Medical and Economic Burden of Heparin-Induced Thrombocytopenia: Data from the National Inpatient Sample 2009-2011

Abstract Background Although generally safe, heparin use can trigger an immune response in which platelet factor 4-heparin complexes set off an antibody-mediated cascade that can result in heparin-induced thrombocytopenia (HIT). Although older studies report incidences as high as 5% in high-risk subgroups of surgical patients, recent studies report a much lower incidence (0.02% of hospital admissions and <0.1-0.4% among patients exposed to heparin). As hospitals transition to the less immunogenic low molecular weight heparins, reassessment of the overall national burden of HIT would help inform needs for monitoring strategies for this potentially fatal complication of anticoagulation. Methods We used the 2009-2011 National Inpatient Sample database to identify patients aged ≥18 years with primary and secondary diagnoses of HIT (International Classification of Diseases, 9th Revision, Clinical-Modification [ICD-9-CM] code 289.84). We derived the prevalence rate of HIT overall as well as among subgroup of patients undergoing 3 types of surgeries (cardiac, vascular and orthopedic surgeries). We compared characteristics of patients diagnosed with versus without HIT, and HIT with thrombosis (HITT) versus those without thrombosis. Statistical analysis was performed using Stata 13.1, which accounted for the complex survey design and clustering. We used a 2-sided p- value of <0.05 to determine statistical significance. Results We identified 72,515 cases of HIT among a total of 98,636,364 hospitalizations (0.07%). Arterial and venous thromboses were identified in 24,880 (34.3%) of cases with HIT. Males were slightly more likely to be diagnosed with HIT (50.12% vs. 49.88%, odds ratio, OR 1.48, 95% CI: 1.46-1.51), but females had higher rates of post-cardiac and vascular surgery-associated HIT (OR: 1.41, 95% confidence interval, CI: 1.26-1.58, p<0.001 and OR 1.42, 95% CI: 1.29-1.57, p<0.001 respectively). Prevalence rates of HIT among cardiac, vascular and orthopedic surgeries were 0.53% (95% CI: 0.51-0.54%), 0.28% (95% CI: 0.28-0.29%) and 0.05% (95% CI: 0.05-0.06%) respectively. Patients with HIT and HITT were significantly more likely to be fatal than cases without diagnosed HIT (9.63% and 12.28% versus 2.19% respectively, p<0.001), and have significantly higher costs ($137401 and $179735 versus $35905) and length of stay (14.07 and 16.51 days versus 4.76 days). Conclusion Although rates of HIT appear lower in the modern era of widespread low molecular weight heparin use, patients undergoing cardiac and vascular surgeries remain at significant risk. Even in recent years, one-third of patients with HIT develop thrombosis, which significantly increases mortality, cost and length of stay. Strategies to monitor and mitigate that risk in high-risk patients appear to be warranted. Table 1. In-hospital mortality, mean LOS and Mean hospital charges for patients with heparin induced thrombocytopenia (HIT) and HIT with thrombosis (HITT) No HIT HIT P HIT without thrombosis HITT P In-hospital mortality 2.19% 9.63% (OR 4.75, 95% CI 4.45-5.08) <0.001 8.24% 12.28% (OR 1.56, 95% CI 1.40-1.74) <0.001 Mean LOS (days) 4.76 (95% CI 4.71-4.82) 14.07 (95% CI 13.67-14.48) <0.001 12.80 (95% CI 12.38-13.23) 16.51 (95% CI 15.96-17.06) <0.001 Mean total hospital charge (USD) 35905 (95% CI 34626- 37185) 137401 (95% CI 129369-145433) <0.001 115456 (95% CI 108251-122661) 179735 (95% CI 168582-190889) <0.001 HIT= Heparin induced thrombocytopenia; HITT= Heparin induced thrombocytopenia with thrombosis; LOS=Length of stay; USD=US Dollars. Disclosures No relevant conflicts of interest to declare.

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Heparin-Induced Thrombocytopenia: Prevalence in a Large Cohort of Patients and Confirmed Role of PF4/Heparin Complex as the Main Antigen for Antibodies

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602969700300309 ◽

1997 ◽

Vol 3 (3) ◽

pp. 203-209 ◽

Cited By ~ 3

Author(s):

Fabrizio Fabris ◽

Immacolata Cordiano ◽

Federica Salvan ◽

Leopoldo Saggin ◽

Giuseppe Cella ◽

...

