Advances in Heparins and Related Research. An Epilogue.

The discovery of heparin in 1916 by Jay McLean, a medical student at Johns Hopkins University, not only provided a universal anticoagulant, but also laid the foundation for the discipline of hemostasis and thrombosis[...].

Safety and tolerability of intermittent androgen deprivation therapy: a literature review.

Androgen deprivation therapy is commonly used in men with advanced prostate cancer; however, it is associated with many short- and long-term side-effects. Intermittent androgen deprivation therapy was first suggested as an alternative regimen in the early 1990s and is now part of treatment guidelines as a result of its ability to reduce adverse events associated with continuous androgen deprivation therapy without decreasing its efficacy. Although many publications evaluated intermittent androgen deprivation therapy's efficacy, the safety and tolerability information of this regimen is relatively limited. The goal of this literature review was to analyze clinical trials that have reported safety and tolerability data in prostate cancer patients treated with intermittent androgen deprivation therapy, as well as assessing quality of life outcomes. A literature search was carried out using biomedical and pharmaceutical databases for published information comparing intermittent androgen deprivation therapy with continuous androgen deprivation therapy. A total of 13 randomized and non-randomized studies were selected and reviewed based on their relevance to the safety, tolerability and quality of life of intermittent androgen deprivation therapy. Benefits for intermittent androgen deprivation therapy were observed for the short-term side-effects (hot flushes and sexual functions) mainly during the off-treatment phase, whereas the data for the long-term side-effects were not as conclusive. Quality of life evaluations are more in support of intermittent androgen deprivation therapy. Although there are some safety, tolerability and quality of life benefits associated with intermittent androgen deprivation therapy, the overall evidence is still limited.

Beractant and poractant alfa in premature neonates with respiratory distress syndrome: a systematic review of real-world evidence studies and randomized controlled trials.

Findings from previous meta-analyses of randomized clinical trials (RCTs) in premature infants with respiratory distress syndrome (RDS) varied as to whether clinical outcomes differed by type of animal-derived pulmonary surfactant; real-world evidence (RWE) was excluded. We extracted study characteristics and outcomes from full-text articles from a systematic search for studies that compared beractant with poractant alfa for RDS in preterm infants. RWE data were tabulated; RCT data were subjected to meta-analyses. Designs, patient characteristics, and follow-up durations varied widely among studies (4 RWE, 15 RCT). RWE studies with adjusted odds ratios (ORs) found no statistically significant between-treatment differences in outcomes. In RCT meta-analyses, no statistically significant between-treatment differences were observed for death (OR [95% confidence interval], 1.35 [0.98-1.86]), bronchopulmonary dysplasia (1.25 [0.96-1.62]), pneumothorax (1.21 [0.72-2.05]), and air leak syndrome (2.28 [0.82-6.39]). Collectively, outcomes were similar with beractant and poractant alfa in RWE studies and pooled RCTs.

Risk factor assessment for new onset diabetes: literature review.

Metabolic syndrome (MS), typified by hypertension, abdominal obesity, dyslipidaemia and impaired glucose metabolism, is a precursor of type 2 diabetes. Thiazide diuretics (TD) and beta-blockers are associated with increased risk of diabetes in patients with hypertension; however, the role of these agents in development of diabetes in MS patients is unknown. We reviewed the literature regarding risk factors for diabetes development and compared this with data from the Study of Trandolapril/Verapamil SR And Insulin Resistance (STAR), which investigated the effects of two fixed-dose combinations (FDCs) [trandolapril/verapamil SR and losartan/hydrochlorothiazide (L/H)] on glucose control and new diabetes in MS patients. In STAR, logistic regression modelling identified haemoglobin A1c [odds ratio (OR) 4.21 per 1% increment; p = 0.003), L/H treatment (OR 4.04; p = 0.002) and 2-h oral glucose tolerance test glucose levels (OR 1.39 per 10 mg/dl increments; p < 0.001) as baseline predictors of diabetes. These data support prior analyses and suggest that choice of antihypertensive agent is important. Patients with MS may be at lower risk of diabetes when using a FDC calcium channel blocker + angiotensin-converting enzyme inhibitor compared with an angiotensin receptor blocker + TD.

