Comparison of the effectiveness and safety of low-molecular weight heparin versus unfractionated heparin anticoagulation after heart valve surgery

Although unfractionated heparin (UFH) is used routinely after heart valve surgery at many institutions, cardiovascular surgery patients have a particularly high risk for developing heparin-induced thrombocytopenia (HIT). The aim of this study was to compare the efficacy and safety of low-molecular-weight heparin (LMWH) or UFH after heart valve surgery by conducting a retrospective evaluation of consecutive cardiovascular surgery patients in whom the LMWH dalteparin (n = 100) was used as the postoperative anticoagulant. This group was compared to an earlier group of patients who received UFH (n = 103). The main outcomes included the efficacy of the anticoagulant regimens (determined by the incidence of valve thrombosis, arterial thromboembolic events, and venous thromboembolic events) and the safety (determined by major bleeding, HIT, thrombotic events in HIT-positive cases, and death). Overall, there were for fewer thrombotic events in the LMWH-treated group (4% vs 11%, p = 0.11). There was a higher rate of bleeding events in the UFH-treated group (10% vs 3%, p = 0.08). Six patients in the UFH-treated group developed HIT, 4 of whom had thrombotic events (HIT with thrombosis). In the LMWH-treated group, 3 patients developed HIT, 1 of whom had HIT with thrombosis. In conclusion, in this study, an LMWH regimen after heart valve surgery was effective and safe, with fewer thrombotic, bleeding, HIT, and HIT with thrombosis events.     

Heparin-induced thrombocytopenia

BACKGROUND AND OBJECTIVE: There are two types of heparin-induced thrombocytopenia (HIT). HIT I is characterized by a transitory, slight and asymptomatic reduction in platelet count, occurring in the first 1-2 days of therapy, that resolves spontaneously; in contrast, HIT II, which has an immunologic origin, is characterized by a significant thrombocytopenia generally after the fifth day of therapy that usually resolves in 5-15 days only after therapy withdrawal. HIT II is the most frequent and dangerous side-effect of heparin therapy; in fact, in spite of thrombocytopenia, it can be complicated by venous and arterial thrombosis. Therefore, the recognition of HIT II may be difficult due to the underlying thrombotic symptoms for which heparin is administered. The aim of this article is to review the most recent advances in the field and to give critical guidelines for the clinical diagnosis and treatment of HIT II. STATE OF THE ART: The prevalence of HIT II, as confirmed by laboratory tests, seems to be about 2% in patients receiving unfractionated heparin (UH), while it is much lower in those receiving low molecular weight heparin (LMWH). The immunologic etiology of HIT II is largely accepted. Platelet factor 4 (PF4) displaced from endothelial heparan sulphate or directly from the platelets, binds to the heparin molecule to form an immunogenic complex. The anti-heparin/ PF4 IgG immunocomplexes activate platelets and provoke an immunologic endothelial lesion with thrombocytopenia and/or thrombosis. The IgG anti-heparin/PF4 immunocomplex activates platelets mainly through binding with the FcgRIIa (CD32) receptor. The onset of thrombocytopenia is independent of the dosage, schedule and route of administration of heparin. Orthopedic and cardiovascular surgery patients receiving post-surgical prophylaxis or treatment for deep venous thrombosis are at higher risk of HIT II. Besides thrombocytopenia, cutaneous allergic manifestations and skin necrosis may be present. Hemorrhagic events are not frequent, while the major clinical complications in 30% of patients are both arterial and venous thromboses which carry a 20% mortality. The diagnosis of HIT II should be formulated on the basis of clinical criteria and in vitro demonstration of heparin-dependent antibodies. Functional tests, such as platelet aggregation and (14)C-serotonin release assay and immunologic tests, such as the search for anti-PF4/heparin complex antibodies by an ELISA method are available. If HITT II is probable, heparin must be immediately suspended and an alternative anticoagulant therapy should be initiated before resolution of thrombocytopenia and the following treatment with a vitamin K antagonist. The general opinion is to administer low molecular weight heparin (in the absence of in vitro cross-reactivity with the antibodies), heparinoids such as Orgaran or direct thrombin inhibitors such as hirudin. PERSPECTIVES: Further studies are required to elucidate the pathogenesis of HIT II and especially to discover the clinical and immunologic factors that induce the occurrence of thrombotic complications. The best therapeutic strategy remains to be confirmed in larger clinical trials.     