Keyword(s):

Molecular Weight ◽

Platelet Count ◽

Platelet Factor 4 ◽

Enzyme Linked Immunosorbent Assay ◽

Low Molecular Weight ◽

Dependent Manner ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Heparin Treatment ◽

Daily Dose

We performed a retrospective study on the prevalence of heparin-induced thrombocytopenia (HIT) in 233 patients receiving hog mucosa heparin therapy. Of these, 82 patients received s.c. calcium heparin, 130 patient received unfractionated (UF) i.v. heparin, and 21 patients received low molecular weight heparins (LMWH). An additional four patients, referred to our consultation and diagnosed by us as having clinically active type II HIT (HIT-II) were also studied. The mean platelet count of the 233 patients receiving heparin showed a significant decrease after 2 days of heparin treatment and a following significant increase 6 days later (basal: 257 ± 147 x 109 platelets/L; day 2: 239 ± 122, p < 0.0002; day 6: 286 ± 119, p < 0.004). Of the 212 patients receiving UF heparin, 13 (6%) fulfilled the criteria for HIT-II: seven of these had received i.v. heparin (mean daily dose 26,600 ± 4,082 IU ± SD) and six had received s.c. heparin (mean daily dose 21,428:t 6,900 IU). Their mean basal platelet count was 226 ± 100 SD × 109 platelets/L and the nadir during heparin treatment was 78 ± 39 x 10 9 platelets/L. Thrombotic complications occurred in four (30.7%) of the 13 patients with HIT-II. Since the immunological mechanism has been demonstrated for HIT-II and since platelet factor 4 (PF4) was identified as the co-factor for the binding of heparin-related antibodies, we set up our own enzyme-linked immunosorbent assay (ELISA) for testing antibodies against PF4/heparin complex bound through electrostatic bridges to the solid phase. The highest binding capacity of HIT-related IgG to the multimolecular complex was obtained at 20 μg/ml for PF4 and 3 μg/ml for heparin, corresponding to 250 ng of PF4 and 42 ng of heparin in each microtiter well. Such binding was inhibited in a dose-dependent manner by increasing amounts of heparin, protamine hydrochloride, and a monoclonal antibody anti-human PF4 clone 1OB2. We observed that HIT-related antibodies bound also to PF4/LMWH complexes but the optimal PF4/glycosaminoglycan ratio appeared more critical for LMWH (enoxaparin, fraxiparin, and pamaparin) than for UF heparin. Sera from eight patients with HIT-II were tested by PF4/heparin ELISA; six of these had IgG against the complex PF4/heparin and three also had IgM. The persistence of HIT-related antibodies was investigated in three patients: in one such antibodies were still detectable 3 years after the acute episode, while in the other two, they disappeared after 6 months and 1 year, respectively. Key Words: Heparin-related anti body—Platelet factor 4 (PF4)—Heparin—Low molecular weight heparin—Thrombocytopenia—Thrombosis.

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Adequate Use of the 4T´s Score As a Primary Screening Tool for Heparin Induced Thrombocytopenia

Blood ◽

10.1182/blood.v128.22.5911.5911 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5911-5911

Author(s):

Ilana Miriam Schlam ◽

Eithan Orlev-Shitrit ◽

Chelsea Beaton ◽

Ping Wang ◽

Charles Glueck ◽

...

Keyword(s):