Verapamil-sustained release-based treatment strategy is equivalent to atenolol-based treatment strategy at reducing cardiovascular events in patients with prior myocardial infarction: an INternational VErapamil SR-Trandolapril (INVEST) substudy.

BACKGROUND: In patients with prior myocardial infarction (MI), beta-blockers reduce mortality by 23% to 40%. However, despite this favorable effect, adverse effects limit compliance to this medication. The purpose of the study was to compare a beta-blocker-based strategy with a heart rate-lowering calcium antagonists-based strategy in patients with prior MI. METHODS: We evaluated 7,218 patients with prior MI enrolled in the INternational VErapamil SR-Trandolapril (INVEST) substudy randomized to verapamil-sustained release (SR)- or atenolol-based strategies. Primary outcome was time to first occurrence of death (all-cause), nonfatal MI, or nonfatal stroke. Secondary outcomes included death, total MI (fatal and nonfatal), and total stroke (fatal and nonfatal) considered separately. RESULTS: During the 2.8 +/- 1.0 years of follow-up, patients assigned to the verapamil-SR-based and atenolol-based strategies had comparable blood pressure control, and the incidence of the primary outcome was equivalent. There was no difference between the 2 strategies for the outcomes of either death or total MI. However, more patients reported excellent/good well-being (82.3% vs 78.0%, P = .02) at 24 months with a trend toward less incidence of angina pectoris (12.0% vs 14.3%, adjusted P = .07), nonfatal stroke (1.4% vs 2.0%; P = .06), and total stroke (2.0% vs 2.5%, P = .18) in the verapamil-SR-based strategy group. CONCLUSIONS: In hypertensive patients with prior MI, a verapamil-SR-based strategy was equivalent to a beta-blocker-based strategy for blood pressure control and prevention of cardiovascular events, with greater subjective feeling of well-being and a trend toward lower incidence of angina pectoris and stroke in the verapamil-SR-based group.

Tolerability of sibutramine during a 6-week treatment period in high-risk patients with cardiovascular disease and/or diabetes: a preliminary analysis of the Sibutramine Cardiovascular Outcomes (SCOUT) Trial.

Uncertainties about the cardiovascular safety of sibutramine led to the SCOUT trial that is investigating sibutramine plus weight management in high-risk, overweight/obese patients. A 6-week lead-in period during which all patients received sibutramine permitted an initial assessment of tolerability. A total of 10,742 patients received sibutramine and 3.1% of these discontinued due to an adverse event; issues affecting more than 10 patients were drug intolerance, headache, insomnia, nausea, dry mouth, and constipation-, tachycardia-, and hypertension-related events. Serious adverse events, most commonly associated with the System Organ Class, Cardiac disorders, were reported by 2.7% of patients; however, the majority was not considered sibutramine-related. Adverse events relating to high blood pressure and/or pulse rate, whether reported as adverse events leading to discontinuation, or serious adverse events were reported by less than 0.2% of patients. No serious or individual events leading to discontinuation occurred in more than 25 patients. There were 15 (0.1%) deaths; 10 were attributed to a cardiovascular cause. Discontinuations for adverse events were lower than anticipated. Serious adverse events generally reflected sibutramine's known pharmacology or were related to cardiac disorders already present in this high-risk population. When compared with epidemiological data, overall mortality rate was low and sibutramine was well tolerated in this mainly off-label population. No new safety issues were detected.

Effects of calcium channel blockers on proteinuria in patients with diabetic nephropathy.

Diabetic nephropathy management should include the use of an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker with additional antihypertensive medications to reduce proteinuria and cardiovascular events. Some studies suggest that adding a nondihydropyridine rather than a dihydropyridine calcium channel blocker (CCB) may more effectively lower proteinuria. We hypothesized that a trandolapril/verapamil SR (T/V) fixed-dose combination (FDC) was superior to a benazepril/amlodipine (B/A) FDC for reducing albuminuria in 304 hypertensive diabetic nephropathy patients when treated for 36 weeks. No statistically significant differences were observed between groups in the primary end point; adjusted percentage change in urinary albumin/creatinine ratio (UACR), which increased (mean T/V, 29.29%; mean B/A, 8.49%; difference, 20.80%; P=.34); or in change in absolute UACR, which decreased (mean [g/g] T/V, -0.11; mean [g/g] B/A, -0.08; difference -0.03; P=.78). There were significant reductions in log UACR (mean change in T/V, -0.28; P<.01; mean change in B/A, -0.31; P<.001) and diastolic blood pressure in both groups and in systolic blood pressure in the B/A group. T/V was not superior to B/A for reducing UACR. Both ACEI/CCB FDCs may reduce albuminuria; in the case of T/V, this appears to be independent of systolic blood pressure reduction in patients who had previously been treated and had baseline blood pressure levels of 142/77 mm Hg.

