Recent Advances in Hematology-2 Renu Saxena, HP Pati, VP Choudhry
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Advances in the Diagnosis and Treatment of Heparin-induced Thrombocytopenia1

Sarfraz Ahmad,
Renu Saxena
Keywords• Heparin-induced Thrombocytopenia • Heparin PF4 Antibodies • Diagnostic Tests • Treatment Options • Direct Thrombin Inhibitors • Patient Management • Thrombusis  
INTRODUCTION
Heparin, a mysterious agent, is one of the most widely used parenteral drugs in modern medicine. Its use in the treatment and prevention of thromboembolic (TE) disorders is well established, with the use of trillions of units worldwide. Beneficial characteristics of heparin therapy include proven efficacy, rapid onset of action, ease of laboratory monitoring, rapid neutralization, and a significantly low cost.1 Despite these attributes, heparin is associated with a few drawbacks, including a potentially life- and limb-threatening syndrome known as heparin-induced thrombocytopenia (HIT). HIT is a serious, immune-related complication of heparin therapy, often resulting in devastating TE outcomes.2-5 HIT is most often associated with exposure to unfractionated heparin (UFH), but it may also occur with low-molecular weight heparins (LMWH); albeit at an approximately 10-fold lower risk.6-8 Advances in the diagnosis and treatment of HIT syndrome in the past few years have led to incremental awareness.
HIT syndrome, also referred to as HIT type II, is caused by antibodies to the complex formed between the heparin (H) and platelet factor 4 (PF4) molecules.9 These HPF4 antibodies activate platelets/endothelial cells (EC) through FcγIIa (CD32) receptors, leading to the release of procoagulant platelet microparticles (PMP), excessive thrombin generation, thrombocytopenia, and a profound hypercoagulable state.10 2 Heparin binds PF4 in relation to the chain length and degree of sulfation, perhaps explaining why UFH is more likely to cause HIT than LMWH. Among individuals exposed to heparin, depending on the patient population, about 7-50 percent develops HPF4 antibodies and about 1-5 percent develops clinical HIT.11 In the US alone, approximately 12 × 106 patients receive heparin annually, translating to approximately 360,000 new HIT cases each year.11
The hallmark symptoms of HIT are a drastic fall in platelet count, i.e. patients with HIT typically experience a 35-50 percent drop in platelet count, often to < 150 × 109/L, usually 5-10 days after starting the heparin therapy.11 HIT may also occur within hours/days of starting heparin in a patient with recent heparin exposure12 or may be delayed for up to 3 weeks in some patients, even until after hospital discharge.13 Isolated HIT (i.e. thrombocytopenia only; without testing positive for HPF4 antibodies with the currently available tests) treated solely by heparin cessation is associated with a 19-52 percent risk of new thrombosis.3 Presumably, some of these HIT-associated antibodies are directed again the heparin complexes formed with other chemokines such as interleukin-8 (IL-8), neutrophil-activating peptide-2 (NAP-2), etc. for which the ELISA tests are yet to be developed. The mortality of HIT with thrombosis treated by heparin cessation is approximately 20-30 percent.3 Other symptoms of HIT may include cutaneous reactions, from a simple allergic reaction to lesions to necrosis.
 
RECENT ADVANCES IN HIT RESEARCH
During the past decade, a reasonably good understanding has been achieved in this area despite some myths and misconceptions about HIT. Due to enormous information that exists in the literature, it will not be possible for us to cover all aspects of HIT research and development in this chapter. However, our aim here is to succinctly update the hematologists and other health care professionals with some of the most recent advances with regards to the diagnostic and treatment options that are available (or under development) for HIT.
 