Molecular Weight ◽

Length Of Stay ◽

Unfractionated Heparin ◽

Screening Test ◽

Low Molecular Weight Heparin ◽

Screening Tests ◽

Low Molecular Weight ◽

Heparin Induced Thrombocytopenia ◽

Confirmatory Tests ◽

Work Up

Abstract Introduction:Thrombocytopenia is a common problem in hospitalized patients, which has a diverse etiology. One of the infrequent causes is heparin-induced thrombocytopenia (HIT), a complex immune disorder in which heparin leads to the production of IgG antibodies, targeting platelet factor 4 (PF4). HIT diagnosis is based on a decrease in the platelet count of more than 50% beginning 5 to 10 days after starting heparin, in association with platelet-activating HIT antibodies (screening test), positive functional tests (confirmatory tests), in patients with no alternative causes for thrombocytopenia, necrosis or thrombosis (Figure 1). Most patients admitted to our institution receive unfractionated or low molecular weight heparin for venous thromboembolism prophylaxis. The risk of HIT depends on the type of heparin the patient receives. Even though HIT is rare, we tend to have a high suspicion and low threshold to order laboratory workup for this condition, occasionally without using the 4T«s score (Table 1). The 4T«s score is a validated system with a very high negative predictive value (NPV) of up to 99%, when the score is ²3. The aim of this study is to determine if the 4T«s score has been used appropriately in our institution. It is a very useful tool with a high negative likelihood ratio and using it systematically may decrease unnecessary laboratory testing, consequently decreasing costs and potentially length of stay. Methods:This is a retrospective descriptive study from a single teaching community hospital. Between January and December of 2015, 57 HIT screening tests (PF4 ELISA) were ordered in our institution. We reviewed all of the patient charts to determine their 4T«s score. The patients were divided into low, moderate and high pretest probability based on their score (low probability if ²3, intermediate 4-5, and high if ³6). The data analysis was completed with SPSS software. Results:57 tests were ordered, 5 patient charts did not have enough information to calculate 4T«s score and were excluded. 52 charts were reviewed, 28 patients were male and 24 were female (53 and 46% respectively), and they were between 25 and 89 years of age. 7 (13.4%) did not receive heparin (during current hospitalization or within 100 days), 11 (21.1%) received therapeutic doses of unfractionated heparin, 11 (21.1%) received prophylactic doses of unfractionated heparin, and 23 (44.2%) received prophylactic low molecular weight heparin (enoxaparin). The 4T«s score was calculated for each patient; 40 were low risk, 10 intermediate risk and 2 high risk (76.9, 19.2, 3.8% respectively). All the patients had HIT screening antibodies ordered; only 10 (19.2%) were positive and from those only 1 (1.9%) was confirmed by the serotonin release assay. This confirmed patient had a 4T«s score of 6. Of the 7 tested patients who did not receive heparin, none had a positive screening test (all had 4T«s score of 1 or 2). 35 of the screening tests were ordered by internal medicine residents, 5 by surgical residents, 12 by attending physicians (67.3, 9.6 and 23% respectively). Previous studies validated that a 4T«s score of ²3 can predict negative results for the confirmatory tests. By using theMcNemar«stest for matched pairs, we attempted to determine a cut off for the 4T«s score that would predict a negativeHIT screeningtest. We found that a 4T«s score ²2 predicted a negativeHIT screeningtest, with aNPVof 75% (p=0.0018). Since our study included a small patient cohort and due to the possibility of laboratory work up not being ordered in patients with a low 4T«s score, we suspect theNPVis actually lower than our current finding. A prospective study with a larger cohort of patients would be necessary to confirm these findings. Conclusions:Only 12% of the patients had a 4T«s score ³4 that would warrant laboratory work up, therefore we concluded that PF4 ELISA screening tests have been over utilized in our institution, increasing false positive results, length of stay and cost of hospitalization in patients without a significant risk for HIT. This could be avoided by calculating the 4T«s score before obtaining any further laboratory tests. The 4T«s scoring system has been validated by multiple studies with large cohorts in the past. We will continue to work with our staff, especially the residents, to improve education on HIT and adequate diagnosis, based on current guidelines. Disclosures No relevant conflicts of interest to declare.

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Heparin-induced Thrombocytopenia: Yet Another Treatment Paradox?

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615945 ◽

2001 ◽

Vol 85 (06) ◽

pp. 947-949 ◽

Cited By ~ 20

Author(s):

Theodore Warkentin

Keyword(s):

Molecular Weight ◽

Unfractionated Heparin ◽

Platelet Activation ◽

Low Molecular Weight Heparin ◽

Clinical Situation ◽

Low Molecular Weight ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Prevention And Treatment ◽

Underlying Theme

SummaryFew topics in medicine rival heparin-induced thrombocytopenia (HIT) for the unexpected twists and turns enough to rival the plot of many a mystery novel. The underlying theme- anticoagulant-induced thrombosis- seems improbable, but is well-established: despite thrombocytopenia, patients rarely bleed spontaneously or even exhibit petechiae (1); rather, thrombosis develops in 30-75% of patients with HIT, depending upon the clinical situation, and in proportions far greater than expected based on the original reason for receiving heparin (2-4).But even beyond this fundamental contradiction, there exists for the unwary and uninformed practitioner several counterintuitive treatment paradoxes. One is the dichotomous nature of low-molecular-weight heparin (LMWH) respecting prevention and treatment of HIT. LMWH is far less likely to cause HIT than standard, unfractionated heparin (4, 5). Yet, for the patient with acute HIT caused by unfractionated heparin, LMWH is contraindicated (6, 7). The reason: LMWH preparations contain some heparin molecules with 12 or greater saccharide units, which are sufficiently long to bind platelet factor 4 (PF4), creating the multimolecular complexes bearing the HIT antigens. Consequently, ongoing platelet activation, thrombocytopenia, and thrombosis occur in many patients so treated (8).