Predictors of bone maturation, growth rate and adult height in children with central precocious puberty treated with depot leuprolide acetate.

BACKGROUND: Children with central precocious puberty (CPP) are treated with gonadotropin-releasing hormone agonists (GnRHa) to suppress puberty. Optimizing treatment outcomes continues to be studied. The relationships between growth, rate of bone maturation (bone age/chronological age [ΔBA/ΔCA]), luteinizing hormone (LH), predicted adult stature (PAS), as well as variables influencing these outcomes, were studied in children treated with depot leuprolide (LA Depot) Methods: Subjects (64 girls, seven boys) with CPP received LA Depot every 3 months for up to 42 months. Multivariate regression analyses were conducted to examine the predictors affecting ΔBA/ΔCA, PAS and growth rate. RESULTS: Ninety percent of subjects (18 of 20) were suppressed (LH levels <4 IU/L) at 42 months. Over 42 months, the mean growth rate declined 2 cm/year, the mean BA/CA ratio decreased 0.21 and PAS increased 8.90 cm for girls (n=64). PAS improved to mid-parental height (MPH) in 46.2% of children by 30 months of treatment. Regression analysis showed that only the Body Mass Index Standardized Score (BMI SDS) was significantly associated (ß+0.378 and +0.367, p≤0.05) with growth rate. For PAS, significant correlations were with MPH (ß+0.808 and +0.791, p<0.001) and ΔBA/ΔCA (ß+0.808 and +0.791, p<0.001). For ΔBA/ΔCA, a significant association was found only with BA at onset of treatment (ß-0.098 and -0.103, p≤0.05). Peak-stimulated or basal LH showed no significant influence on growth rate, ΔBA/ΔCA or PAS. CONCLUSIONS: Growth rate and bone maturation rate normalized on treatment with LA Depot. LH levels were not significantly correlated with growth rate, ΔBA/ΔCA or PAS, suggesting that suppression was adequate and variations in gonadotropin levels were below the threshold affecting outcomes.

Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome.

OBJECTIVE: We sought to test the hypothesis that a fixed-dose combination of trandolapril/verapamil-SR (T/V) is superior to a fixed-dose combination of losartan/hydrochlorothiazide (L/H) on glucose tolerance in hypertensive patients with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: A prospective, randomized, open-label, blinded-end points design was used to assess the effects of a T/V versus L/H combination in patients with IGT and hypertension (n = 240) followed for up to 1 year. Doses were titrated to a systolic blood pressure <130 mmHg. Primary outcome was change from baseline in a 2-h glucose on oral glucose tolerance test (OGTT) at study end (mean [+/-SD] at follow-up, 46.9 +/- 13.5 weeks). Secondary outcomes included changes in insulin sensitivity, office and 24-h ambulatory blood pressure, incidence of new-onset diabetes, lipids, and inflammatory markers. Data are expressed as means +/- SE unless otherwise noted. RESULTS: Changes at study end were noted in 2-h OGTT glucose (T/V -0.21 +/- 0.36 vs. L/H +1.44 +/- 0.36 mmol/l; P < 0.001) and insulin level (-30.13 +/- 38.38 vs. +84.86 +/- 38.33 pmol/l, respectively; P = 0.025). Worsening of insulin resistance occurred by week 12 (T/V 0.000 +/- 0.001 vs. L/H -0.005 +/- 0.001; P = 0.016). A higher incidence of new-onset diabetes (T/V 11.0 vs. L/H 26.6%; P = 0.002) and HbA1c >7% (2.6 vs. 9.6%, respectively; P = 0.05) occurred at study end. CONCLUSIONS: In patients with IGT, normal kidney function, and hypertension, the fixed-dose combination of T/V reduces the risk of new-onset diabetes compared with an L/H-based therapy.