DIAGNOSIS OF HIT
 
Clinical Features
HIT is a “clinicopathologic” syndrome, whereby (i) the diagnosis is made most confidently when the patient has an episode of thrombocytopenia that cannot otherwise be readily explained, and (ii) together with the presence of HPF4 antibodies that usually give strong positivity using sensitive/specific laboratory assay(s). 3Clinical recognition of HIT is paramount—the diagnosis of HIT is largely based on clinical findings, i.e. typically a falling platelet count with or without arterial/venous thrombosis in patients currently (or recently) exposed to heparin.11 Currently available laboratory tests for the diagnosis of HIT are not “ideal”, i.e. they are not 100 percent sensitive or specific. Although, these laboratory tests do provide subsequent confirmation or exclusion of the diagnosis (of clinically suspected HIT), and should therefore, be performed. To adequately evaluate patients, hematologists and other clinicians should know which tests are locally available to them, understand the predictive value of each test, and weigh the clinical value of test results in light of the pre-test probability of HIT. If at all possible, both immunologic and functional (platelet activating) laboratory tests should be performed to confirm the HIT diagnosis.
The timing of the onset of thrombocytopenia shows three characteristic profiles. The most common, which is observed in up to 70 percent of patients, is referred to as “typical onset HIT”, in which the platelet count begins to fall 5-10 days after starting heparin therapy.12 This characteristic delay reflects the usual short interval for heparin to initiate a humoral immune response. In contrast, the “rapid-onset HIT” is recognized in about 25-30 percent of patients where platelet count falls abruptly within 24 hours of starting heparin therapy. This syndrome result from a previous immunizing exposure to heparin (usually within the past few weeks), and the platelet count falls quickly because the patient already has circulating HIT-associated antibodies when the heparin is re-administered. The third or last syndrome called “delayed-onset HIT”, a rare though often clinically serious, is observed in only < 5 percent of patients and recognized by a fall in the platelet count that begins several days after heparin therapy has been stopped.14 This situation is associated with high titer functional HPF4 antibodies (often referred to as “superactive” class of HPF4 antibodies) that do not require exogenous/ongoing heparin administration to exert their pathogenic effects.5,15,16 While keeping these facts in mind, the clinicians must evaluate the patient for other potential explanations for the thrombocytopenia, such as perioperative hemodilution, sepsis, multiorgan dysfunction syndrome, immune thrombocytopenia caused by other drugs, and post-transfusion purpura, etc.
 