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.     

Successful use of fondaparinux in a patient with a mechanical heart valve replacement and a history of heparin-induced thrombocytopenia

The development of heparin-induced thrombocytopenia (HIT) is an antibody-mediated clinicopathologic syndrome. The resultant thrombocytopenia and thrombosis can be severe and life-threatening. Fondaparinux is a parenteral factor Xa inhibitor used for venous thromboembolism prevention and treatment. Fondaparinux has minimal affinity for platelet factor 4, making it an alternative agent to unfractionated heparin (UFH) and low-molecular weight heparin (LMWH) and a plausible consideration for patients with a history of HIT. The use of fondaparinux in patients with mechanical heart valve replacement and a history of HIT has never been discussed in the literature. We report on the case of a patient with a mechanical aortic heart valve replacement and a history of HIT who was successfully bridged postoperatively with fondaparinux. While there is currently no literature to support the use of fondaparinux in patients with mechanical heart valves, this drug may offer an option for management of such patients who cannot use heparin products. However, further clinical investigations are warranted to confirm both the safety and efficacy of this agent in the mechanical heart valve population.     

Heparin-induced thrombocytopenia in hemodialysis. Case report and review of the literature

Thrombocytopenia is a potential complication of heparin therapy. There are two forms of heparin-induced thrombocytopenia (HIT). Type-I HIT is characterized by a mild decrease in platelet count that occurs within the first 2-4 days after heparin initiation. The platelet count often returns to normal without stop heparin treatment. The mechanism of thrombocytopenia appears to be due to a direct effect of heparin on platelet activation. The second form (type-II) is an immune-mediated disorder characterized by severe thrombocytopenia, which may include both arterial and venous thrombosis. We present a case of type-II HIT occurred in a hemodialysis patient resulting in acute pulmonary embolism and peripheral venous thrombosis, and review the literature.     

Hirudin for prophylaxis and treatment of deep vein thrombosis

Since recombinant hirudin (r-hirudin) has become available, several studies have been published on hirudin for prophylaxis and treatment of thromboembolic complications. Vr-hirudin was shown to be superior even to low-molecular-weight heparin (LMWH) for prophylaxis of deep venous thrombosis (DVT), especially in high-risk patients. Consequently, r-hirudin was expected to be more effective than heparins are in the treatment of thromboembolic events. Vr-hirudin was proved to be safe and efficacious in the therapy of thromboembolic events. However, no benefit could be shown in comparison with heparin. In contrast, in patients suffering from HIT type II, r-hirudin is the drug of choice for the therapy of thromboembolic complications.     

Heparin-induced thrombocytopenia: 2008 update

Opinion statement Unfractionated heparin (UFH) and the low molecular weight heparin (LMWH) preparations are two of the most commonly prescribed medications in the hospital, and indications for their use are increasing. An increasingly recognized untoward effect of either UFH or LMWH is heparin-induced thrombocytopenia (HIT), a transient, prothrombotic condition that may result in venous or arterial thrombosis and amputation or death. This immune-mediated process generally develops within 4 to 14 days of administration, although it may occur more rapidly if there has been a recent exposure; it may even occur days to weeks after UFH or LMWH has been discontinued. Although once considered necessary for the diagnosis of HIT, thrombocytopenia is no longer essential. A 50% reduction in the platelet count from pre-heparin treatment levels is now considered a more specific finding. Prompt recognition, discontinuation of the offending agent, and initiation of an alternative anticoagulant are essential for prevention and/or treatment of these potentially devastating complications.     