Monitoring treatment of central precocious puberty using basal luteinizing hormone levels and practical considerations for dosing with a 3-month leuprolide acetate formulation.

BACKGROUND: Peak gonadotropin-releasing hormone or agonist (GnRHa) stimulated luteinizing hormone (LH) testing with leuprolide acetate (LA) is commonly used to document suppression during therapy for central precocious puberty (CPP). The objective of the study was to investigate suitability of using basal LH levels to monitor GnRHa treatment and to determine optimal transition from 1-month to 3-month LA formulations via a post hoc analysis of a randomized, open-label, 6-month study. METHODS: A total of 42 children with CPP, pretreated with 7.5-, 11.25-, or 15-mg 1-month LA formulations were randomized to 11.25- or 30-mg 3-month LA. Basal LH/peak-stimulated LH levels were measured at weeks 0, 4, 8 and 12. Positive/negative predictive values and sensitivities/specificities were determined for basal LH vs. LH-stimulation results. RESULTS: Pretreatment with any 1-month formulation for the most part did not affect continuation of suppression after transitioning to 3-month formulation (mean peak-stimulated LH levels remained < 4 IU/L). Basal LH predicted suppression escape (basal LH-level cutoff ≥ 0.6 IU/L predicted 70% of those failing suppression). Tolerability was similar, regardless of dose. CONCLUSIONS: Our data indicate that a basal level of <0.60 IU/L is adequate for monitoring suppression approximately two-thirds of the time. Furthermore, the effectiveness and safety of 3-month LA treatments are not influenced by previous CPP therapies.

Dose-finding and pharmacokinetic profiles of prophylactic doses of a low molecular weight heparin (reviparin-sodium) in pediatric patients.

INTRODUCTION: The low molecular weight heparin (LMWH), reviparin-sodium was studied in dose-finding and pharmacokinetic studies in children with central venous lines (CVLs). MATERIALS AND METHODS: The dose-finding study was performed in 24 patients aged 3 days to 16 years. Dose adjustments were made using a nomogram based on anti-factor Xa levels (units (U)/ml) (target of 0.1-0.3 U/ml). The pharmacokinetic study was performed in 19 patients, 9 less than or equal to 5 kg (7 of whom were less than 3 months) and 10 greater than 5 kg (all more than 3 months). RESULTS: The dose-finding study demonstrated that children over 5 kg required 30 International Units (IU)/kilogram (kg), subcutaneous (SC) twice daily (BID), and children less than or equal to 5 kg required 50 IU/kg, SC BID, to achieve target levels. The pharmacokinetic study demonstrated that 80% of anti-factor Xa levels were within the target range with both patient groups having similar peak (average=0.26 U/ml) and trough (average=0.13 U/ml) levels. CONCLUSIONS: Peak anti-factor Xa levels (0.1-0.3 U/ml) using reviparin-sodium are achieved by administering 50 IU/kg in children greater than 3 months of age and 30 U/kg in children less than 3 months of age.

Differential effects of clivarin and heparin in patients undergoing hip and knee surgery for the generation of anti-heparin-platelet factor 4 antibodies.

The pathophysiology of heparin-induced thrombocytopenia (HIT) syndrome is mediated via a heterogeneous group of heparin(s)-platelet factor 4 (H-PF4) complexes bound to their antibodies. These anti-H-PF4 (AHPF4) antibodies that are capable of binding to the FcgammaRIIA receptor [cluster of differentiation (CD) 32] on platelets, resulting in platelet activation, widely vary in their specific activities as platelet activation (functionality). Predisposing factors related to specific pathologic conditions may also contribute to the generation of these antibodies and their relative functionality during HIT syndrome. To understand this phenomenon, a sub-study was carried out in patients undergoing elective total hip and knee replacement surgery (ECHOS Study) and who were treated with unfractionated heparin (UFH) and a low-molecular-weight heparin (LMWH; Clivarin). Approximately 600 patients per arm [UFH=7,500 anti-Xa U twice a day (b.i.d.) subcutaneous (s.c.) and clivarin=4200 U once daily (o.d.) s.c.], age >40 years, received prophylactic treatment for a minimum of 11-14 days. Plasma samples were collected at pre-dose, days 2-4, days 11-14 and at follow-up 6-8 weeks after discharge and were analyzed for AHPF4 antibody titers. Functionality of the enzyme-linked immunosorbant assay (ELISA)-positive AHPF4 antibodies to cause platelet activation was tested by 14C-serotonin release assay (SRA). Both UFH and clivarin treatments in orthopedic surgical patients resulted in a progressive generation of AHPF4 antibodies. The relative prevalence/functionality of AHPF4 antibodies in clivarin arm was markedly lower (two- to threefold, p<0.001) as compared to UFH at each time point. Most of the samples in clivarin group were found to be SRA negative, suggesting the presence of AHPF4 antibodies that did not activate platelets (nonfunctional). Within the UFH arm, the relative prevalence/functionality of AHPF4 antibodies was much higher (p<0.002) in knee group compared to the corresponding hip group. This study, for the first time, reports on the elevated levels of AHPF4 antibodies generated by heparin associated with the pathogenesis of knee surgery. Clinical significance of the differential generation of HIT-associated antibodies remains unexplored at this time.

