluded two patients who had VTE at trial entry: dalteparin, three of 1,566 (0.2%) vs UFH, 12 of 1,561 (0.8%); hazard ratio, 0.27 (95% CI, 0.08-0.98); P = .046; Fisher exact test, P = .021.

The current study had two objectives. First, we sought to characterize the clinical picture of HIT in critically ill patients enrolled in PROTECT (timing and severity of thrombocytopenia and frequency of HIT-associated thrombosis and other sequelae [eg, HIT-associated anaphylactoid reactions6]). We were particularly interested in determining whether SRA+ patients in whom heparin was continued (because of low clinical suspicion of HIT) had subsequent platelet count recovery, a phenomenon reported in some patients with HIT who continue to receive heparin.7

Second, we sought to determine whether the reduced risk of HIT with dalteparin observed in PROTECT reflected decreased seroconversion (ie, lower immunogenicity) by the study drug (dalteparin vs UFH), or decreased breakthrough of HIT-related thrombocytopenia and/or thrombosis among SRA+ patients while receiving the study drug (dalteparin vs UFH), or both. We undertook this analysis to address the role of confounding open-label heparin in PROTECT and because there are two distinct heparin-dependent pathophysiologic events to explain a given episode of HIT: (1) formation of HIT antibodies (seroconversion to SRA+ status) and, subsequently, (2) platelet activation, resulting in thrombocytopenia and/or thrombosis among SRA+ patients (breakthrough).8

Testing for HIT Antibodies

Detailed methods regarding the design, conduct, and results of PROTECT have been published.5,9 All patients or their designated surrogates provided written informed consent (REB Project No. 05-2572). This report describes a retrospective analysis of patients with HIT in PROTECT. In the trial, HIT antibody testing was performed if any of the following occurred: the platelet count fell to < 50 × 109/L or by > 50% from the value at ICU admission, if venous thrombosis was documented, or if HIT was otherwise clinically suspected.10 Compression ultrasonography was performed within 2 days after enrollment, twice-weekly, and as clinically indicated to diagnose the primary outcome (proximal leg DVT).5 The SRA, performed by the McMaster Platelet Immunology Laboratory,11 was considered positive at a 50% threshold of serotonin release (mean at 0.1 and 0.3 U/mL heparin)12; this threshold, which differs from the 20% threshold described originally,11 increases diagnostic specificity for HIT13 and was prespecified to define HIT.10 Patients also underwent testing using the McMaster IgG-specific anti-PF4/heparin enzyme-linked immunosorbent assay (ELISA) (reference range, < 0.45 units of optical density [OD])13 and a commercial polyspecific ELISA, the PF4 ENHANCED X-HAT45 (Hologic Gen-Probe) that detects IgG, IgA, and IgM (reference range, < 0.40 OD units).14

HIT Case Review

For the 17 SRA+ patients, we abstracted from the case report forms the dates/times of study drug administration, platelet counts, thrombosis, and hospital mortality. We obtained additional information from the local investigators regarding open-label heparin exposure(s), any possible HIT-related thrombotic events, and dates/times of additional platelet counts (only one platelet count was recorded per day in the trial database).

After completion of the trial, one investigator (T. E. W.) determined a 4Ts score15 based on the entire hospitalization, taking into account open-label heparin administered. A maximum of 1 point was given for the 4Ts category, other,15 because being in the ICU justified at most 1 point for a plausible non-HIT explanation for thrombocytopenia, and 0 points were given for patients with obvious explanations for thrombocytopenia (eg, bacteremia). In many cases, this 4Ts score differed from those of the local research coordinators and central investigators, because these individuals performed a 4Ts score at the time of HIT antibody testing and, thus, could not consider information available subsequently (such as later platelet count changes, thrombosis, and so forth). Also, whereas the local investigators usually were aware of open-label heparin given preenrollment, the central investigators were not.

Definitions

For SRA+ patients, the day of onset of HIT was the first day of HIT-related platelet count decline or of HIT-associated thrombosis, assessed in relation to the presumed immunizing heparin exposure (generally, the first in-hospital heparin exposure, whether open label or study drug [= day 0]). HIT-associated thrombosis was any proven venous or arterial thrombosis that occurred in an SRA+ patient on/after day 5 after immunizing heparin exposure.16 An HIT-associated anaphylactoid reaction was defined as any of the following occurring within 30 min of an IV bolus of heparin: chills/fever, flushing, dyspnea, or cardiorespiratory arrest.6

Plausible study drug-related seroconversion was defined as SRA+ status that could reasonably have been associated with the administration of the study drug (ie, administration of the study drug occurred ≥ 5 days prior to the SRA+ status and associated onset of HIT). Confounding heparin was defined as any documented open-label prophylactic or therapeutic-dose heparin that could have also plausibly explained the patient’s SRA+ status. Plausible study drug-related breakthrough of thrombocytopenia and/or thrombosis was defined by an HIT-associated platelet count fall and/or by thrombosis that occurred while receiving the study drug.

Data Analysis

Table 1 describes how the study drug-related seroconversion and study drug-related thrombocytopenia/thrombosis breakthrough of HIT were analyzed. To examine whether there may have been a lower risk of anti-PF4/heparin antibody seroconversion with dalteparin vs UFH, we determined the frequency of anti-PF4/heparin antibodies by SRA and both ELISAs among all 409 patients tested in the central laboratory. UFH exposure in catheters (eg, heparin flushes) was not considered when evaluating study-drug related seroconversion and breakthrough of HIT because of its minor expected contributory role compared with the substantially larger exposures through prophylactic- and therapeutic-dose exposures required to reach stoichiometrically optimal immunizing concentrations of heparin.17

Table Graphic Jump Location
Table 1 —Assessment of Study Drug-Related Seroconversion to SRA+ Status and Study Drug-Related Breakthrough of Thrombocytopenia and/or Thrombosis

HIT = heparin-induced thrombocytopenia; SRA+ = serotonin-release assay positive.

