Pathophysiology Of Heparin-induced Thrombocytopenia Research Articles

How to Solve the Conundrum of Heparin-Induced Thrombocytopenia during Cardiopulmonary Bypass.

Heparin-induced thrombocytopenia (HIT) is a major issue in cardiac surgery requiring cardiopulmonary bypass (CPB). HIT represents a severe adverse drug reaction after heparin administration. It consists of immune-mediated thrombocytopenia paradoxically leading to thrombotic events. Detection of antibodies against platelets factor 4/heparin (anti-PF4/H) and aggregation of platelets in the presence of heparin in functional in vitro tests confirm the diagnosis. Patients suffering from HIT and requiring cardiac surgery are at high risk of lethal complications and present specific challenges. Four distinct phases are described in the usual HIT timeline, and the anticoagulation strategy chosen for CPB depends on the phase in which the patient is categorized. In this sense, we developed an institutional protocol covering each phase. It consisted of the use of a non-heparin anticoagulant such as bivalirudin, or the association of unfractionated heparin (UFH) with a potent antiplatelet drug such as tirofiban or cangrelor. Temporary reduction of anti-PF4 with intravenous immunoglobulins (IvIg) has recently been described as a complementary strategy. In this article, we briefly described the pathophysiology of HIT and focused on the various strategies that can be applied to safely manage CPB in these patients.

Heparin-induced thrombocytopenia: An update for the COVID-19 era.

The increased use of heparin during the current COVID-19 pandemic has highlighted the risk of a rare but potentially serious complicationof heparin therapy, viz. heparin-induced thrombocytopenia (HIT). This is a short review on the pharmacology of heparin and itsderivatives, and the pathophysiology of HIT. Guidance on laboratory testing for and clinical management of HIT is presented in accordancewith international guidelines. There are important similarities and differences between HIT and the new entity of vaccine-induced immune thrombotic thrombocytopenia, also known as thrombosis with thrombocytopenia syndrome, which clinicians need to be aware of.

Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors.

Fcγ receptors have critical roles in the pathophysiology of heparin-induced thrombocytopenia (HIT), a severe immune-mediated complication of heparin treatment. Activation of platelets, monocytes and neutrophils by platelet-activating anti-PF4/heparin IgG antibodies results in thrombocytopenia, hypercoagulability and thrombosis in susceptible patients, effects that depend on FcγRIIA. In addition, FcγRIIIA receptors probably contribute to clearance of platelets sensitised by HIT immune complexes. FcγRI has also been reported to be involved in monocyte activation by HIT IgG antibodies and synthesis of tissue factor. This review focuses on the role of these FcγRs in HIT pathophysiology, including the potential influence of several gene variations associated with variable risk of HIT and related thrombosis. In particular, the 276P and 326Q alleles of CD148, a protein tyrosine phosphatase that regulates FcγRIIA signalling, are associated with a lower risk of HIT, and platelets from healthy donors expressing these alleles are hyporesponsive to anti-PF4/H antibodies. It was also recently demonstrated that the risk of thrombosis is higher in HIT patients expressing the R isoform of the FcγRIIA H131R polymorphism, with HIT antibodies shown to activate RR platelets more efficiently, mainly explained by an inhibitory effect of normal IgG2, which bound to the FcγRIIA 131H isoform more efficiently. Environmental risk factors probably interact with these gene polymorphisms affecting FcγRs, thereby increasing thrombosis risk in HIT.

Redefining transfusion-related acute lung injury: don't throw the baby out with the bathwater.