36-month treatment experience of two doses of leuprolide acetate 3-month depot for children with central precocious puberty.

CONTEXT: We have recently demonstrated short-term (6-month) efficacy and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with central precocious puberty (CPP). OBJECTIVE: To assess long-term (36-month) hypothalamic-pituitary-gonadal axis suppression and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with CPP. DESIGN: Open-label, 36-month extension. SETTING: Twenty pediatric endocrine centers. PATIENTS: Seventy-two children (mean age, 8.5 ± 1.6 y; 65 females) with CPP completed and showed maintenance of LH suppression after a 6-month lead-in study. INTERVENTION: Leuprolide acetate depot (11.25 or 30 mg) administered im every 3 months. MAIN OUTCOME MEASURES: Peak-stimulated LH, estradiol, T, growth rate, pubertal progression, and adverse events (AEs). RESULTS: Twenty-nine of 34 subjects in the 11.25-mg group and 36 of 38 subjects in the 30-mg group had LH values < 4 mIU/mL after day 1 at all time points. All seven subjects who escaped LH suppression at any time still maintained sex steroid concentrations at prepubertal levels and showed no signs of pubertal progression. AEs were comparable between groups, with injection site pain being the most common (26.4% overall). No AE led to discontinuation of study drug. The safety profile over 36 months was comparable to that observed during the 6-month pivotal study. CONCLUSIONS: The two doses of leuprolide acetate 3-month depot were associated with an acceptable safety profile and provided maintenance of LH suppression in the majority of children with CPP during the 36 months of the study or until readiness for puberty.

Sustained release of tissue factor following thrombosis of lower limb trauma.

This study was undertaken to provide evidence for the mechanism of venous thromboembolism (VTE) in healthy patients with minor lower limb injury (fracture; Achilles tendon rupture) that was medically managed with plaster cast/brace immobilization. The Plaster Cast clinical trial provided a unique opportunity to identify the natural history of VTE using placebo-controlled patients (n = 183) with validation of the mechanism using the low-molecular-weight heparin (LMWH; reviparin)-treated patients (n = 182). Confirmed VTE in this population was associated with a burst of tissue factor release (and a minor fibrinolytic deficit) leading to thrombin generation that was sustained at least 5 weeks, greater with fractures than with soft-tissue injuries and greater with surgery than with conservative treatment. The root cause likely involves platelet/leukocyte activation (inflammation) rather than endothelial cell injury. Thromboprophylaxis with a low dose of LMWH reduced thrombin generation, with patients undergoing surgery benefitting the most.

Six-month leuprorelin acetate depot formulations in advanced prostate cancer: a clinical evaluation.

For nearly three decades, gonadotropin-releasing hormone (GnRH) agonists, particularly leuprorelin acetate (LA), have served as an important part of the treatment armamentarium for prostate cancer. The introduction of LA depot formulations provided a significant improvement in the acceptance of this therapy; however, their indicated treatment duration of 1 to 4 months was still not long enough to satisfy all medical needs. For this reason some manufacturers developed new injectable formulations that provide testosterone suppression for 6 months. This review article assesses key publications in order to compare these long-acting, commercially available, LA depot formulations and their clinical performance. The literature search identified 14 publications; by excluding reviews, duplications, and non-English articles, only three original papers describing clinical trial remained for review: two focused on microsphere-based LA formulations with either a 30 mg or 45 mg dose and one focused on a gel-based leuprorelin acetate with a 45 mg dose. All products were tested in individual clinical trials and have demonstrated their efficacy and safety.