Summary statistics are presented as median (range). The Wilcoxon rank sum test was used to compare points scored for UFH vs dalteparin with respect to (1) plausible role in explaining seroconversion and (2) thrombocytopenia/thrombosis breakthrough, as well as (3) combined analysis. The Fisher exact test was used for other categorical analyses. All comparisons are two tailed. A P value < .05 was considered statistically significant.

Table 2 summarizes the clinical and serologic features of the 17 SRA+ patients (nine men, eight women) diagnosed with HIT (frequency, 17 of 3,746: 0.5% [95% CI, 0.3% to 0.7%]). The median age was 69 years (range, 22-88 years). Median onset of HIT was day 8 (range, day 5 to day 12). Ten of the 17 patients had undergone major surgery during the current hospital admission prior to developing HIT; however, only four patients were admitted directly from the operating room and, therefore, classified in the PROTECT report as surgical; the remaining 13 were classified as medical.5,18

Table Graphic Jump Location
Table 2 —Clinical and Laboratory Summary of 17 SRA+ Patients

ELISA = enzyme-linked immunosorbent assay; F = female; L = left; M = male; Med = medical; R = right; Surg = surgical; UFH = unfractionated heparin. See Table 1 legend for expansion of other abbreviations.

a 

When more than one assay was performed, the highest value of mean percent serotonin release or units of optical density is shown.

b 

Underwent surgery prior to developing HIT (although classified as “medical” patient per PROTECT protocol).

c 

Right and left peroneal DVTs detected prior to onset of HIT; these are, therefore, not categorized as HIT-associated thrombosis.

d 

Abrupt fall in platelet count from 296 to 132 when open-label therapeutic-dose UFH was given on day 11.

e 

Autopsy-proven bilateral popliteal artery thrombosis; intracardiac thrombosis; DVTs (bilateral calf veins; right internal jugular vein), pulmonary embolism; thrombotic death.

f 

Patient had ultrasound-documented DVT on day 7, in association with 10% platelet count decline from 474 (day 7) to 427 (day 8); developed bradycardia, myocardial ischemia (per ECG), and cardiac arrest beginning 15 min after 5,000-units IV bolus of UFH, classified as HIT-associated anaphylactoid reaction. However, no repeat platelet count performed at the time of cardiac arrest, and, thus, a substantial post-UFH bolus drop in platelet count cannot be excluded. See also Fig 1C.

g 

Status corrected here because the patient was admitted with metabolic acidosis (ie, medical patient), but erroneous initial data submission classified this patient as “surgical” in the original PROTECT database.

h 

Left common femoral vein DVT detected prior to onset of HIT; this was, therefore, not categorized as HIT-associated thrombosis.

i 

Sample tested repeatedly negative in the ELISA-IgG/A/M.

The median percent serotonin release was 99% (range, 69% to 100%). Strongly positive results were also seen in the IgG-specific ELISA (median, 2.59 units; range, 1.42-2.87 units) and the polyspecific ELISA (median, 2.58 units; range, 0.30-3.03 units); one patient (No. 17) tested negative repeatedly by commercial ELISA. No patient investigated for HIT antibodies in the PROTECT trial had a weakly positive SRA (serotonin release, 20% to 49.9%).

Almost all patients (16 of 17) had a clinical picture consistent with HIT (ie, 4Ts score of at least 4 points; median, 6 points; range, 2-7 points). HIT-associated thrombosis was documented in 10 of 17 patients (58.8%): nine patients had one or more venous thromboses (usually DVT), and two patients had one or more arterial thromboses. One patient (No. 4) had multiple autopsy-proven arterial and venous thromboses; another patient (No. 8) had a fatal anaphylactoid reaction after UFH bolus. Two patients (No. 1 and 16) who did not have HIT-associated thrombosis nevertheless had DVT documented prior to development of HIT (ie, DVT occurred before day 5).

Table 3 shows the open-label heparin received for the 17 SRA+ patients, as well as the potential role of the study drug in explaining seroconversion, breakthrough (of thrombocytopenia/thrombosis), and combined analysis. In seven patients, SRA+ status clearly could not be attributed to the study drug, but rather to prior open-label heparin exposure (see SRA+ patients receiving 0 points in seroconversion column in Table 3). For seroconversion assessment, a total of 8 points were attributable to patients randomized to UFH, and only 2 points were attributable to patients randomized to dalteparin (P = .058). For assessment of breakthrough, a total of 19 points were attributable to patients randomized to UFH, and only 6 points to patients randomized to dalteparin (P = .032). When the two analyses were combined, there was a total of 27 points for patients randomized to UFH and 8 points for those randomized to dalteparin (P = .020).

Table Graphic Jump Location
Table 3 —Role(s) of Study Drug in Explaining Seroconversion and/or Clinical Breakthrough of HIT (Platelet Count Fall and/or Thrombosis)

CPB = cardiopulmonary bypass; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; qd = once-daily; SC = subcutaneous; U = units. See Table 1 and 2 legends for expansion of other abbreviations.

a 

The HIT-related platelet count fall began ≥ 5 d after preenrollment open-label heparin was given and ≥ 5 d after beginning study drug (seroconversion, 1 point); the HIT-related platelet count fall began while receiving study drug and continued to fall while receiving open-label UFH after enrollment (breakthrough, 1 point) = total, 2 points.

b 

HIT-related thrombocytopenia and SRA+ status occurred < 5 d after starting study drug but ≥ 5 d after preenrollment open-label heparin was given (seroconversion, 0 points); HIT-related thrombocytopenia began while receiving open-label heparin and progressed while receiving study drug (breakthrough, 1 point) = total, 1 point.

c 

HIT-related thrombocytopenia occurred < 5 d after starting study drug but ≥ 5 d after preenrollment open-label heparin was given (seroconversion, 0 points); HIT-related thrombocytopenia (and, where applicable, HIT-related thromboses [patient Nos. 4, 7, and 13]) occurred while (or after) receiving study drug and without postenrollment open-label heparin being given (breakthrough, 2 points) = total, 2 points.