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Efficacy of Fondaparinux in the Treatment of Heparin-Induced Thrombocytopenia with Venous Thromboembolism: Reduction of Thromboembolic Burden, Normalization of Platelet Count and Disappearance of Anti-Platelet Factor 4/Heparin Antibodies.

Blood ◽

10.1182/blood.v108.11.575.575 ◽

2006 ◽

Vol 108 (11) ◽

pp. 575-575 ◽

Cited By ~ 1

Author(s):

Franco Piovella ◽

Marisa Barone ◽

Chiara Beltrametti ◽

Chiara Piovella ◽

Andrea M. D’Armini ◽

...

Keyword(s):

Molecular Weight ◽

Platelet Count ◽

Venous Thromboembolism ◽

Platelet Factor 4 ◽

Enzyme Linked Immunosorbent Assay ◽

Surgical Patient ◽

Low Molecular Weight ◽

Low Molecular Weight Heparins ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia

Abstract Heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia with thrombosis (HITT) may develop during anticoagulant treatment in patients submitted to various regimens of unfractionated or low-molecular weight heparins. Several molecules have been studied as alternative anticoagulants in patients with HIT or HITT, including danaparoid, argatroban, lepirudin. Lepirudin requires dosage adjustments in patients with renal insufficiency and has potential for antibody formation. Argatroban requires dosage adjustments in patients with hepatic insufficiency. Argatroban increases the International Normalized Ratio (INR) when co-administered with warfarin, leading to dosage difficulties when transitioning to warfarin therapy. Anticoagulation of patients with HIT or HITT may be limited by antibodies cross-reactivity with danaparoid and by new generation of antibodies with lepirudin. Fondaparinux is the first of a new class of synthetic antithrombotics: the selective inhibitors of coagulation factor Xa. It is the most advanced competitor of low molecular weight heparins, which are the reference drugs in prophylaxis and treatment of venous thromboembolism. Fondaparinux does not bind to platelet factor 4 (PF4) and does not react with anti-PF4/heparin antibodies in in vitro testing. We treated 20 patients who develop HIT (3 patients) or HITT (17 patients, of whom 4 had both DVT and PE). Nine patients were previously submitted to extracorporeal circulation with unfractionated heparin (UFH) followed by low-molecular weight heparin (LMWH) for major cardiac surgery. The remaining patients had been previously treated with either UHF or LMWH at therapeutic or prophylactic dosage in internal medicine or surgery wards. In the 17 patients who developed HITT, we applied therapeutic dosages of fondaparinux, i.e. 7.5 mg QD or lower, accordingly with their bleeding risk. To the remaining patients with HIT we gave prophylactic dosages of fondaparinux, i.e. 2.5 mg QD. Patients with HITT were treated for 4 to 25 days before starting warfarin. Fondaparinux was stopped when INR of 2.0 or more was reached. All patients showed a significant reduction of their thromboembolic burden. One episode of major bleeding was recorded in a post-surgical patient. All patients but one showed sustained normalization of the platelet number. In the remaining patient platelet count remained unchanged. Treatment was switched from fondaparinux to lepirudin and after few days her platelets reverted to close-to-normal levels. In seven patients, submitted to therapeutic dosages of fondaparinux, anti-PF4/heparin antibody titers were determined using a PF4/heparin enzyme-linked immunosorbent assay (ELISA): in all cases antibody levels progressively decreased close to disappearance by 30–45 days. This series of cases provides further evidence for the safety and efficacy of fondaparinux in the treatment of both HIT or HITT.

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Adherence to Guidelines for Monitoring for Heparin-Induced Thrombocytopenia in Patients Treated with Low Molecular Weight Heparin

Blood ◽

10.1182/blood.v112.11.1282.1282 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1282-1282

Author(s):

Maarten ten Berg ◽

Patricia Van den Bemt ◽

Albert huisman ◽

Fred Schobben ◽

Toine Egberts ◽

...

