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.     

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.     

New Concepts in Heparin-Induced Thrombocytopenia: Diagnosis and Management

Heparin-induced thrombocytopenia (HIT) is a clinicopathologic condition and adverse drug reaction caused by immunoglobulin G (IgG) antibodies directed against the heparin-platelet factor 4 complex. In most patients, the onset of thrombocytopenia begins while the patient is receiving heparin. In less than 5% of patients, the onset of thrombocytopenia begins several days following heparin discontinuation and has been termed “delayed-onset” HIT. This review summarizes the presentation and clinical course of published reports of delayed-onset HIT occurring in 30 patients. The diagnosis of delayed-onset HIT should be considered in all patients presenting with venous thromboembolism (VTE) and all patients with recent heparin exposure (within the past 14 days) who present with a low platelet count. Most patients with HIT are treated with direct thrombin inhibitors and transitioned to warfarin oral anticoagulation. Administration of direct thrombin inhibitors requires close monitoring for bleeding, dose adjustments based upon coagulation monitoring and is costly. Fondaparinux, a synthetic pentasaccharide and indirect-acting factor-Xa inhibitor, has little to no cross-reactivity with the heparin-platelet factor 4 antibody in in vitro testing. This review summarizes dosing, monitoring and outcomes of preliminary reports of fondaparinux successfully administered to 13 patients with subacute HIT and 22 patients with acute HIT. While several reports have described the treatment and prophylaxis of thrombosis in patients with HIT using fondaparinux, clinical trials should be conducted and reported before fondaparinux becomes a therapy of choice for HIT.     

Have You Been HIT?

This review is specifically designed to aid the vascular surgeon in the management of heparin-induced thrombocytopenia (HIT). Heparin-induced thrombocytopenia is a rare complication of heparin administration, which poses significant morbidity and mortality. Its onset is usually 5 to 10 days after the heparin administration and should be suspected if platelet counts drop by at least 50%. Confirmation is given by the presence of HIT antibodies on an enzyme-linked immunosorbent assay (ELISA) or in functional platelet activation assays. The major complication is thrombosis and surprisingly bleeding is rare. Heparin must be stopped immediately if there is a clinical suspicion of HIT and alternative anticoagulation must be started. Anticoagulation is required for at least 2 to 3 months to prevent recurrence of thrombosis. Oral anticoagulation with warfarin should not be initiated until the platelet count has been recovered and there should be an overlap of at least 5 days between starting warfarin and stopping the alternative anticoagulant.     

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.     

Heparin induced thrombocytopenia

This article describes the pathogenesis, diagnostics, treatment and prevention of heparin induced thrombocytopenia (HIT). Although HIT is considered to be a hematological diagnosis, every physician who treats patients with heparin can encounter it in daily practice. It is even more probable that surgeons of any specialisation will meet with HIT patients. A section of them elude diagnostic detection. There are two forms of HIT - HIT I and HIT II. HIT I is caused by a direct pro-aggregation effect of heparin. It has no clinic significance. HIT II is an antidote mediated adverse reaction to heparin. Antidotes will generate only after the exposure to heparin. They are targeted against the platelet factor 4 and they act only at the presence of heparin. They may lead to the aggregation of thrombocytes in the vascular system (there is a decrease in thrombocyte count). This event can be accompanied by a development of venous or arterial thrombosis that can have a rapid and even fatal course. This fact clarifies the importance of HIT II diagnostics. Diagnosis of HIT II is based on recognizing of the typical decrease in thrombocyte count usually 1 day after heparin administration is initiated. Clinical manifestations are more likely in patients with already damaged endothelium. If thrombocyte count decrease is not connected with clinical manifestations, it is the so called isolated HIT II and in patients who display the signs of thrombosis, it is HIT II associated with thrombosis. The goal of this article is apart from implementing the recommendations of the 7th conference of the American Respiratory Society in real life also the exploration of the diagnostic and therapeutic limits (availability) in the Czech Republic.     