d 

HIT-related platelet count fall began ≥ 5 d after preenrollment open-label heparin and ≥ 5 d after beginning study drug (seroconversion, 1 point); HIT-related platelet count fall began and HIT-related thrombotic event (prompting SRA testing) occurred while receiving study drug and before any open-label therapeutic-dose UFH, if applicable (patient Nos. 5, 8, and 14), was given (breakthrough, 2 points) = total, 3 points.

e 

HIT-related platelet count fall began ≥ 5 d after preenrollment open-label heparin and ≥ 5 d after beginning study drug (seroconversion, 1 point); HIT-related thrombocytopenia (prompting SRA testing) occurred while receiving study drug (breakthrough, 2 points) = total, 3 points.

f 

HIT-related platelet count fall began ≥ 5 d after preenrollment open-label heparin and ≥ 5 d after beginning study drug (seroconversion, 1 point); HIT-related platelet count fall and new left peroneal DVT occurred in association with use of therapeutic-dose open-label IV UFH (breakthrough, 0 points) = total, 1 point.

g 

DVT and SRA+ status were present prior to receiving any study drug (seroconversion and breakthrough, 0 points each) = total, 0 points. Additionally, for patient No. 16, the platelet count fell after stopping study drug and while receiving therapeutic-dose open-label IV UFH (with repeat SRA now yielding 100% serotonin release).

Table 4 shows the frequency of heparin-dependent antibodies in the dalteparin and UFH study groups in patients who were investigated serologically for HIT in the central laboratory. A significant difference was seen in the risk of anti-PF4/heparin IgG antibodies, with approximately twice as many patients randomized to UFH vs dalteparin testing positive (27.3% vs 13.5%; P < .001).

Table Graphic Jump Location
Table 4 —Results of HIT Antibody Test Results in 409 Patients Who Were Investigated Serologically for HIT in PROTECT

Data are presented as No. of total (%). The reference range for the ELISA-IgG is < 0.45 OD units, whereas for the commercial ELISA-IgG/A/M, the reference range is < 0.40 OD units. Note that 216 of 1,873 patients (11.5%) randomized to UFH underwent serologic testing for HIT antibodies in the central laboratory, compared with 193 of 1,873 patients (10.3%) randomized to dalteparin (P = .249, Fisher exact test). OD = optical density; PROTECT = Prophylaxis for Thromboembolism in Critical Care Trial. See Table 1 and 2 legends for expansion of other abbreviations.

a 

One sample was inadvertently discarded prior to testing in the polyspecific ELISA. For 10 patients (seven with UFH, three with dalteparin), more than one sample was tested in the central laboratory; the strongest result is shown, which for seven of the 10 patients was the latest sample.

Table 5 shows the treatment(s) initiated after the SRA+ blood testing. Twelve patients received non-heparin anticoagulant after stopping the study drug or subsequent open-label UFH: danaparoid (n = 5); fondaparinux (n = 3); argatroban (n = 2); lepirudin/urokinase during emergency thrombectomies (n = 1); and warfarin (n = 1). In some cases, new thrombotic events occurred (eg, late brachial artery thrombosis despite low-dose danaparoid administration and platelet count recovery in patient No. 13). Another with fatal necrotizing pancreatitis had anticoagulation stopped after undergoing diagnostic testing for HIT (patient No. 12).

Table Graphic Jump Location
Table 5 —Outcomes of Anticoagulation Instituted After SRA+ Blood Draw

CVC = central venous catheter; IVC = inferior vena cava. See Table 1, 2, and 3 legends for expansion of other abbreviations.

a 

All eight patients treated with either danaparoid or fondaparinux received low (prophylactic) dosing.

b 

Therapeutic-dose UFH was given to four patients with SRA+ status because the patients had documented DVT (three patients) or PE (one patient), which prompted SRA testing; the patients were not considered by the treating physicians to have had HIT.

In the four remaining patients (No. 5, 8, 14, and 17), laboratory testing for HIT antibodies was ordered per trial protocol because of VTE. Because the platelet counts were in the normal range and had not fallen by > 50%, and because the physicians were not suspicious of HIT, therapeutic-dose UFH was given. For two of these patients (No. 5 and 14), the platelet count fell substantially with therapeutic-dose UFH (by > 50%, but not below 150 × 109/L) but then subsequently recovered despite continued UFH treatment (Figs 1A, 1B). However, patient No. 8, beginning 15 min after 5,000-unit IV UFH bolus, developed bradycardia, hypotension, ECG changes of acute myocardial infarction, and fatal cardiac arrest (anaphylactoid reaction) (Fig 1C).