Recently two articles have been published in TRANSFUSION in which the authors propose to change the current definition on transfusion-related acute lung injury (TRALI). It was proposed to view TRALI from the perspective of detectability versus nondetectability of leukoreactive alloantibodies (Transfusion 2015;55:1128-34). The authors argue that only cases in which leukoreactive alloantibodies can be detected should be defined as "true" TRALI in analogy with the understanding of the pathophysiology of heparin-induced thrombocytopenia. In the other article (Transfusion 2015;55:947-52), the authors propose to redefine possible TRALI to transfused acute respiratory distress syndrome (ARDS) as their study in intensive care unit patients did not show a relation between the number of transfusions and possible TRALI.We discuss these two propositions in light of the current evidence on pathophysiology of TRALI and possible TRALI. We argue that it is too early to redefine TRALI, as 1) factors, such as storage time of platelets, which induce TRALI in preclinical studies, have not yet been properly investigated in humans. Further research is needed on these agents before it is concluded that antibody-mediated TRALI is the only "true" TRALI. 2) In light of the current knowledge, it makes perfect sense that multiple transfusion is not related to possible TRALI: ARDS risk factors in these patients result in a very sensitive equilibrium in which even only one transfusion induces TRALI. Excluding possible TRALI from the TRALI definition would result in further underrecognition of TRALI induced by alloantibodies and interferes with exclusion of donors related to TRALI cases and thus TRALI prevention.

Syk Is Regulated Downstream Of FcγRIIA In Platelets By Transient Tyrosine Phosphorylation and Ubiquitylation

Platelet FcγRIIA contributes to the pathophysiology of heparin-induced thrombocytopenia (HIT) and other immune-mediated thrombocytopenia and thrombosis syndromes. Activation of FcγRIIA results in tyrosine phosphorylation of Syk in human platelets, but little is known about ubiquitylation of Syk. Protein ubiquitylation has been shown to regulate physiological and pathological cellular processes by regulating signaling networks. In the Platelet RNA and Expression-1 (PRAX1) study, we studied platelets from 154 healthy subjects and identified increased expression of mRNAs encoding proteins involved in ubiquitylation in platelets that were highly reactive to FcγRIIA stimulation. Previously, we (CD, SPK) reported that platelet stimulation via GPVI/FcRγ results in transient Syk phosphorylation and ubiquitylation, involving c-cbl and TULA-2. Briefly, c-Cbl acts as an E3 ligase transferring ubiquitin to the lysine residue of the target protein in the ubiquitylation reaction and TULA-2 is a dephosphorylating enzyme that removes phosphate group from ubiquitinated syk. In this study, we investigated Syk tyrosine phosphorylation and ubiquitylation downstream of platelet FcγRIIA engagement. FcγRIIA on washed human platelets was activated by cross-linking with IV.3 antibody (10ug/ml) and goat anti-mouse antibody (GAM) (30ug/ml). At specific time intervals following activation, platelets were lysed and the lysates were immunoblotted for total Syk and for pY525/526 phospho-Syk. We observed phosphorylation and ubiquitylation of Syk within 15 sec, and peaking within 1 to 3 min. The MW of the Syk species was consistent with 1 to 3 ubiquitin (Ub) moieties per Syk molecule. Alternatively, platelet FcγRIIA was activated via anti-CD9; Ub-Syk was observed at 15 sec, while ubiqutinated and phosphorylated Syk was observed at 2 min. Additional ubiquitinated bands appeared by 2 min; all diminished after 5 min. To understand if the ubiquitinated Syk was degraded by the proteasomal system, human platelets were pre-treated with proteasomal inhibitors (MG132 or Epoxomicin) followed by activation of FcγRIIA. There was no accumulation of Ub-Syk observed for up to 5 minutes after FcγRIIA stimulation in the presence of proteasomal inhibitors compared to controls, indicating that Ub-Syk is not degraded by the proteasomes and inactivated. Activation of FcγRIIA by cross linking with IV.3/GAM in HEL cells, a cell line model, showed a transient increase in ubiquitylation and phosphorylation of Syk within 15 sec which decreased by 3 min. To understand if activation of Syk by upstream Src-family kinases is necessary for ubiquitylation in this model system, SFK inhibitor (PP2) (10uM) was pre-incubated with HEL cells followed by FcγRIIA activation. Western blot analysis showed elimination of phosphorylated and ubiquitinated Syk upon activation of FcγRIIA in HEL cells in presence of PP2. In contrast, ubiquitylation and phosphorylation of Syk was observed in control cells treated with PP3 or vehicle (DMSO) and as well as in untreated cells. HEL cells were also pretreated with proteasomal inhibitors (MG132 or Epoxomicin) followed by activation of FcγRIIA. There was no accumulation of phosphorylated and ubiquitinated Syk observed for up to 10 min of stimulation of FcγRIIA in HEL cells in presence of proteasomal inhibitors compared to controls indicating no degradation of Ub-syk by proteasomal complex. Finally, we directly compared the ubiquitylation and phosphorylation of Syk in GPVI/FcRγ-stimulated vs.FcγRIIA-stimulated platelets from the same donors. Of note, FcγRIIA-stimulated platelets demonstrated both different kinetics and extent of Syk ubiquitylation than did GPVI/FcRγ-stimulated platelets. In this study, we demonstrated that FcγRIIA signaling results in transient Syk tyrosine phosphorylation and ubiquitylation in platelets and HEL cells. The ubiquitinated Syk is not destined for proteasomal degradation. Limited ubiquitylation of proteins has been noted to modulate downstream signaling events and protein-protein interactions. Further studies are needed to decipher the molecular partners of ubiquitinated Syk following FcγRIIA activation, and to elucidate the differences between GPVI/FcRγ and FcγRIIA signaling via Syk. Disclosures: No relevant conflicts of interest to declare.