Risk of heparin-induced thrombocytopenia in patients receiving thromboprophylaxis

Heparin-induced thrombocytopenia (HIT) is a clinicopathological syndrome associated with heparin therapy that is characterized by a decrease in platelet counts and/or the development of a new thrombosis. Two types of HIT exist, type I is nonimmune and self-resolves, whereas type II is immune-mediated and clinically important. The formation of antibodies against the platelet factor 4-heparin complexes results in platelet activation and thrombin formation, which lead to an increased risk of thrombosis. Unfractionated heparin is associated with a higher risk of HIT than low-molecular-weight heparins. Surgical patients, particularly those undergoing orthopedic or cardiac surgery, are at higher risk of HIT than medical patients. Treatment of HIT involves heparin cessation together with anticoagulation with direct thrombin inhibitors or indirect factor Xa inhibitors.     

Cerebral venous thrombosis due to essential thrombocythemia and worsened by heparin-induced thrombocytopenia and thrombosis

This case describes the medical history of a 61-year-old woman treated for cerebral venous thrombosis (CVT) leading to diagnosis of essential thrombocythemia (ET). During treatment with unfractionated heparin, after initial improvement of clinical state, signs of cerebral hypertension reappeared. Although the platelet count decreased, heparin-induced thrombocytopenia (HIT) was only suspected 2 days later when it dropped below the standard 150?×?10⁹?L^?1 threshold. HIT diagnosis was confirmed by the presence of anti-PF4/heparin IgG. This late finding was the cause of the extension of CVT with worsening of cerebral hypertension necessitating decompressive craniectomy. Elevated basal platelet count due to ET can delay diagnosis and treatment of HIT. In this case, physicians should be more attentive to platelet count variations rather than thrombocytopenia threshold.     

Pathogenicity of IgA and/or IgM antibodies to heparin–PF4 complexes in patients with heparin-induced thrombocytopenia

Antibodies to heparin–PF4 (H-PF4) complexes have been tested and isotyped in 38 patients who developed severe heparin-induced thrombocytopenia (type II HIT). All the patients had a platelet count < 120 × 10⁹/l or a reduction of >30% of the initial value, occurring at least 5 d after the onset of heparin. Thrombocytopenia, which rapidly reversed following the withdrawal of heparin, was associated with thrombosis in nine patients. Although IgG isotypes were found in most cases (n = 26), the presence of only IgM and/or IgA was observed in 12 patients, including three cases showing a thrombotic complication. Our results indicate that type II HIT may be induced by IgA and/or IgM anti-H-PF4 antibodies even in the absence of IgG isotypes. This finding demonstrates that platelet Fc receptors (FcγRII) are not necessarily involved in the pathogenicity of heparin-dependent antibodies and emphasizes the major role of platelet PF4 receptors. The increased expression of the latter following a slight activation by thrombin, and the subsequent binding of IgM and IgA antibodies to H-PF4 on the platelet surface, may directly trigger platelet activation, aggregation and thrombosis. Alternatively, thrombocytopenia could be indirectly induced through the mediation of neutrophils, monocytes and lymphocytes which expose receptors for IgA (FcαR) or IgM (FcμR). IgM–platelet complexes may also bind and activate complement, leading to platelet activation or destruction. Moreover, the reactivity of the antibodies with glycosaminoglycans–PF4 complexes present on the endothelial surface could also induce endothelial lesions and promote procoagulant activity and predisposition to thrombosis.     