Figure Jump LinkFigure 1. Variable outcomes when IV therapeutic-dose UFH was given to three SRA+ patients in PROTECT with VTE. For each patient shown, the SRA was performed because of imaging evidence of VTE (DVT, n = 2; PE, n = 1), rather than because of investigator suspicion of heparin-induced thrombocytopenia (HIT). Besides study drug (UFH, n = 2; dalteparin, n = 1), each patient shown additionally received open-label prophylactic-dose UFH pre-trial enrollment, as well as open-label therapeutic-dose UFH after VTE was diagnosed by study ultrasound. A fourth SRA+ patient (No. 17, not shown in the figure) who received IV therapeutic-dose UFH for DVT developed progressive thrombocytopenia (platelet count, 169 to 63 × 109/L) over a 6-day treatment period; death was attributed to septic shock (secondary to laparotomy-proven GI perforation/peritonitis), and any contributory role of HIT was unclear. A, Patient No. 5 developed a 57% platelet count fall (from 559 to 240 × 109/L) that began on day 7 of heparin thromboprophylaxis (open-label UFH followed by study drug UFH). Therapeutic-dose UFH was given beginning on day 9 because of PE (platelet count = 453 × 109/L). The platelet count declined further (to a nadir of 240 × 109/L on day 13) but then recovered to 620 × 109/L (day 20) despite continuing therapeutic-dose UFH. No adverse clinical events occurred. B, Patient No. 14 developed a 59% platelet count fall (from 527 to 216 × 109/L) that began on day 9 of heparin thromboprophylaxis (open-label UFH followed by study drug dalteparin). Therapeutic-dose UFH was given beginning on day 13 because of left peroneal DVT (platelet count = 380 × 109/L). The platelet count declined further (to a nadir of 216 × 109/L on day 16) but then recovered to 582 × 109/L (day 22) despite continuing therapeutic-dose UFH followed by enoxaparin. No adverse clinical events occurred. C, Patient No. 8 developed features of an anaphylactoid reaction (fatal cardiac arrest) after IV UFH bolus. Left gastrocnemius vein DVT was diagnosed on day 7; the platelet count was 474 × 109/L. The next day, the platelet count had fallen to 427 × 109/L, and open-label UFH treatment of DVT was started. Fifteen minutes after 5,000-unit UFH bolus, the patient developed bradycardia, severe hypotension, and ECG changes consistent with myocardial infarction, with subsequent fatal cardiac arrest. Blood sampling for SRA testing was obtained per study protocol (because of DVT detection by compression ultrasonography), and not because the physicians suspected a diagnosis of HIT. Three doses (5,000 U each) of open-label dalteparin given prior to day 0 are not shown in the figure. PE = pulmonary embolism; SC = subcutaneous; SRA = serotonin-release assay; UFH = unfractionated heparin.Grahic Jump Location

This trial of 3,746 critically ill patients identified 17 patients (0.5%) with HIT based on SRA+ status. This overall frequency of HIT is similar to that reported in other studies in similar populations.1921 The moderate degree of thrombocytopenia (median platelet count nadir, 69 × 109/L), the usual onset between day 5 and day 10 (somewhat later [day 12] in two patients receiving dalteparin), and the high frequency of HIT-associated thrombosis (58.8%) are also consistent with prior studies.2125 Six patients (35.3%) died; in two patients (No. 4 and 8), HIT explained fatal thrombosis.

Although a lower risk of HIT with LMWH compared with UFH has been documented previously,2,3,2628 the relative difference has not been examined carefully in patients in the ICU. Several factors in PROTECT (and in critically ill patients more generally) pose challenges to examining the effect of LMWH vs UFH, including the high frequency of coadministration of open-label heparin, the high frequency of thrombocytopenia and its multifactorial cause during critical illness,20,21,29 and the lack of diagnostic specificity of testing for anti-PF4/heparin antibodies in general practice, particularly the commonly used ELISAs.1,1214

Nevertheless, several observations in our study support a lower risk of HIT with dalteparin compared with UFH thromboprophylaxis. First, we identified more patients (eight vs two) in whom the study drug (UFH vs dalteparin) could have explained SRA+ status. When we applied an analytic system that formally evaluated the plausibility of the study drug as an explanation for seroconversion, we found a trend favoring UFH over dalteparin (8 vs 2 points, P = .058) (Table 3). Additionally, we found that among the 409 patients who underwent testing for HIT antibodies, twice as many patients randomized to UFH vs dalteparin tested positive in the ELISA-IgG (27.3% vs 13.5%, P < .001), although for the commercial (polyspecific) ELISA, a significant difference was seen only at a high cutoff of 2.00 OD units (5.6% vs 1.6%, P = .0357) (Table 4). We also found more patients (11 vs three) in whom the study drug could have contributed to breakthrough of thrombocytopenia/thrombosis; when we applied a systematic approach that formally evaluated the plausibility of the study drug as an explanation for breakthrough of HIT, we found a significantly greater effect with UFH over dalteparin (19 vs 6 points, P = .032) (Table 3). A combined analysis of seroconversion and breakthrough showed a significantly greater effect with UFH over dalteparin (27 vs 8 points, P = .020).

These observations are consistent with those in our primary trial report,5 in which we reported a significantly lower frequency of HIT with dalteparin vs UFH in the per-protocol analysis and a trend to a lower frequency of HIT in the intention-to-treat analysis. As shown in Table 3, the per-protocol analysis results when patients No.16 and No. 17 are excluded from analysis (because SRA+ status was present prior to these patients receiving the study drug as a result of DVT being documented on their first study ultrasound).

Our study also illustrates the wide potential range of outcomes when therapeutic-dose UFH is given to an SRA+ patient. Figures 1A and 1B illustrate two patients with transient worsening of thrombocytopenia followed by platelet count recovery, without adverse consequences. This surprising finding is consistent with that of a previous study,7 which reported platelet count recovery in two patients, together with waning of HIT antibody levels, despite continued heparin administration. In contrast, Figure 1C illustrates a patient who developed a fatal presumed anaphylactoid reaction that began 15 min after IV UFH bolus, a rare but well-documented complication of HIT.6,30,31

The limitations of our study include the small number of patients with HIT, consistent with other studies of this uncommon adverse drug reaction. Moreover, only one HIT expert (TEW) performed the in-depth review and analysis of the 17 patients with HIT using a newly developed structured approach. Confounding by nonstudy heparin exposure is a limitation in that all 17 SRA+ patients were prescribed prophylactic- or therapeutic-dose open-label UFH, either before or after trial enrollment (Table 3). However, such exposure would tend to add random, rather than systematic, error, attenuating any relationship between HIT and either UFH or dalteparin, such that without this confounding, the relationship we observed would likely have been stronger.

The strengths of our study include the use of a functional (platelet activation) assay for HIT antibodies performed in a central laboratory and the systematic investigation for lower-limb DVT by twice-weekly ultrasound (the primary outcome of this clinical trial), which helped in identifying cases of HIT-associated thrombosis that may otherwise have gone undetected. Enrollment of patients in 67 centers in six countries enhances the generalizability of these findings.