Heparin-Induced Thrombocytopenia in Cardiovascular Patients

Heparin-induced thrombocytopenia is a life-threatening immune-mediated platelet activation condition that can cause arterial and venous thromboembolism. The triggering complex, platelet factor 4/heparin antibody, has several unique immunologic characteristics that have not been well elucidated until recently. In patients undergoing cardiovascular procedures such as percutaneous coronary intervention and coronary artery bypass graft surgery, the prevalence of platelet factor 4/heparin antibody is significantly higher than that in the general population. The acuity and graveness of the thromboembolic phenomenon requires early diagnosis and empirical initiation of treatment, even before confirmatory test results are available. Also, although multiple therapeutic modalities exist, the safety and efficacy of each option depends upon the clinical setting. Therefore, this review will focus on the updated pathophysiology of heparin-induced thrombocytopenia, new diagnostic criteria, and the various treatment options for cardiovascular patients with different conditions.

Heparin-Induced Thrombocytopenia

Unfractionated heparin is widely used for numerous clinical situations. A well-known adverse effect of heparin exposure is thrombocytopenia. Heparin-induced thrombocytopenia is a clinicopathologic syndrome that can be associated with severe complications and significant mortality. The pathophysiology of heparin-induced thrombocytopenia includes an immune-mediated reaction to heparin that activates platelets and results in an acquired hypercoagulability. Diagnosis of heparin-induced thrombocytopenia should incorporate clinical signs and symptoms and laboratory testing for heparin-induced thrombocytopenia antibodies. Therapy should include discontinuation of heparin, initiation of a direct thrombin inhibitor, and eventually therapy with warfarin (only after the platelet count is at least 100 x 10(9)/L).

Endothelial cell damage in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia type II is a severe complication of heparin treatment that may result in thrombosis. When thrombosis occurs it carries a 50% mortality rate. The exact pathophysiology is not fully understood but in the majority of cases it is associated with the production of heparin/platelet factor 4 antibodies. The endothelium provides a protective anticoagulant surface over which blood flows. Perturbation of the endothelial cells causes a reversal of the anticoagulant properties of the cells to that of a procoagulant surface. This is often due to release or down-regulation of the anticoagulant membrane proteins such as thrombomodulin and up-regulation of procoagulant factors such as tissue factor. We studied 10 patients in our cardiothoracic institute with clinically and laboratory-confirmed heparin-induced thrombocytopenia type II for evidence of endothelial cell damage. There was a statistically significant rise in the concentrations of von Willebrand factor (P < 0.0001) and soluble thrombomodulin (P = 0.004) when patients with heparin-induced thrombocytopenia type II were compared with healthy laboratory controls and patients having had cardiopulmonary bypass surgery (von Willebrand factor 324 versus 103 versus 108 U/dl and soluble thrombomodulin 9.5 versus 2.3 versus 1.2 ng/ml, respectively). Our findings suggest that endothelial cell damage is a major factor in the pathophysiology of heparin-induced thrombocytopenia.