An overview of the heparin-induced thrombocytopenia syndrome

Heparin-induced thrombocytopenia (HIT) is caused by heparin-dependent, platelet-activating IgG antibodies that increase thrombin generation in vivo, producing a prothrombotic phenotype. In addition to platelet activation, there is in vitro evidence that activation of endothelium and monocytes occurs, perhaps directly by HIT antibodies, but more likely through activated platelet (or microparticle)-endothelial-leukocyte interactions. Patients with cardiac disease receiving heparin present important diagnostic and therapeutic issues when unexpected thrombocytopenia arises. Concomitant vascular disease burden and intravascular catheter use further increase risk of HIT-associated arterial thrombosis in this patient population. Whether arterial thrombosis simply reflects the "hypercoagulability state" of HIT interacting with diseased or injured arteries, or whether arterial "white clots" reflect additional prothrombotic effects of HIT via endothelial and monocyte activation, remains uncertain. Patients with HIT can also develop deep-vein thrombosis, which can progress to limb loss if coumarin (warfarin) leads to severe protein C depletion (coumarin-induced venous limb gangrene). Therapy for patients strongly suspected to have HIT should focus on inhibiting thrombin (or its generation) pharmacologically. Two direct thrombin inhibitors (lepirudin, argatroban) are approved for treating HIT. When using these agents, coumarin anticoagulation should be delayed pending substantial resolution of thrombocytopenia, before cautiously introducing overlapping coumarin therapy.     

Heparin-induced thrombocytopenia in renal insufficiency undergoing dialysis and percutaneous coronary intervention after acute myocardial infarction: A case report

BACKGROUNDHeparin-induced thrombocytopenia (HIT) is a rare complication of heparin therapy, and is characterized by arteriovenous thrombosis and bleeding events. The incidence of HIT after percutaneous coronary intervention (PCI) in patients with myocardial infarction complicated with renal failure is rarely reported.CASE SUMMARYWe report a 73-year-old man with acute myocardial infarction and renal failure who underwent hemodialysis and PCI, and developed a progressive decline in platelets and subcutaneous hemorrhage of both upper limbs after heparin treatment. In addition to a gradual decrease in platelets, the patient’s 4T''s score was 7, and HIT antibody was positive, confirming the diagnosis of HIT.CONCLUSIONPatients receiving heparin combined with antiplatelet therapy should be monitored closely, especially for their platelet count. In the case of thrombo-cytopenia, HIT should be highly suspected. When the diagnosis of HIT is confirmed, timely individualized treatment should be delivered.     

Safety of warfarin anticoagulation in patients with heparin-induced thrombocytopenia

OBJECTIVES: Venous limb gangrene has been reported to occur after high warfarin doses in heparin-induced thrombocytopenia (HIT), and this observation has been used to exclude warfarin management in this condition. The outcome of patients receiving modest doses of warfarin was studied. DESIGN: Retrospective study of 114 consecutive HIT patients who received diagnoses by platelet aggregometry; 51 of the 114 patients received warfarin. SETTING: Tertiary-care medical center. RESULTS: Thirty-five patients received warfarin for non-HIT indications, and 16 received warfarin for heparin-associated thrombosis. Warfarin was given to 23 patients (47%) 2.4 +/- 0.4 days prior to the onset of HIT, in 19 while receiving IV heparin for an overlap of 2.7 +/- 0.4 days. Twenty-eight patients (53%) received warfarin 2.8 +/- 1.0 days after the diagnosis of HIT. Patients received 11 +/- 1 doses of warfarin over 16 +/- 2 days, with a mean daily dose of 3.5 +/- 0.5 and a maximum dose of 9 +/- 0.5 mg. Prothrombin time at discharge was 17.3 +/- 0.4 s with a maximum of 22.8 +/- 0.8. The final international normalized ratio was 2.9 +/- 0. 3, and the maximum was 7.5 +/- 1.4. The minimum therapeutic range was reached in 59% of determinations. When compared to the 63 patients who did not receive warfarin, warfarin patients received more IV heparin (86% vs 41%; p < 0.001), open heart surgery (78% vs 43%; p < 0.001), and had a lower mortality (8% vs 43%; p < 0.001), but had no differences in thrombosis. CONCLUSIONS: Modest doses of warfarin were not associated with a worse outcome in patients with HIT.     