In summary, we observed a high frequency of HIT-associated thrombosis in this medical-surgical critically ill population. The tendency to develop HIT less often in patients receiving dalteparin vs UFH thromboprophylaxis appears to be related to both decreased antibody formation (lower seroconversion) and decreased HIT breakthrough among patients forming antibodies.

Author contributions: Drs Warkentin, Crowther, and Cook and Ms Heels-Ansdell had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Warkentin: contributed to the planning and supervision of the HIT antibody studies in the central laboratory and interpretation of test results, review and analysis of the individual patient data, preparation of the first draft of the manuscript, critical review of the manuscript for intellectual content, and approval of its final version.

Ms Sheppard: contributed to the HIT antibody studies in the central laboratory, critical review of the manuscript for intellectual content, and approval of its final version.

Ms Heels-Ansdell: contributed to the biostatistical analyses, confirmation of the interpretation of the analysis, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Marshall: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr McIntyre: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Rocha: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Mehta: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Davies: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Bersten: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Crozier: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Ernest: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Vlahakis: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Hall: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Wood: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Poirier: contributed to the review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Crowther: contributed to the planning of the HIT antibody studies, obtaining of funding for the HIT analyses, review and analysis of patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Dr Cook: contributed to the planning of the HIT antibody studies, supervision of other data collection in the study, review and analysis of patient data, review of local patient data, critical review of the manuscript for intellectual content, and approval of its final version.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Warkentin has served as consultant and/or has received honoraria for speaking on behalf of companies that manufacture LMWH (Pfizer Canada, Inc; Sanofi), heparin-coated grafts (W. L. Gore & Associates Inc), heparin-like molecules (Paringenix Inc), and non-heparin anticoagulants for management of HIT (Canyon Pharmaceuticals, GlaxoSmithKline). His institution has received funding from GlaxoSmithKline and Instrumentation Laboratories, as well as from the Heart and Stroke Foundation of Ontario for research related to HIT. Dr Warkentin has also received royalties from Informa for the book, Heparin-Induced Thrombocytopenia. He receives compensation for medicolegal consultation and testimony regarding thrombocytopenic disorders including HIT. Ms Sheppard is employed through grants received from the Heart and Stroke Foundation of Ontario for research pertaining to HIT. Dr Ernest has served as a consultant to and received grant monies from Hospira, Inc, a company that manufactures heparin. Dr Vlahakis is employed by Genentech, a company that manufactures thrombolytic agents (alteplase, tenecteplase). Dr Crowther has sat on advisory boards for Leo Pharma Inc; Pfizer Inc; Bayer; Boehringer-Ingelheim GmbH; Alexion Pharmaceuticals, Inc; CSL Behring; and Artisan Pharma, Inc. Dr Crowther has prepared educational materials for Pfizer Inc; Octapharma Plasma, Inc; and CSL Behring. Dr Crowther has provided expert testimony for Bayer and for Merck & Co. Dr Crowther holds a Career Investigator award from the Heart and Stroke Foundation of Ontario, and is the Leo Pharma Chair in Thromboembolism Research at McMaster University. His institution has received funding for research projects from Boehringer-Ingelheim, Octapharma Plasma, Inc; Pfizer Inc; and Leo Pharma Inc. Dr Crowther has received funding for presentations from Leo Pharma Inc and CSL Behring. Ms Heels-Ansdell and Drs Marshall, McIntyre, Rocha, Mehta, Davies, Bersten, Crozier, Hall, Wood, Poirier, and Cook have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The study drug was provided by Pfizer, Inc, for Canada, Australia, Saudi Arabia, Brazil, and the United Kingdom; Eisai Inc provided the study drug for the United States.

Other contributions: We appreciate the assistance of Nicole Zytaruk, RN; Suzanne Duchesne; and Katherine Krolicki, BChE, for management of clinical data for this study. We thank Fiona Auld, RN; Maedean Brown, BA; Lisa Julien, RN; Elisha Matheson, RN; Laurie Meade, RN; Inga Mercer, RN; Isabelle Neas, RN; Orla Smith, PhD; Shirley Vallance, RN; and Irene Watpool, RN, for providing patient data. We acknowledge Ryan Zarychanski, MD, and John Muscedere, MD, for reviewing the manuscript on behalf of the Canadian Critical Care Trials Group. We are grateful to all the patients, families, research coordinators, and physicians who participated in this study.

Additional information: The e-Appendix can be found in the “Supplemental Materials” area of the online article.

ELISA

enzyme-linked immunosorbent assay

HIT

heparin-induced thrombocytopenia

LMWH

low-molecular-weight heparin

OD

optical density

PF4

platelet factor 4

PROTECT

Prophylaxis for Thromboembolism in Critical Care Trial

SRA

serotonin-release assay

SRA+

serotonin-release assay positive

UFH

unfractionated heparin

Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH; Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost. 2011;9(12):2498-2500. [CrossRef] [PubMed]
 
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106(8):2710-2715. [CrossRef] [PubMed]
 
Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006;108(9):2937-2941. [CrossRef] [PubMed]
 
National Institutes of Health Clinical Center. Prophylaxis for thromboembolism in critical care trial (PROTECT). NCT00182143. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2005. http://clinicaltrials.gov/ct2/show/NCT00182143. Updated January 7, 2011.
 