Novel Single Agents with Combined Anti-Coagulant and Anti-Platelet Activities: Potential Treatment Option for the Management of HIT.

A recently introduced series of antithrombotic agents brings the novel characteristic of dual anti-coagulant and anti-platelet actions in one molecule. These low molecular weight, synthetic, serine protease inhibitors, depending on structural modifications, have variable ratios of both anti-thrombin and anti-platelet activities. Studies have shown that these agents produce stronger antithrombotic actions relative to single targeted therapeutic agents (O. Iqbal #P0521 and D. Hoppensteadt #OR335, ISTH meeting Sydney, Australia August 2005). Heparin-induced thrombocytopenia (HIT) is an adverse effect of heparin in which both thrombin generation and platelet activation augment hypercoagulable and inflammatory states leading to a high probability of developing severe thrombosis. Current guidelines for patients who have HIT recommend the use of a direct thrombin inhibitor (DTI) to prevent or treat associated thrombosis. Clinical trial data, as well as practice outcomes, show that DTI treatment alone is not sufficient to overcome the pathology and resultant thrombosis in all HIT patients. Thus, more optimal treatment options are needed. A focus of treatment on inhibiting both platelet and coagulation activation is logical based on the pathophysiology of HIT. This study was undertaken to determine if the novel CanAm series of agents may have a role in the management of patients with HIT. Eight agents (MC45301, MC45308, CA207, CA216, CA234, CA247, CA250, CA254) with varying ratios of anticoagulant/anti-platelet activities were studied using the 14C-serotonin release assay (SRA) and flow cytometry for the detection of platelet P-selectin expression and platelet microparticle generation. The DTI argatroban, the FXa inhibitor fondaparinux, and the platelet GPIIb/IIIa receptor antagonist eptifibatide were included for comparison. Both cross-reactivity to HIT antibodies and amelioration of HIT antibody-induced platelet activation were assessed. In the absence of heparin, at 1-100 μg/ml none of the CanAm agents caused platelet activation in the presence of serum from patients with HIT (n=12) ruling out cross-reactivity with HIT antibodies. None of the comparator drugs showed cross reactivity with HIT antibodies. In the presence of heparin (0.1 U/ml) and serum from patients with HIT (n=12), the CanAm agents were able to inhibit all platelet activation responses at concentrations of 10–100 μg/ml. In comparison, the DTI and FXa inhibitor were not able to inhibit the HIT antibody/heparin induced platelet activation with any HIT serum. The GPIIb/IIIa inhibitor, however, showed a concentration-dependent inhibition of the platelet activities with complete blockade at 1 μg/ml, suggesting the importance of platelet activation inhibition for the treatment of HIT. Thus, compared to mono-therapeutic agents such as DTIs and fondaparinux, the dual-acting CanAm agents not only lack cross reactivity with HIT antibodies, but they have the added ability to block the antibody-induced platelet activation that occurs during an acute episode of HIT. A dual-acting anticoagulant/anti-platelet drug may, therefore, be of more value than single targeted anti-thrombin drugs for the management of HIT and associated thrombosis.