Outpatient therapy with low-molecular-weight heparins: new perspectives for treatment of deep vein thrombosis

Subcutaneous administration of low-molecular-weight heparin (LMWH) has been demonstrated to be as safe and effective for treatment of acute venous thrombosis as conventional treatment with unfractionated heparin, which requires intravenous infusion. In addition, LMWHs appear to provide an improved quality of life for patients with less impairment of physical activity. The ease of administration of LMWHs could be exploited in the clinical management of patients to increase the extent of LMWH outpatient therapy and reduce the number of hospitalizations for venous thrombosis, thus providing a more cost-effective therapy than conventional heparin. Efficient support services, patient education and careful follow up will be required for home treatment to be successful.     

No difference in risk for thrombocytopenia during treatment of pulmonary embolism and deep venous thrombosis with either low-molecular-weight heparin or unfractionated heparin: a metaanalysis

BACKGROUND: Low-molecular-weight heparin (LMWH) is a popular alternative to unfractionated heparin (UH) for the treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT), in part based on the perception of a lower risk for heparin-induced thrombocytopenia (HIT). To investigate the evidence supporting this perception, we performed a metaanalysis to compare the incidence of thrombocytopenia between LMWH and UH during PE and/or DVT treatment. METHODS: Randomized trials comparing LMWH with UH for PE and/or DVT treatment were searched for in the MEDLINE database, bibliographies, and by correspondence with published investigators. Two reviewers independently selected high-quality studies and extracted data regarding heparin-associated thrombocytopenia (HAT), HIT confirmed by laboratory testing, and heparin-induced thrombocytopenia with thrombosis (HITT). Outcome rates between LMWH and UH were compared using a binomial, generalized linear mixed model with a logit link and Gaussian random effects for study. RESULTS: Thirteen studies involving 5,275 patients met inclusion criteria. There were no statistically significant differences in HAT rates between the two treatments (LMWH, 1.2%; UH, 1.5%; p = 0.246). The incidence of documented HIT and HITT was too low to make an adequate comparison between groups. CONCLUSIONS: Our review disclosed no statistically significant difference in HAT between LMWH and UH and insufficient evidence to conclude that HIT and HITT rates were different between them. There was no evidence from randomized comparative trials to support the contention that patients receiving treatment for PE or DVT with UH are more prone to these complications than those receiving LMWH.     

Rapid T‐cell chimerism switch and memory T‐cell expansion are associated with pre‐engraftment immune reaction early after cord blood transplantation

Until recently, both the British Society for Haematology and American College of Chest Physicians recommended platelet monitoring in all surgical patients receiving prophylactic low molecular weight heparin (LMWH) for the early diagnosis of heparin‐induced thrombocytopenia (HIT). These guidelines were reversed in 2012 based upon an analysis considering resource expenditure, assay result timeframes, and complications relating to HIT treatment. However, there are no large studies reviewing lower limb arthroplasty patients on an individual basis to determine the incidence of HIT in this patient group. This study investigated 10 797 patients who underwent primary hip or knee arthroplasty with LMWH prophylaxis over a 5 years period. 32·6% of patients (n = 3515) had platelet counts recorded up to 14 d postoperatively with 13 patients (0·37%) developing thrombocytopenia. Platelet counts recovered spontaneously in five patients, and two patients had other identifiable causes. Only one of the remaining six patients developed thrombosis indicating an incidence of HIT‐related thrombosis of 0·03%. The potential for identifying HIT with platelet monitoring in patients receiving LMWH prophylaxis is low and therefore routine monitoring for HIT is not justified.     

Determination of heparin-induced thrombocytopenia: a rapid flow cytometric assay for direct demonstration of antibody-mediated platelet activation.