Keyword(s):

Molecular Weight ◽

Platelet Count ◽

Clinical Guidelines ◽

Low Molecular Weight Heparin ◽

Low Molecular Weight ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Alternative Anticoagulation ◽

Life Threatening ◽

Platelet Count Monitoring

Abstract Laboratory monitoring for early detection of adverse drug reactions is recommended for many drugs. For patients treated with low molecular weight heparin (LMWH), the Summary of Product Characteristics (SPC) and clinical guidelines recommend to monitor the platelet count for heparin-induced thrombocytopenia (HIT), a potentially life-threatening adverse event, characterised by a typical drop in platelet count. When the platelet count drops without obvious explanation in these patients, testing for heparin-platelet factor 4 antibodies (HPF4-Ab) and initiating alternative anticoagulation are advised. In the current study adherence to recommended platelet count monitoring in clinical patients without thrombocytopenia-associated diseases treated with LMWH for at least five days at our institution, and adherence to recommended testing for HPF4-Ab and initiation of alternative anticoagulation in patients with potential HIT (defined as a drop of at least 50% in platelet count between days 5 and 14 following the start of LMWH treatment, or stopdate, whichever occurred first, compared to the highest platelet count within days 1–4) were investigated. Data from the Utrecht Patient Oriented Database (UPOD) were used for this retrospective cohort study. Inpatients exposed to the LMWHs dalteparin or nadroparin for at least five days during the period 2004–2005 were included. Patients with thrombocytopenia-related diseases were excluded. Firstly, adherence to recommended platelet count monitoring, based on recommendations from SPCs and clinical guidelines, was investigated. Secondly, the association between patient- and treatment characteristics and obtaining at least 2 platelets counts during treatment was investigated. Thirdly, adherence to recommended testing for HPF4-Ab and initiating treatment with danaparoid was investigated in patients with potential HIT. 6,804 patients with 7,770 episodes of LMWH treatment of at least five days were included. Adherence to the recommendations for platelet count monitoring from the SPC of nadroparin and dalteparin was 36.5% and 26.3% respectively. Adherence to the different platelet count monitoring recommendations from the 2002 clinical guideline on HIT was 23.0% and 41.5%. Obtaining at least 2 platelet counts during treatment was found to be strongly associated with ICU admission, previous UFH exposure, and a treatment duration of at least 10 days. There were 98 patients with potential HIT. Adherence to testing for HPF4-Ab in patients with potential HIT was 6.1%. Adherence to starting alternative anticoagulation in patients with potential HIT treatment was 0%. The results of this study suggest that adherence to recommendations for monitoring for HIT with LMWH is low at our institution. The results of this study justify to say that there is a need to think of appropriate actions for improving the awareness of HIT as an adverse reaction to LMWH, and to secure the safe use of LMWH.

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In Vivo Studies on the Inhibition of Coagulation by Fractionated Heparin and by a Heparin Analogue I. Effects of Heparin Fractions

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653429 ◽

1981 ◽

Vol 46 (03) ◽

pp. 612-616 ◽

Cited By ~ 18

Author(s):

U Schmitz-Huebner ◽

L Balleisen ◽

F Asbeck ◽

J van de Loo

Keyword(s):

Molecular Weight ◽

Day Treatment ◽

Gel Filtration ◽

Weight Fraction ◽

In Vivo Studies ◽

Low Molecular Weight ◽

High Molecular Weight Fraction ◽

Platelet Factor ◽

Heparin Fractions

SummaryHigh and low molecular weight heparin fractions obtained by gel filtration chromatography of sodium mucosal heparin were injected subcutaneously into six healthy volunteers and compared with the unfractionated substance in a cross-over trial. Equal doses of 5,000 U were administered twice daily over a period of three days and heparin activity was repeatedly controlled before and 2, 4, 8 hrs after injection by means of the APTT, the anti-Xa clotting test and a chromogenic substrate assay. In addition, the in vivo effect of subcutaneously administered fractionated heparin on platelet function was examined on three of the volunteers. The results show that s.c. injections of the low molecular weight fraction induced markedly higher anti-Xa activity than injections of the other preparations. At the same time, APTT results did not significantly differ. Unfractionated heparin and the high molecular weight fraction enhanced ADP-induced platelet aggregation and collagen-mediated MDA production, while the low molecular weight fraction hardly affected these assays, but potently inhibited thrombin-induced MDA production. All heparin preparations stimulated the release of platelet Factor 4 in plasma. During the three-day treatment periods, no side-effects and no significant changes in the response to heparin injections were detected.

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