The Pathophysiology of Heparin-Induced Thrombocytopenia: Biological Basis for Treatment

Heparin was discovered > 80 years ago, 1 Howell WH Holt E Two new factors in blood coagulation: heparin and pro-antithrombin. Am J Physiol. 1918; 47: 328-341 Crossref Google Scholar and within a short interval it was used as an anticoagulant. 2 Crafoord C Preliminary report on post-operative treatment with heparin as a preventive of thrombosis. Acta Chir Scand. 1936; 53: 407-426 Google Scholar Heparin has advantages that led to its widespread use, including its immediate onset of action, its relatively short half-life (3 h), and its ability to be reversed using protamine.

Differential prevalence of anti-heparin-PF4 immunoglobulin subtypes in patients treated with clivarin and heparin: implications in the HIT pathogenesis.

Heparin-induced thrombocytopenia (HIT) syndrome is a catastrophic complication of heparin therapy that may result in arterial/venous thromboembolic events. The pathophysiology of HIT is mediated by the generation of a functionally and molecularly heterogeneous group of anti-heparin-platelet factor 4 (AHPF4) antibodies that cause platelet/endothelial cell activation/destruction. These AHPF4 antibodies may be of various subtypes and cause differential pathogenic responses during HIT. This study evaluated the differential prevalence and functionality of AHPF4 Ig subtypes (IgA, IgG, and IgM) in plasma samples obtained from clinically suspected HIT patients (n = 111) and two clinical trials. In these trials, a low-molecular-weight heparin, clivarin and unfractionated heparin (UFH) were used to treat deep-vein thrombosis (CORTES) and for prophylaxis of the orthopedic surgery (ECHOS). In the CORTES study, three randomized groups of patients (n = 312-328) received prophylactic treatment with either UFH or clivarin (o.d. or b.i.d.). In the ECHOS study, there were approximately 600 patients per group. Citrated plasma samples were analyzed for cumulative IgA/IgG/IgM and individual Ig subtypes of AHPF4 utilizing ELISA. Functionality of the ELISA-positive samples was ascertained by 14C-serotonin release assay. In clinically confirmed HIT patients (and UFH-treated CORTES and ECHOS samples), the Ig subtyping revealed a predominance of IgG AHPF4 antibodies in contrast to the asymptomatic high AHPF4 antibody titers, which were found to be mostly IgM and/or IgA subtypes. In the clivarin-treated patients in both trials, the prevalence of AHPF4 antibodies was found to be lower (2-3 fold, p < 0.01) in comparison to UFH group. In addition, the clivarin-treated patients with positive AHPF4 antibodies were found to be predominantly of the non-functional type and were found in the order of IgM > IgA > IgG Together, these observations demonstrate that ELISA-detectable IgG subtype in UFH-treated patients may be more likely to cause functional/pathologic responses during HIT syndrome. Thus, determination of IgG subtype of AHPF4 antibodies during HIT syndrome may be crucial in the diagnosis; however, the relevance of the pathologically non-functional (IgA and/or IgM) antibodies and the overall mechanism(s) of these HIT-associatied antibodies need further investigation.

Newer insights on the mechanism of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) type II is a complex clinical syndrome. It is an immune reaction to heparin in which the formation of antibodies targeted against the heparin-platelet factor 4 complex results in platelet activation. Platelet activation plays a central role in HIT; however, platelet activation does not occur as an isolated physiologic response. To elucidate further the mechanism of thrombogenesis in HIT, we undertook studies to determine the effect of heparin antibodies on endothelial cells, leukocytes, and the inflammatory state. We summarize our previous and new findings. For endothelial cells: Antiheparin antibodies bind to and directly activate microvascular endothelial cells, whereas binding to and activating macrovascular endothelial cells requires preactivation by platelets or tumor necrosis factor alpha (TNFalpha). Increased circulating levels of hemostatic activation factors as observed with thrombosis, particularly soluble P-selectin, plasminogen activator inhibitor type 1 (PAI-1), tissue factor, and thrombomodulin, were associated with endothelial cell activation and were also found in the blood circulation of patients with HIT. For the inflammatory state: Neutrophils and monocytes (but not lymphocytes) bind to and form complexes with platelets in the presence of HIT antibodies. Activated monocytes bind to endothelial cells and produce a procoagulant state. Patients with HIT have an increased level of cytokines in their blood circulation. For HIT antibodies: Only heparin fractions larger than 5 kd interacted with HIT antibodies, explaining why low-molecular-weight heparin (LMWH) usually does not generate antibodies. HIT antibodies are heterogeneous in structure, affinity, and specificity. These data suggest that, in addition to the platelet component, several other mechanisms are associated with the pathophysiology of HIT. These include an inflammatory state, endothelial cell remodeling, and the known procoagulant state. Differences between patients in the levels of the inflammatory markers may relate to various stages of the inflammatory/procoagulant state that exists in patients with HIT. The variations within the HIT antibodies may influence their ability to activate platelets, endothelial cells, and leukocytes, and thus contribute further to the variations in the pathogenicity of HIT.