Heparin-induced thrombocytopenia (HIT) and thrombosis are serious complications of heparin therapy. Recently, we have reported a practical and rapid functional flow cytometric assay (FCA) for the diagnosis of HIT with high specificity and sensitivity compared with the radioactive serotonin-release assay (SRA). In the present study, we added an immune-neutralization assay to directly demonstrate the antibody-mediated process, and tested the immune compatibility of low-molecular-weight heparin (LMWH) Lovenox and the heparinoid Orgaran (danaproid) using plasma from 18 patients with HIT confirmed by both FCA and SRA. The clinical utility of this modified method is demonstrated by a pediatric patient with a complex clinical presentation who developed thrombocytopenia with multiple thromboses while on heparin therapy. ELISA and SRA (performed in three independent laboratories) for diagnosis of HIT were both negative. In contrast, the FCA for detecting activated platelets expressing anionic phospholipids, was highly and reproducibly positive with both unfractionated and LMWH. Another FCA also demonstrated the surface expression of the alpha-granule membrane p-selectin (CD62p). Compatibility testing with the heparinoid Orgaran was also positive (and with plasma from 4 of the 18 patients with HIT). Heparin was discontinued, along with full recovery of the platelet count. The capacity of the patient's plasma to activate platelets in the presence of heparin gradually decreased over 4 weeks consistent with antibody clearance. The responsible mechanism was clarified using an immune-neutralization assay, which showed a dose response neutralization of the plasma activity by antibodies against human Immunoglobulin G (IgG) and IgM. This assay was also reproducible in the 18 patients with HIT. We conclude that the functional FCA with its modification is practical, sensitive, and specific for reliable diagnosis of HIT. It can simultaneously assess the compatibility of alternative therapies and directly confirm the antibody-mediated process. Further, it is particularly useful to clarify mechanisms of thrombocytopenia and thrombosis and to direct therapy in patients with a complex presentation and confounding laboratory results who often need prompt diagnosis and treatment.     

Heparin‐induced thrombocytopenia complicating children after the Fontan procedure: Single‐center experience and review of the literature

Heparin‐induced thrombocytopenia (HIT) is a life‐threatening complication of heparin therapy. The risk for HIT correlates with the cumulative dosage of heparin exposure. In Fontan patients, recurrent systemic anticoagulation, traditionally with heparin, is used to alleviate the thrombotic complications that may occur postoperatively when the venous pressure rises and the systemic venous flow into the pulmonary arteries becomes sluggish, putting them at increased risk. As a pressure gradient‐dependent circulation, elevation in systemic venous pressure, most often by venous thrombosis, contributes to circuit failure. Therefore, when HIT complicates patients after the Fontan procedure, it is associated with a high thrombotic morbidity and mortality; thus, a high index of suspicion is mandatory, based on the clinical signs of HIT. It is crucial to intervene early with alternative anticoagulants when HIT is suspected as this step may improve outcome in these patients.     

HITlights: a career perspective on heparin-induced thrombocytopenia

Two decades of research into heparin-induced thrombocytopenia (HIT) permit a personal historical perspective on this fascinating syndrome. Previously, the frequency of HIT was unknown, although complicating thrombosis was believed to be rare and primarily arterial. The opportunity to apply a remarkable test for "HIT antibodies"--the (14) C-serotonin-release assay (SRA)--to serial plasma samples obtained during a clinical trial of heparin thromboprophylaxis, provided insights into the peculiar nature of HIT, such as, its prothrombotic nature--including its strong association with venous thrombosis (RR = 11.6 [95%CI, 6.4-20.8; P < 0.0001); its more frequent occurrence with unfractionated versus low-molecular-weight heparin; the "iceberg" model, which states that among the many patients who form anti-PF4/heparin antibodies during heparin therapy, only a minority whose antibodies evince strong platelet-activating properties develop HIT; and the characteristic HIT timeline, whereby serum/plasma antibodies are readily detectable at or prior to the HIT-associated platelet count fall. Applying the SRA also to patients encountered in clinical practice led to recognition of warfarin-induced venous limb gangrene (for which HIT is a major risk factor via its extreme hypercoagulability) and delayed-onset HIT (whereby thrombocytopenia begins or worsens following heparin discontinuation, due to the ability of HIT antibodies strongly to activate platelets even in the absence of heparin--so-called heparin-"independent" platelet activation). Recent concepts include the increasing recognition of HIT "overdiagnosis" (due to the low diagnostic specificity of the widely-applied PF4-dependent immunoassays), and the observation that HIT-associated consumptive coagulopathy is a risk factor for treatment failure with PTT-adjusted direct thrombin inhibitor therapy ("PTT confounding" secondary to HIT-associated coagulopathy).     