Cook D, Meade M, Guyatt G, et al; PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011;364(14):1305-1314. [CrossRef] [PubMed]
 
Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndromes. Expert Opin Drug Saf. 2009;8(2):129-144. [CrossRef] [PubMed]
 
Greinacher A, Kohlmann T, Strobel U, Sheppard JA, Warkentin TE. The temporal profile of the anti-PF4/heparin immune response. Blood. 2009;113(20):4970-4976. [CrossRef] [PubMed]
 
Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011;9(suppl 1):105-117. [PubMed]
 
Cook D, Meade M, Guyatt G, et al PROphylaxis for ThromboEmbolism in Critical Care Trial protocol and analysis plan. J Crit Care. 2011;26(2):223.e1-e9. [CrossRef]
 
Crowther MA, Cook DJ, Albert M, et al; Canadian Critical Care Trials Group. The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients. J Crit Care. 2010;25(2):287-293. [CrossRef] [PubMed]
 
Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood. 1986;67(1):27-30. [PubMed]
 
Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6(8):1304-1312. [CrossRef] [PubMed]
 
Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96(5):1703-1708. [PubMed]
 
Warkentin TE, Sheppard JI, Moore JC, Kelton JG. The use of well-characterized sera for the assessment of new diagnostic enzyme-immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost. 2010;8(1):216-218. [CrossRef] [PubMed]
 
Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765. [CrossRef] [PubMed]
 
Warkentin TE. Think of HIT. Hematology (Am Soc Hematol Educ Program). 2006;:408-414.
 
Warkentin TE, Cook RJ, Marder VJ, Greinacher A. Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization. J Thromb Haemost. 2010;8(3):504-512. [CrossRef] [PubMed]
 
Finfer S, Chittock DR, Su SY, et al; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. [CrossRef] [PubMed]
 
Verma AK, Levine M, Shalansky SJ, Carter CJ, Kelton JG. Frequency of heparin-induced thrombocytopenia in critical care patients. Pharmacotherapy. 2003;23(6):745-753. [CrossRef] [PubMed]
 
Crowther MA, Cook DJ, Meade MO, et al. Thrombocytopenia in medical-surgical critically ill patients: prevalence, incidence, and risk factors. J Crit Care. 2005;20(4):348-353. [CrossRef] [PubMed]
 
Trehel-Tursis V, Louvain-Quintard V, Zarrouki Y, Imbert A, Doubine S, Stéphan F. Clinical and biologic features of patients suspected or confirmed to have heparin-induced thrombocytopenia in a cardiothoracic surgical ICU. Chest. 2012;142(4):837-844. [CrossRef] [PubMed]
 
Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344(17):1286-1292. [CrossRef] [PubMed]
 
Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost. 2011;9(12):2389-2396. [CrossRef] [PubMed]
 
Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol. 2003;121(4):535-555. [CrossRef] [PubMed]
 
Gruel Y, Pouplard C, Nguyen P, et al; French Heparin-Induced Thrombocytopenia Study Group. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol. 2003;121(5):786-792. [CrossRef] [PubMed]
 
Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335. [CrossRef] [PubMed]
 
Greinacher A, Eichler P, Lietz T, Warkentin TE. Replacement of unfractionated heparin by low-molecular-weight heparin for postorthopedic surgery antithrombotic prophylaxis lowers the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia. Blood. 2005;106(8):2921-2922. [CrossRef] [PubMed]
 
Lubenow N, Hinz P, Thomaschewski S, et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood. 2010;115(9):1797-1803. [CrossRef] [PubMed]
 
Selleng K, Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia in intensive care patients. Crit Care Med. 2007;35(4):1165-1176. [CrossRef] [PubMed]
 
Ansell JE, Clark WP Jr, Compton CC. Fatal reactions associated with intravenous heparin. Drug Intell Clin Pharm. 1986;20(1):74-75. [PubMed]
 
Mims MP, Manian P, Rice L. Acute cardiorespiratory collapse from heparin: a consequence of heparin-induced thrombocytopenia. Eur J Haematol. 2004;72(5):366-369. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Variable outcomes when IV therapeutic-dose UFH was given to three SRA+ patients in PROTECT with VTE. For each patient shown, the SRA was performed because of imaging evidence of VTE (DVT, n = 2; PE, n = 1), rather than because of investigator suspicion of heparin-induced thrombocytopenia (HIT). Besides study drug (UFH, n = 2; dalteparin, n = 1), each patient shown additionally received open-label prophylactic-dose UFH pre-trial enrollment, as well as open-label therapeutic-dose UFH after VTE was diagnosed by study ultrasound. A fourth SRA+ patient (No. 17, not shown in the figure) who received IV therapeutic-dose UFH for DVT developed progressive thrombocytopenia (platelet count, 169 to 63 × 109/L) over a 6-day treatment period; death was attributed to septic shock (secondary to laparotomy-proven GI perforation/peritonitis), and any contributory role of HIT was unclear. A, Patient No. 5 developed a 57% platelet count fall (from 559 to 240 × 109/L) that began on day 7 of heparin thromboprophylaxis (open-label UFH followed by study drug UFH). Therapeutic-dose UFH was given beginning on day 9 because of PE (platelet count = 453 × 109/L). The platelet count declined further (to a nadir of 240 × 109/L on day 13) but then recovered to 620 × 109/L (day 20) despite continuing therapeutic-dose UFH. No adverse clinical events occurred. B, Patient No. 14 developed a 59% platelet count fall (from 527 to 216 × 109/L) that began on day 9 of heparin thromboprophylaxis (open-label UFH followed by study drug dalteparin). Therapeutic-dose UFH was given beginning on day 13 because of left peroneal DVT (platelet count = 380 × 109/L). The platelet count declined further (to a nadir of 216 × 109/L on day 16) but then recovered to 582 × 109/L (day 22) despite continuing therapeutic-dose UFH followed by enoxaparin. No adverse clinical events occurred. C, Patient No. 8 developed features of an anaphylactoid reaction (fatal cardiac arrest) after IV UFH bolus. Left gastrocnemius vein DVT was diagnosed on day 7; the platelet count was 474 × 109/L. The next day, the platelet count had fallen to 427 × 109/L, and open-label UFH treatment of DVT was started. Fifteen minutes after 5,000-unit UFH bolus, the patient developed bradycardia, severe hypotension, and ECG changes consistent with myocardial infarction, with subsequent fatal cardiac arrest. Blood sampling for SRA testing was obtained per study protocol (because of DVT detection by compression ultrasonography), and not because the physicians suspected a diagnosis of HIT. Three doses (5,000 U each) of open-label dalteparin given prior to day 0 are not shown in the figure. PE = pulmonary embolism; SC = subcutaneous; SRA = serotonin-release assay; UFH = unfractionated heparin.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Assessment of Study Drug-Related Seroconversion to SRA+ Status and Study Drug-Related Breakthrough of Thrombocytopenia and/or Thrombosis

HIT = heparin-induced thrombocytopenia; SRA+ = serotonin-release assay positive.