Benefit-risk assessment of treatments for heparin-induced thrombocytopenia.

Patients with heparin-induced thrombocytopenia (HIT) are at high risk of thrombosis and should be treated with alternative anticoagulant therapy to reduce complications. The current treatment of choice is one of the approved direct thrombin inhibitors, argatroban or lepirudin. These drugs have been proven to be safe and effective in multicentre clinical trials where dosage regimens have been established for prophylaxis and treatment of thrombosis. Argatroban has also been tested and approved for use in invasive cardiology procedures in the HIT patient. Dosage regimens for other clinical uses, such as cardiac surgery, have not yet been established for either drug. The safety and effectiveness of the thrombin inhibitors is dependent on their use according to established guidelines. Other treatment options that may be effective for the patient with HIT include dextran, plasmapheresis, intravenous gammaglobulin and aspirin (acetylsalicylic acid). Although used historically, these options have not been tested in rigorous clinical trials. For life- and limb-threatening thrombosis, thrombolytic agents and/or surgery may provide benefit. Because the risk of bleeding is high from these procedures, they should be performed only by an experienced practitioner. Several studies have shown that patients with HIT requiring continued anticoagulation are best managed with a warfarin derivative initiated while under full anticoagulation with a thrombin inhibitor. There is a risk of skin necrosis and bleeding if guidelines for dose administration and monitoring of warfarin are not followed. Subsequent use of heparin or a low molecular weight heparin after resolution of the clinical episode of HIT can be hazardous, particularly within the first 3 months. If laboratory testing is negative, heparin may be cautiously reinstituted for short-term use (1-2 hours) with monitoring for platelet count decrease and thromboembolism. The pregnant patient with HIT requiring anticoagulation represents a particular challenge, where there is no drug of choice at present. Although today there are realistic treatment options for the patient with HIT, the morbidity and mortality associated with this disease have not been eliminated. Awareness and early treatment of HIT remain important components of the clinical care for patients exposed to heparins. Future therapeutic developments based on a better understanding of the pathophysiology of HIT may further improve clinical outcomes. Despite some limitations, the current treatment options for patients with HIT provide unparalleled benefit compared with the treatment options available only a few years ago.

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 FcγRIIA 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=7500 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.

Heparin-induced thrombocytopenia: an overview

Heparin-induced thrombocytopenia (HIT) is the most important immunological drug reaction that patients face today. HIT typically develops in patients 5 days after starting heparin therapy, but can occur sooner with recent heparin exposure or rarely have a delayed onset. The platelet count typically drops below 150×109/L (average 60×109/L), and patients may experience a thrombotic episode simultaneously or shortly after the onset of thrombocytopenia. The thrombocytopenia and the associated thrombotic episodes are now considered to be overlapping outcomes of the same syndrome. The pathophysiology of HIT has been characterized: immune complexes of IgG and heparin in association with a small platelet peptide, platelet factor 4 (PF4), activate platelets by binding to the Fc receptors (FcR) and releasing procoagulant-active, platelet-derived microparticles. The recognition that HIT is characterized by intense thrombin generation dictates the use of antithrombin agents in HIT therapy. Therapeutic approaches that are currently prevalent in the management of HIT will be discussed.