Heparin-induced thrombocytopenia

Thrombocytopenia is a common adverse effect of heparin therapy which may occur with bovine or porcine heparin when it is given either intravenously or subcutaneously. There are two main clinical types: a common, mild thrombocytopenia of early onset, probably due to the platelet proaggregating effect of heparin itself and a severe delayed-onset thrombocytopenia caused by an immune mechanism. Patients with mild thrombocytopenia due to heparin are usually asymptomatic. However, patients with severe thrombocytopenia may develop thromboembolic complications which often result in disastrous sequelae such as limb gangrene necessitating amputation or death. The thromboembolic complications may be attributed to an IgG heparin-dependent platelet antibody which induces thromboxane production and platelet aggregation. The diagnosis of heparin-induced thrombocytopenia is made clinically and may be confirmed by the demonstration of the heparin-dependent antibody in vitro by platelet aggregometry or [14C] serotonin release. In patients with delayed-onset severe thrombocytopenia, heparin should be stopped and warfarin commenced. Antiplatelet drugs and/or dextran may also be added. Recently low molecular weight heparin has been used with some success. Conversely, heparin may be continued in patients with asymptomatic mild thrombocytopenia provided the patients' condition and the platelet counts are closely monitored.     

The management of heparin-induced thrombocytopenia

The Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology has produced a concise practical guideline to highlight the key issues in the management of heparin-induced thrombocytopenia (HIT) for the practicing physician in the UK. The guideline is evidence-based and levels of evidence are included in the body of the article. All patients who are to receive heparin of any sort should have a platelet count on the day of starting treatment. For patients who have been exposed to heparin in the last 100 d, a baseline platelet count and a platelet count 24 h after starting heparin should be obtained. For all patients receiving unfractionated heparin (UFH), alternate day platelet counts should be performed from days 4 to 14. For surgical and medical patients receiving low-molecular-weight heparin (LMWH) platelet counts should be performed every 2-4 d from days 4 to 14. Obstetric patients receiving treatment doses of LMWH should have platelet counts performed every 2-4 d from days 4 to 14. Obstetric patients receiving prophylactic LMWH are at low risk and do not need routine platelet monitoring. If the platelet count falls by 50% or more, or falls below the laboratory normal range and/or the patient develops new thrombosis or skin allergy between days 4 and 14 of heparin administration HIT should be considered and a clinical assessment made. If the pretest probability of HIT is high, heparin should be stopped and an alternative anticoagulant started at full dosage unless there are significant contraindications while laboratory tests are performed. Platelet activation assays using washed platelets have a higher sensitivity than platelet aggregation assays but are technically demanding and their use should be restricted to laboratories experienced in the technique. Non-expert laboratories should use an antigen-based assay of high sensitivity. Only IgG class antibodies need to be measured. Useful information is gained by reporting the actual optical density, inhibition by high concentrations of heparin, and the cut-off value for a positive test rather than simply reporting the test as positive or negative. In making a diagnosis of HIT the clinician's estimate of the pretest probability of HIT together with the type of assay used and its quantitative result (enzyme-linked immunosorbent assay, ELISA, only) should be used to determine the overall probability of HIT. Clinical decisions should be made following consideration of the risks and benefits of treatment with an alternative anticoagulant. For patients with strongly suspected or confirmed HIT, heparin should be stopped and full-dose anticoagulation with an alternative, such as lepirudin or danaparoid, commenced (in the absence of a significant contraindication). Warfarin should not be used until the platelet count has recovered. When introduced in combination with warfarin, an alternative anticoagulant must be continued until the International Normalised Ratio (INR) is therapeutic for two consecutive days. Platelets should not be given for prophylaxis. Lepirudin, at doses adjusted to achieve an activated partial thromboplastin time (APTT) ratio of 1.5-2.5, reduces the risk of reaching the composite endpoint of limb amputation, death or new thrombosis in patients with HIT and HIT with thrombosis (HITT). The risk of major haemorrhage is directly related to the APTT ratio, lepirudin levels and serum creatinine levels. The patient's renal function needs to be taken into careful consideration before treatment with lepirudin is commenced. Severe anaphylaxis occurs rarely in recipients of lepirudin and is more common in previously exposed patients. Danaparoid in a high-dose regimen is equivalent to lepirudin in the treatment of HIT and HITT. Danaparoid at prophylactic doses is not recommended for the treatment of HIT or HITT. Patients with previous HIT who are antibody negative (usually so after >100 d) who require cardiac surgery should receive intraoperative UFH in preference to other anticoagulants that are less validated for this purpose. Pre- and postoperative anticoagulation should be with an anticoagulant other than UFH or LMWH. Patients with recent or active HIT should have the need for surgery reviewed and delayed until the patient is antibody negative if possible. They should then proceed as above. If deemed appropriate early surgery should be carried out with an alternative anticoagulant. We recommend discussion of these complex cases requiring surgery with an experienced centre. The diagnosis must be clearly recorded in the patient's medical record.     