Reversal of diuretic-associated impaired glucose tolerance and new-onset diabetes: results of the STAR-LET study.

Reversal of new-onset diabetes secondary to thiazide diuretic use remains questionable. STAR-LET was a 6-month extension of the Study of Trandolapril/Verapamil SR and Insulin Resistance (STAR), which assessed the effects of a fixed-dose renin-angiotensin system inhibitor (RASI)/hydrochlorothiazide (HCTZ) combination on changes in 2-hour oral glucose tolerance test (OGTT) results. STAR-LET explored whether the glycemic impact of HCTZ could be reversed by conversion to a RASI/verapamil combination. The primary outcome was change in 2-hour OGTT results. Fifty-one percent of the STAR patients were enrolled in STAR-LET. The 2-hour OGTT value (mmol/L) was unchanged from STAR baseline in the RASI/verapamil group (7.7+/-2.4 vs 8.1+/-3.3; P=.18) and improved in those who were switched from RASI/HCTZ to RASI/verapamil (8.5+/-3.0 vs 7.2+/-2.3; P<.001). This exploratory study suggests that the impairment in glycemic control seen with use of a thiazide diuretic combined with a RASI can be reversed by switching to a regimen that does not include a diuretic.

Antihypertensive properties of a high-dose combination of trandolapril and verapamil-SR.

The superior diastolic blood pressure reduction (BP) of high-dose combination therapy with trandolapril (Tr) and verapamil-SR (Ve) compared with monotherapy has previously been reported. Guideline changes, placing greater emphasis on systolic BP, prompted a re-evaluation of TV-51 and an assessment of a subset of patients from the INternational VErapamil-SR Trandolapril STudy (INVEST). The objective of this analysis was to determine if the short-term antihypertensive effects of high-dose Tr+Ve (Tr/Ve study) could be confirmed in a sample of higher-risk INVEST patients with longer follow-up. The Tr/Ve study was a double-blind, randomized, parallel-group, placebo-controlled trial to evaluate the antihypertensive effects of trandolapril and verapamil-SR alone or in combination in 631 patients randomized to placebo, 4 mg trandolapril, 240 mg verapamil-SR or 4 mg/240 mg Tr+Ve combination for 6 weeks; 581 INVEST patients were selected for comparison with 24-month BP data, 90% use of trandolapril and verapamil-SR combination therapy and no triple therapy. Tr+Ve combination treatment achieved significantly greater systolic and diastolic BP reduction versus monotherapy. The BP-lowering effects of high-dose Tr+Ve achieved during short-term treatment were confirmed in INVEST during longer follow-up. Despite differences in the risk profiles of previously studied patients and INVEST patients, the antihypertensive effects of Ve+Tr were similar.

Decreased prevalence of heparin-induced thrombocytopenia with low-molecular-weight heparin and related drugs.

Heparin-induced thrombocytopenia (HIT) Type II represents a disease spectrum associated with a high risk of thrombosis leading to limb loss and death. The pathophysiology of HIT is based on the development of antibodies to the heparin-platelet factor 4 (PF4) complex. Unfractionated heparin (UFH) is heterogeneous in molecular chain length and degree of sulfation accounting in part, for, the heterogeneity of HIT antibodies. Because of its smaller size, low-molecular-weight heparin (LMWH) does not interact with PF4 and platelets as efficiently as does UFH. This translates into a lower risk of immune sensitization with LMWH than with UFH treatment. LMWH is less likely than UFH to cause antibody generation and thus patients do not develop clinical HIT at the same frequency with LMWH as with UFH treatment. The antibodies generated by LMWH treatment are more often immunoglobulin A (IgA) and IgM as opposed to IgG antibodies, which are associated with symptomatic clinical HIT generated by exposure to UFH. However, platelet activation/aggregation can occur from LMWHs in the presence of most pre-existing HIT antibodies that had been generated from UFH exposure, although the response is less than that caused by UFH plus HIT antibody. With the expanded use of LMWH, the frequency of clinical HIT may naturally decline, given that LMWHs are less likely to generate HIT antibody.