Anticoagulation for acute coronary syndromes and percutaneous coronary intervention in patients with heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is not uncommon in clinical practice, and may go unrecognized in a substantial number of patients. The pathophysiology of HIT has only recently been better understood. Patients with HIT may require anticoagulation for thrombotic complications that result in severe morbidity and mortality. These patients may also require anticoagulation for acute coronary syndromes (ACS), or during percutaneous coronary interventions (PCIs). The direct thrombin inhibitors are currently the anticoagulant of choice in HIT patients with ACS or those undergoing PCI, based on data from several large clinical trials in ACS and PCI populations, and data from smaller experiences, specifically in patients with HIT.

Pathophysiology of heparin-induced thrombocytopenia. Clinical and diagnostic implications--a review.

This review of heparin-induced thrombocytopenia (HIT), the most frequent and dangerous side effect of heparin exposure, covers the epidemiology, pathophysiology, clinical presentation, diagnosis, and treatment of this disease syndrome. Current consensus of opinion is given based on literature reports, as well as new information where available. A comprehensive analysis of the reasons for discrepancies in incidence numbers is given. The currently known mechanism is that HIT is mediated by an antibody to the complex of heparin->platelet factor 4, which binds to the Fc receptor on platelets. New evidence suggests a functional heterogeneity in the anti-heparin-platelet factor 4 antibodies generated to heparin, and a "superactive" heparin-platelet factor 4 antibody that does not require the presence of heparin to promote platelet activation or aggregation has been identified. Up-regulation of cell adhesion molecules and inflammatory markers, as well as preactivation of platelets/endothelial cells/leukocytes, are also considered to be related to the pathophysiology of HIT. Issues related to the specificity of currently available and new laboratory assays that support a clinical diagnosis are addressed in relation to the serotonin-release assay. Past experience with various anticoagulant treatments is reviewed with a focus on the recent successes of thrombin inhibitors and platelet GPIIb/IIIa inhibitors to combat the platelet activation and severe thrombotic episodes associated with HIT. The pathophysiology of HIT is multifactorial. However, the primary factor in the mediation of the cellular activation is due to the generation of an antibody to the heparin-platelet factor 4 complex. This review is written as a reference for HIT research.

Heparin-Induced Thrombocytopenia: Laboratory Studies

This report describes studies into the pathophysiology of heparin-induced thrombocytopenia. The IgG fraction from each of nine patients with heparin-induced thrombocytopenia caused heparin-dependent platelet release of radiolabeled serotonin. Both the Fc and the Fab portions of the IgG molecule were required for the platelet reactivity. The platelet release reaction could be inhibited by the Fc portion of normal human or goat IgG, and patient F(ab')2, but not F(ab')2 from healthy controls. These results suggested that the Fab portion of IgG binds to heparin forming an immune complex and the immune complexes initiate the platelet release reaction by binding to the platelet Fc receptors. To directly challenge this hypothesis, we preincubated the serotonin-labeled platelets with the monoclonal antibody against the platelet Fc receptor (IV.3). This monoclonal antibody completely inhibited the release reaction caused by heparin and patient sera, as well as heat aggregated IgG, but did not block collagen or thrombin-induced platelet release. Heparin-dependent platelet release also could be inhibited in vitro by the addition of monocytes and neutrophils, but not by red cells, presumably because the Fc receptors on the phagocytic cells have a higher binding affinity for IgG complexes than do platelets. Platelets from patients with congenital deficiencies of specific glycoproteins Ib and IX (Bernard-Soulier syndrome) and IIb and IIIa (Glanzmann's thrombasthenia) displayed normal heparin-dependent release indicating that the release reaction did not require the participation of these glycoproteins. These studies indicate that heparin-induced thrombocytopenia is an IgG-heparin immune complex disorder involving both the Fab and Fc portion of the IgG molecule.