Heparin-induced thrombocytopenia

Summary Heparin-induced thrombocytopenia (HIT), next to bleeding complications, is the most important side-effect of heparin therapy in cardiac patients and the most frequently found thrombocytopenia induced by medication. Two types of HIT are distinguished on the basis of both severity of disease, and pathophysiology: type I HIT is an early, transient, clinically harmless form of thrombocytopenia, due to direct heparin-induced platelet aggregation. Thromboembolic complications are usually not seen. No treatment is required. A normalization of platelet count even if heparin is continued is a usual observation. Type II HIT is more severe than type I HIT and is frequently complicated by extension of preexisting venous thromboembolism or new arterial thrombosis. The thrombocytopenia is caused by a pathogenic heparin-dependent IgG antibody (HIT-IgG) that recognizes as its target antigen a complex consisting of heparin and platelet factor IV. Type II HIT should be suspected when the platelet count falls to less than 100,000 per cubic millimeter or less than 50% of the base line value 5 to 15 days after heparin therapy is begun, or sooner in a patient who received heparin in the recent past. The clinical diagnosis of type II HIT can be confirmed by several sensitive assays. In cases of type II HIT, heparin must be stopped immediately. However, if the patient requires continued anticoagulant therapy for an acute event such as deep venous thrombosis, substitution of an alternative rapid-acting anticoagulant drug is often needed. In the authors experience Danaparoid sodium, a low-sulfated heparinoid with a low cross-reactivity (10%) to heparin, can be regarded as an effective anticoagulant in patients with type II HIT. Preliminary experiences with intravenous recombinant hirudin are also encouraging and suggest that this direct thrombin inhibitor will emerge as a valuable alternative treatment for patients who suffer from HIT.     

Current agents for the treatment of patients with heparin-induced thrombocytopenia

Several counterintuitive treatment paradoxes complicate the management of immune heparin-induced thrombocytopenia (HIT). For example, simple discontinuation of heparin often fails to prevent subsequent HIT-associated thrombosis. Thus, current treatment guidelines recommend substituting heparin with a rapidly acting alternative anticoagulant (eg, danaparoid, lepirudin, or argatroban) even when HIT is suspected on the basis of thrombocytopenia alone ("isolated HIT"). Another paradox-coumarin (warfarin) anticoagulation-can lead to venous limb gangrene in a patient with HIT-associated deep-vein thrombosis. Thus, warfarin is not recommended during acute thrombocytopenia secondary to HIT. However, warfarin can be given as overlapping therapy with an alternative anticoagulant, provided that (1) initiation of warfarin is delayed until substantial platelet count recovery has occurred (to at least above 100 x 10(9)/L); (2) low initial doses of warfarin are used; (3) at least 5 days of overlapping therapy are given; and (4) the alternative agent is maintained until the platelet count has normalized. It has recently been recognized that HIT antibodies are transient and usually do not recur upon subsequent re-exposure to heparin. This leads to a further paradox-patients with previous HIT can be considered for a brief re-exposure to heparin under exceptional circumstances; for example, heart surgery requiring cardiopulmonary bypass, if HIT antibodies are no longer detectable using sensitive assays. For patients with acute or recent HIT who require urgent heart surgery, other approaches include use of alternative anticoagulants (eg, lepirudin or danaparoid) for cardiopulmonary bypass or antiplatelet agents (eg, tirofiban or epoprostenol) to permit intraoperative use of heparin.     