Heparin-induced thrombocytopenia in pediatrics.

As in adult patients, heparin is used for prophylaxis and treatment of thromboembolism in newborns, children, and adolescents. Patients receiving heparin are potentially at risk to develop heparin-induced thrombocytopenia (HIT). HIT type II has been extensively described in the adult population; only a few reports address HIT type II in pediatric patients (total of 15 neonates, 4 young children, 12 older children and adolescents). The available data are discussed, and the case of a patient with recurrent thrombosis and HIT type II without thrombocytopenia is presented. The review of the literature reveals that HIT type II occurs especially in neonates and adolescents, corresponding to the two age peaks of thrombosis in pediatric patients. Risk factors for thrombosis include hereditary factors, immobilization, and surgery. HIT complications are severe and partly lead to life-threatening thromboembolism. In three patients, an increasing heparin demand was found. In five cases, thrombocytopenia was absent. Heparin was replaced mostly by danaparoid sodium; in three patients hirudin was used as an alternative anticoagulant. HIT type II represents a potentially dangerous complication of heparin therapy in pediatric patients and should be taken into consideration whenever heparin is given for prophylactic or therapeutic use in newborns, children, or adolescents.     

Heparin-induced thrombocytopenia

Opinion statement Treatment with heparin is associated with two types of thrombocytopenia. The most worrisome of these is the immune-mediated heparin-induced thrombocytopenia (HIT type II). Suspicion of HIT type II mandates immediate cessation of heparin adminis-tration and consideration of an alternative anticoagulation therapy. Hirudin and argatroban are approved alternative anticoagulants with no cross-reactivity with the HIT antibody. HIT type II is a clinicopathologic syndrome, and therefore diagnosis requires clinical and laboratory confirmation. The laboratory evaluation for HIT type II should also determine whether or not there is HIT-antibody cross-reactivity with danaparoid and low molecular weight heparin. Patients with HIT type II who require coronary artery bypass graft surgery present a particularly difficult situation, as there is no ideal alternative to heparin anticoagulation.     

Lethal heparin-associated pulmonary embolism--case reports

Thrombocytopenia is a known adverse reaction occurring in some patients receiving heparin. Two different types of heparin-induced thrombocytopenia have been described. Heparin-induced thrombocytopenia type I is a mild thrombocytopenia after 1 to 4 days of heparin therapy, attributed to a direct interaction between heparin and circulating platelets. No specific treatment is necessary. Heparin-induced thrombocytopenia type II is a severe thrombocytopenia mediated by an immunologic mechanism. Type II generally develops after 5 to 10 days of heparin therapy and can be associated with potentially devastating thromboembolic complications. The incidence of heparin-induced thrombocytopenia type II is below 3%. Thromboembolic events are always accompanied by a decrease in the platelet count, however, complications in the absence of absolute thrombocytopenia have been reported. Diagnosis of HIT type II is based on clinical features and laboratory studies for the heparin-dependent platelet antibody. Immediate cessation of heparin administration is essential. Several alternative anticoagulant therapies have been studied and have shown promising results when used for this purpose. Two patients undergoing coronary artery bypass surgery are presented in whom pulmonary embolism developed due to heparin-induced thrombocytopenia type II. In both cases, platelet counts were within the subnormal range at the time of the first thromboembolic complication. The clinical, therapeutic, and prognostic implications are discussed.     