Table Graphic Jump Location
Table 2 —Clinical and Laboratory Summary of 17 SRA+ Patients

ELISA = enzyme-linked immunosorbent assay; F = female; L = left; M = male; Med = medical; R = right; Surg = surgical; UFH = unfractionated heparin. See Table 1 legend for expansion of other abbreviations.

a 

When more than one assay was performed, the highest value of mean percent serotonin release or units of optical density is shown.

b 

Underwent surgery prior to developing HIT (although classified as “medical” patient per PROTECT protocol).

c 

Right and left peroneal DVTs detected prior to onset of HIT; these are, therefore, not categorized as HIT-associated thrombosis.

d 

Abrupt fall in platelet count from 296 to 132 when open-label therapeutic-dose UFH was given on day 11.

e 

Autopsy-proven bilateral popliteal artery thrombosis; intracardiac thrombosis; DVTs (bilateral calf veins; right internal jugular vein), pulmonary embolism; thrombotic death.

f 

Patient had ultrasound-documented DVT on day 7, in association with 10% platelet count decline from 474 (day 7) to 427 (day 8); developed bradycardia, myocardial ischemia (per ECG), and cardiac arrest beginning 15 min after 5,000-units IV bolus of UFH, classified as HIT-associated anaphylactoid reaction. However, no repeat platelet count performed at the time of cardiac arrest, and, thus, a substantial post-UFH bolus drop in platelet count cannot be excluded. See also Fig 1C.

g 

Status corrected here because the patient was admitted with metabolic acidosis (ie, medical patient), but erroneous initial data submission classified this patient as “surgical” in the original PROTECT database.

h 

Left common femoral vein DVT detected prior to onset of HIT; this was, therefore, not categorized as HIT-associated thrombosis.

i 

Sample tested repeatedly negative in the ELISA-IgG/A/M.

Table Graphic Jump Location
Table 3 —Role(s) of Study Drug in Explaining Seroconversion and/or Clinical Breakthrough of HIT (Platelet Count Fall and/or Thrombosis)

CPB = cardiopulmonary bypass; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; qd = once-daily; SC = subcutaneous; U = units. See Table 1 and 2 legends for expansion of other abbreviations.

a 

The HIT-related platelet count fall began ≥ 5 d after preenrollment open-label heparin was given and ≥ 5 d after beginning study drug (seroconversion, 1 point); the HIT-related platelet count fall began while receiving study drug and continued to fall while receiving open-label UFH after enrollment (breakthrough, 1 point) = total, 2 points.

b 

HIT-related thrombocytopenia and SRA+ status occurred < 5 d after starting study drug but ≥ 5 d after preenrollment open-label heparin was given (seroconversion, 0 points); HIT-related thrombocytopenia began while receiving open-label heparin and progressed while receiving study drug (breakthrough, 1 point) = total, 1 point.

c 

HIT-related thrombocytopenia occurred < 5 d after starting study drug but ≥ 5 d after preenrollment open-label heparin was given (seroconversion, 0 points); HIT-related thrombocytopenia (and, where applicable, HIT-related thromboses [patient Nos. 4, 7, and 13]) occurred while (or after) receiving study drug and without postenrollment open-label heparin being given (breakthrough, 2 points) = total, 2 points.

d 

HIT-related platelet count fall began ≥ 5 d after preenrollment open-label heparin and ≥ 5 d after beginning study drug (seroconversion, 1 point); HIT-related platelet count fall began and HIT-related thrombotic event (prompting SRA testing) occurred while receiving study drug and before any open-label therapeutic-dose UFH, if applicable (patient Nos. 5, 8, and 14), was given (breakthrough, 2 points) = total, 3 points.

e 

HIT-related platelet count fall began ≥ 5 d after preenrollment open-label heparin and ≥ 5 d after beginning study drug (seroconversion, 1 point); HIT-related thrombocytopenia (prompting SRA testing) occurred while receiving study drug (breakthrough, 2 points) = total, 3 points.

f 

HIT-related platelet count fall began ≥ 5 d after preenrollment open-label heparin and ≥ 5 d after beginning study drug (seroconversion, 1 point); HIT-related platelet count fall and new left peroneal DVT occurred in association with use of therapeutic-dose open-label IV UFH (breakthrough, 0 points) = total, 1 point.

g 

DVT and SRA+ status were present prior to receiving any study drug (seroconversion and breakthrough, 0 points each) = total, 0 points. Additionally, for patient No. 16, the platelet count fell after stopping study drug and while receiving therapeutic-dose open-label IV UFH (with repeat SRA now yielding 100% serotonin release).

Table Graphic Jump Location
Table 4 —Results of HIT Antibody Test Results in 409 Patients Who Were Investigated Serologically for HIT in PROTECT

Data are presented as No. of total (%). The reference range for the ELISA-IgG is < 0.45 OD units, whereas for the commercial ELISA-IgG/A/M, the reference range is < 0.40 OD units. Note that 216 of 1,873 patients (11.5%) randomized to UFH underwent serologic testing for HIT antibodies in the central laboratory, compared with 193 of 1,873 patients (10.3%) randomized to dalteparin (P = .249, Fisher exact test). OD = optical density; PROTECT = Prophylaxis for Thromboembolism in Critical Care Trial. See Table 1 and 2 legends for expansion of other abbreviations.

a 

One sample was inadvertently discarded prior to testing in the polyspecific ELISA. For 10 patients (seven with UFH, three with dalteparin), more than one sample was tested in the central laboratory; the strongest result is shown, which for seven of the 10 patients was the latest sample.