The economic impact of treating deep vein thrombosis with low-molecular-weight heparin: outcome of therapy and health economy aspects

Subcutaneous low-molecular-weight heparin (LMWH) is at least as safe and effective as classical intravenous heparin therapy for the treatment of proximal vein thrombosis. Anticoagulant monitoring and intravenous administration are not required with LMWH treatment, therefore this therapy may offer economic advantages. An economic evaluation of these therapeutic approaches was performed comparing the costs and effectiveness. The evaluation was aimed at helping decision-makers to maximize the health of the population served, subject to available resources. The American-Canadian Thrombosis Study was a multicentre, randomized, double-blind clinical trial that compared treatment by initial continuous intravenous infusion of heparin (followed by 3 months of warfarin therapy) with a once-daily dose of subcutaneous LMWH, tinzaparin sodium (followed by 3 months of warfarin treatment) in patients with acute proximal deep vein thrombosis. In the LMWH-treated group, the cost incurred for 100 patients was $399,403 (Canadian) or $335,687 (US) with a frequency of objectively documented recurrent venous thromboembolism of 2.8%. In the intravenous heparin-treated group, the cost incurred for 100 patients was $ 414,655 (Canadian) or $ 375,836 (US), with a frequency of objectively documented recurrent venous thromboembolism of 6.9%. These results show a cost saving of $ 15,252 (Canadian) or $ 40,149 (US) with the use of LMWH. Multiple sensitivity analyses did not alter the findings of the study which indicated that LMWH therapy is at least as safe and effective but less costly than intravenous heparin treatment. The potential for outpatient therapy in up to 37% of patients who are receiving LMWH would substantially augment the cost-saving. The cost-effectiveness findings presented in this paper are based on the assumption that all costs are covered by a single payer. Outpatient management in many countries will shift the healthcare costs from the healthcare payer to the patient, increasing the economic burden to the patient.     

Risk factors for thrombosis in patients with immune mediated heparin-induced thrombocytopenia

BACKGROUND: As reported by major clinical series in the literature, about 2% of patients receiving unfractionated heparin (UFH) develop immune-mediated (type II) heparin-induced thrombocytopenia (HIT) that may be complicated in 30-75% of cases by a paradoxical thrombotic syndrome (HITTS), either arterial or venous. HITTS carries relevant rates of mortality and morbidity, amongst which cerebral and/or myocardial infarction and limb amputations. It is unclear as yet why some patients suffer from isolated thrombocytopenia (HIT), whilst others have HITTS. The aim of the present study was to look for clinical and laboratory features related to the occurrence of HITTS. PATIENTS AND METHODS: We retrospectively analysed the clinical records of 56 patients with proven HIT, as diagnosed on clinical grounds and by in vitro demonstration of immunoglobulin (IgG)/IgM against the PF4/heparin complex. Thirty-four patients (61%) had HITTS (19 venous thrombosis, seven arterial thrombosis, five arterial and venous thrombosis, two skin necrosis, one diffuse intravascular coagulation), whereas 22 had uncomplicated HIT. Amongst HITTS patients, two had limb amputation, five had recurrent thrombosis and seven died. Amongst HIT patients three died from causes unrelated to HIT. RESULTS: No significant difference in sex, age, previous exposure to heparin, UFH route of administration or dose, duration of therapy, time of onset of thrombocytopenia and platelet count recovery, nor antiheparin/PF4 antibodies subtype (IgG or IgM) was detected when comparing HIT and HITTS. In contrast, in the HITTS group a higher prevalence of orthopaedic surgery (15 of 34 vs. 2/22; P=0.01), a significantly lower platelet count nadir (43 +/- 32 vs. 75 +/- 63 x 109/L; P=0.01) and a significantly higher titre of antiheparin/PF4 antibodies, expressed as optical density of enzyme-linked immunosorbent assay (ELISA); (1989 +/- 1024 vs. 1277 +/- 858; P=0.009), were observed in comparison with the HIT group. Amongst HITTS patients, the prevalence of venous thrombosis was significantly higher in orthopaedic patients and in those being treated for venous thromboembolism (18/24 vs. 1/9 patients, chi2 8.4, P=0.004), whilst arterial thrombosis (ART) occurred more often in heparin treatment for arterial disease (3/4 vs. 4/29 patients, chi2 4.6, P=0.03). CONCLUSIONS: Orthopaedic surgery, the severity of thrombocytopenia and high antiheparin/PF4 antibodies titre are adverse prognostic or concurrent factors in the development of HITTS.     