Bilateral lower extremity gangrene requiring amputation associated with heparin-induced thrombocytopenia: a case report

Heparin is a common cause of thrombocytopenia in hospitalized patients. Between 10% and 15% of patients receiving therapeutic doses of heparin develop thrombocytopenia. Heparin-induced thrombocytopenia (HIT) can cause severe bleeding and thrombosis owing to intravascular platelet aggregation. HIT must be distinguished from other causes of thrombocytopenia. Importantly, heparin use is often associated with an early fall in the platelet count that usually occurs within the first 4 days of initiation and recovers without cessation of heparin treatment. This nonimmune heparin-associated thrombocytopenia has not been found to be associated with thrombosis and does not necessitate discontinuation of heparin. The authors present a case report of a 70-year-old man who received heparin therapy following aortic tissue valve replacement and aortic root repair with graft and developed bilateral lower extremity arterial clots 6 days postoperatively in the setting of positive heparin antibody titers. Ultimately the patient required bilateral above-knee amputations.     

The approach to heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) bound to heparin. HIT is an intense hypercoagulability state (increased thrombin generation in vivo) that is complicated more often by venous thromboembolism (deep vein thrombosis, pulmonary embolism) than by arterial thrombosis. HIT is a risk factor for coumarin-induced microthrombosis, particularly affecting acral regions of limbs with deep vein thrombosis (venous limb gangrene). Coumarins (e.g., warfarin) are therefore contraindicated during the acute (thrombocytopenic) phase of HIT. Venous thromboembolism can occur early during an episode of HIT, sometimes even before HIT-associated platelet count declines become clear. Recognition of HIT may be facilitated through the use of a clinical scoring system, the 4Ts ( Thrombocytopenia, Thrombosis, Timing, and o Ther explanations). Anti-PF4/polyanion enzyme-immunoassays (EIAs) and washed platelet activation assays readily detect HIT antibodies, and thus have high diagnostic sensitivity; however, only the platelet activation assays have high diagnostic specificity, suggesting that HIT is likely to be overdiagnosed in settings where EIAs are used exclusively for diagnosis. Treatment of HIT emphasizes substitution of heparin with an alternative nonheparin anticoagulant, such as a direct thrombin inhibitor (lepirudin, argatroban), or an indirect (antithrombin-mediated) inhibitor of factor Xa (danaparoid, fondaparinux?).     

Frequency of anti-heparin-platelet factor 4 antibodies in hemodialysis patients and correlation with recurrent vascular access thrombosis

Heparin-induced thrombocytopenia (HIT), characterized by the formation of antibodies to a complex of platelet factor 4 (PF4) and heparin, is a well-recognized risk factor for thromboembolic complications. The frequency of antibody development varies among patient populations. Hemodialysis patients have repeated heparin exposure and should be at risk of developing HIT. This might, contribute to the development of vascular access thrombosis. We prospectively evaluated 88 hemodialysis patients for the presence of anti-PF4/heparin antibodies. Eighteen patients (20%) had a prior history of 1 or more prior access thrombosis. One patient (1.14%), without a history of graft thrombosis, tested positive for anti-PF4/heparin antibodies. In our study, the presence of anti-PF4/heparin antibodies was rare and was not increased in patients with a history of vascular access thrombosis.