Table Graphic Jump Location
Table 5 —Outcomes of Anticoagulation Instituted After SRA+ Blood Draw

CVC = central venous catheter; IVC = inferior vena cava. See Table 1, 2, and 3 legends for expansion of other abbreviations.

a 

All eight patients treated with either danaparoid or fondaparinux received low (prophylactic) dosing.

b 

Therapeutic-dose UFH was given to four patients with SRA+ status because the patients had documented DVT (three patients) or PE (one patient), which prompted SRA testing; the patients were not considered by the treating physicians to have had HIT.

References

Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH; Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost. 2011;9(12):2498-2500. [CrossRef] [PubMed]
 
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106(8):2710-2715. [CrossRef] [PubMed]
 
Warkentin TE, Sheppard JA, Sigouin CS, Kohlmann T, Eichler P, Greinacher A. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood. 2006;108(9):2937-2941. [CrossRef] [PubMed]
 
National Institutes of Health Clinical Center. Prophylaxis for thromboembolism in critical care trial (PROTECT). NCT00182143. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2005. http://clinicaltrials.gov/ct2/show/NCT00182143. Updated January 7, 2011.
 
Cook D, Meade M, Guyatt G, et al; PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011;364(14):1305-1314. [CrossRef] [PubMed]
 
Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two distinct but overlapping syndromes. Expert Opin Drug Saf. 2009;8(2):129-144. [CrossRef] [PubMed]
 
Greinacher A, Kohlmann T, Strobel U, Sheppard JA, Warkentin TE. The temporal profile of the anti-PF4/heparin immune response. Blood. 2009;113(20):4970-4976. [CrossRef] [PubMed]
 
Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011;9(suppl 1):105-117. [PubMed]
 
Cook D, Meade M, Guyatt G, et al PROphylaxis for ThromboEmbolism in Critical Care Trial protocol and analysis plan. J Crit Care. 2011;26(2):223.e1-e9. [CrossRef]
 
Crowther MA, Cook DJ, Albert M, et al; Canadian Critical Care Trials Group. The 4Ts scoring system for heparin-induced thrombocytopenia in medical-surgical intensive care unit patients. J Crit Care. 2010;25(2):287-293. [CrossRef] [PubMed]
 
Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood. 1986;67(1):27-30. [PubMed]
 
Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6(8):1304-1312. [CrossRef] [PubMed]
 
Warkentin TE, Sheppard JA, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96(5):1703-1708. [PubMed]
 
Warkentin TE, Sheppard JI, Moore JC, Kelton JG. The use of well-characterized sera for the assessment of new diagnostic enzyme-immunoassays for the diagnosis of heparin-induced thrombocytopenia. J Thromb Haemost. 2010;8(1):216-218. [CrossRef] [PubMed]
 
Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-765. [CrossRef] [PubMed]
 
Warkentin TE. Think of HIT. Hematology (Am Soc Hematol Educ Program). 2006;:408-414.
 
Warkentin TE, Cook RJ, Marder VJ, Greinacher A. Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization. J Thromb Haemost. 2010;8(3):504-512. [CrossRef] [PubMed]
 
Finfer S, Chittock DR, Su SY, et al; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13):1283-1297. [CrossRef] [PubMed]
 
Verma AK, Levine M, Shalansky SJ, Carter CJ, Kelton JG. Frequency of heparin-induced thrombocytopenia in critical care patients. Pharmacotherapy. 2003;23(6):745-753. [CrossRef] [PubMed]
 
Crowther MA, Cook DJ, Meade MO, et al. Thrombocytopenia in medical-surgical critically ill patients: prevalence, incidence, and risk factors. J Crit Care. 2005;20(4):348-353. [CrossRef] [PubMed]
 
Trehel-Tursis V, Louvain-Quintard V, Zarrouki Y, Imbert A, Doubine S, Stéphan F. Clinical and biologic features of patients suspected or confirmed to have heparin-induced thrombocytopenia in a cardiothoracic surgical ICU. Chest. 2012;142(4):837-844. [CrossRef] [PubMed]
 
Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344(17):1286-1292. [CrossRef] [PubMed]
 
Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost. 2011;9(12):2389-2396. [CrossRef] [PubMed]
 
Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol. 2003;121(4):535-555. [CrossRef] [PubMed]
 
Gruel Y, Pouplard C, Nguyen P, et al; French Heparin-Induced Thrombocytopenia Study Group. Biological and clinical features of low-molecular-weight heparin-induced thrombocytopenia. Br J Haematol. 2003;121(5):786-792. [CrossRef] [PubMed]
 
Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332(20):1330-1335. [CrossRef] [PubMed]
 
Greinacher A, Eichler P, Lietz T, Warkentin TE. Replacement of unfractionated heparin by low-molecular-weight heparin for postorthopedic surgery antithrombotic prophylaxis lowers the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia. Blood. 2005;106(8):2921-2922. [CrossRef] [PubMed]
 
Lubenow N, Hinz P, Thomaschewski S, et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood. 2010;115(9):1797-1803. [CrossRef] [PubMed]
 
Selleng K, Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia in intensive care patients. Crit Care Med. 2007;35(4):1165-1176. [CrossRef] [PubMed]
 
Ansell JE, Clark WP Jr, Compton CC. Fatal reactions associated with intravenous heparin. Drug Intell Clin Pharm. 1986;20(1):74-75. [PubMed]
 
Mims MP, Manian P, Rice L. Acute cardiorespiratory collapse from heparin: a consequence of heparin-induced thrombocytopenia. Eur J Haematol. 2004;72(5):366-369. [CrossRef] [PubMed]
 
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    Print ISSN: 0012-3692
    Online ISSN: 1931-3543