Risk of thrombosis in patients with malignancy and heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a common immunological drug reaction. After exposure to heparin, some patients develop heparin dependent antibodies with no evidence of thrombosis, while others are at risk of thrombocytopenia, thrombosis, limb loss, and death. We conducted a retrospective chart review on all patients serologically positive for HIT by HPIA ELISA in a single tertiary-care hospital, to determine whether patients with malignancy had an increased risk of thrombotic complications. Medical records of 55 patients who tested positive for HIT and met clinical criteria for HIT were analyzed. All patients had been treated with unfractionated heparin. Malignancy was diagnosed in 11 patients, either at surgery or post-mortem examination. A higher rate of venous thrombosis and pulmonary embolism was observed in patients with HIT and malignant disease when compared to patients with no underlying malignancy (odds ratio 13.6, 95% CI 2.9-63.8).     

Low-molecular weight heparin for deep vein thrombosis prophylaxis in hospitalized medical patients: results from a cost-effectiveness analysis.

Multiple options exist for the prevention of deep vein thrombosis (DVT) in medical inpatients. We sought to determine the cost-effectiveness of low-molecular-weight heparin (LMWH) relative to unfractionated heparin (UFH) for DVT prevention in this setting. We conducted a cost-effectiveness analysis from the perspective of a third-party payer employing a decision model and literature-based estimates for inputs. In the base-case analysis, LMWH had little impact on the rate of DVT. Despite higher acquisition costs, however, LMWHs resulted in net savings. Routine use of LMWH saves approximately US$89 per patient. The lower rate of heparin-induced thrombocytopenia (HIT) with LMWH accounted for this differential. Univariate sensitivity analysis revealed the model was moderately sensitive to the odds ratio of HIT with LMWH and the cost of HIT. Multivariate sensitivity analysis confirmed the LMWH approach dominated financially. 'Worst-case' scenario modeling, where LMWH actually increased the risk for DVT, had little effect on the rate of HIT, and was substantially more costly than UFH, still demonstrated that LMWHs were economically superior. Monte-Carlo simulation indicated the 95% confidence interval around the estimate for savings with LMWH ranged from US$7 to US$373. We conclude that, despite their higher cost, LMWHs for thromboprophylaxis in medical patients result in savings.     

Incidence and clinical relevance of heparin-induced antibodies in patients with deep vein thrombosis treated with unfractionated or low-molecular-weight heparin

The frequency of heparin-induced thrombocytopenia (HIT) varies between different clinical treatment settings and remains unknown for patients treated with unfractionated (UFH) or low-molecular-weight heparin (LMWH) because of deep vein thrombosis. In this multicentre, open-label study, 1137 patients with deep vein thrombosis were randomly assigned to UFH for 5-7 d, reviparin, a LMWH, for 5-7 d (short-treated group) or reviparin for 28 d (long-treated group). Heparin-platelet factor 4 antibodies (HPF4-A) were determined on d 5-7 and d 21. Heparin-induced thrombocytopenia was defined by clinical evaluation. Two patients in the UFH group (incidence: 0.53%, 95% confidence interval (CI): 0.06-1.91) and two patients in the long-treated LMWH group (incidence: 0.53%, 95% CI: 0.06-1.92) had HIT, while no HIT was observed in the short-treated LMWH group. Pulmonary embolism developed in one of the HIT-patients, who had HPF4-A and was treated with UFH. On d 5-7 the incidence of HPF4-A was 9.1% in the UFH group, 2.8% in the short-treated LMWH group and 3.7% in the long-treated LMWH group, with a significant increase to 20.7% in the UFH group and to 7.5% in the long-treated LMWH group on d 21. Therefore the incidence of HPF4-A and heparin-induced thrombocytopenia was lower in patients treated with LMWH compared with UFH for the same duration of treatment.