Laboratory Features
4HIT-associated antibody detection is rapidly becoming a standard of care in hematology and cardiology. Two main class of laboratory tests have thus far been categorized, (i) functional, and (ii) immunologic (also referred to as non-functional), each with its own advantages and disadvantages. Importantly, the functional tests (mainly the serotonin release, platelet aggregation, and flow cytometric assays) take advantage of the ability of HPF4 antibodies to activate platelets in the presence of therapeutic amounts of heparin. By virtue of platelet activation response due to HPF4 antibodies, functional assays determine end-points based directly on the pathophysiology of HIT. All these tests require a source of normal donor platelets and are performed with either washed platelets (greatly preferred) or platelet-rich plasma of the donor. The 14C-serotonin release assay (SRA) is the most preferred test among all the functional assays due to its high degree of diagnostic sensitivity and specificity.17,18 Furthermore, in this test, using special buffer conditions and performing the assay in microtiter wells permits the simultaneous examination of numerous reaction conditions, thus maximizing the sensitivity.2
Despite better laboratory diagnostic test results, the major limitations of these functional assays are their labor-intensive, technically demanding nature and associated high cost, and therefore some of the reference laboratories, particularly in developing countries, are unable to afford it. Additionally, freshly prepared normal donor platelets are pre-requisite for each batch of assays, and all potential donors may not give similar reproducible responses on a day-to-day basis. In fact, only about 40 percent of all the potential healthy donors are reactive in the functional tests, and that's why these assays are poorly standardized between the laboratories. Also, these assays are not well suited for testing large volumes of samples, forcing many reference laboratories to rely on immunoassays. To overcome some of these problems/limitations, newer functional tests for HIT diagnosis at near-bedside, such as thromboelastograph (TEG), etc. are currently under development, where donor's fresh whole blood could be utilized to assess the global clotting parameters that may provide rapid and more clinically relevant information about the HPF4 antibody characteristics in a given patient specimen.
The most commonly used tests for the laboratory diagnosis of HIT are solid-phase HPF4 enzyme immunoassays. These immunologic tests directly demonstrate antibody binding to the PF4 and polyanion (e.g. heparin) complex, and therefore, merely confirm the presence of the antibody (telling no account of its ability to cause functional responses). 5 These tests include the ELISA, the particle gel immunoassay (PaGIA), and flow cytometry for antigen binding. Currently, two types of ELISAs are commercially available, which are approved by the US Food and Drug Administration (FDA), and both of which detect the antibodies of the three major Ig classes (i.e. IgA, IgG, and IgM) against PF4 bound either to heparin (Asserachrome HIPA, Diagnostica Stago, France) or polyvinyl sulfonate (GTI, Inc., Brookfield, WI, USA). The Stago assay utilizes recombinant PF4, whereas the GTI obtains the PF4 from outdated platelets. In these assays, positive results are indicated by an optical density (OD) value above the pre-determined threshold. Many laboratories simply report results as positive or negative; however, recent reports suggest that the higher antibody titers (OD values) in a given patient may have more clinical significance towards causing the HIT pathogenesis.19,20 Using these ELISAs, some research laboratories have the option to detect only a specific class of antibodies (e.g. IgG), which increases specificity for clinical HIT by avoiding the detection of IgA and/or IgM subclasses (largely non-pathogenic in HIT context).21,22
Emerging evidence suggests that knowledge of the patient's actual HPF4 antibody titer (OD value) may be helpful in interpreting the test results.20 For a number of years, we observed a close correlation between the degree of serotonin release (in the functional SRA test) and the ELISA OD. In fact, most often high OD values (>1.0) are much more likely to be associated with a positive functional test result. Chilver-Stainer et al19 recently reported that HPF4 antibody titer as measured by commercial ELISAs and other emerging rapid test correlated with the level of circulating thrombin-antithrombin (TAT) complex, indicating an association between higher levels of HPF4 antibodies and thrombin generation. This may well correlate with antibody-mediated platelet activation assays leading to higher clinical probability of HIT. Although ELISA is widely used, it is still relatively expensive, and is not even readily available in many developing countries, including India.
Currently available laboratory tests for HIT diagnosis are classified as relatively high complexity, take many hours to perform, and often provide confirmation of HIT or HITTS (HIT associated with thrombosis syndrome) after the symptoms are seen in a patient. In view of this, there has been a need for an easily performed, rapid test that may help clinicians identify and treat patients at risk for HIT/HITTS.23,24 Of late, a couple of rapid antigen assays for the detection of HIT-associated antibodies has emerged. 6(1) The PaGIA test (DiaMed, Inc., Basel, Switzerland)—currently available only in Australia, Canada, Europe, and New Zealand, etc. - directly and rapidly demonstrate the presence of HPF4 antibodies (turn-around-time only 15-20 min). This test uses colored, high-density polymer beads coated with the HPF4 antigen, and provides a qualitative result (positive or negative). In this PaGIA test, the patient's serum is mixed with a suspension of the antigen-coated beads (microspheres), and the mixture is subsequently introduced to a gel that has pores of a fixed size. HPF4 antibodies (if present) in the test sample bind and cross-link the antigen-coated beads, producing a complex that is physically too large to pass through the gel. Thus, the degree of migration of the pink-colored bead suspension through the gel matrix indicates the presence or absence of HPF4 antibodies. Additionally, these HPF4-coated polymer beads are now being utilized in some laboratories for a simple and relatively rapid flow cytometry assay, where the beads are exposed to patients serum – binding of HPF4 antibodies can be readily detected with fluorescent dye conjugated to human anti-IgG. Preliminary results from our laboratory using flow cytometry technique appear to correlate well with ELISAs (Ahmad S, et al; unpublished observations). (2) The Particle gel Immuno-Filtration Assay (PIFA; Akers Biosciences, Thorofare, NJ, USA), is a qualitative in vitro diagnostic device designed for the detection of antibodies to PF4 complexed to linear polyanoinoc compounds, and perhaps is the most rapid HPF4 test (results often available within 5 minutes or so). In this PIFA test, dyed microparticles coated with purified PF4 derived from platelet-rich plasma provide the visual signal for the assay results. The ability of matrixed or non-matrixed particles to move through a filter medium is the measure of the reactivity/non-reactivity of the test sample. This manual assay is FDA-approved, and is commercially available mainly in North America. It is; however, to be emphasized that both of these rapid tests recommend the use of serum samples as oppose to other tests where both plasma and serum, or possibly other biological fluids are readily used.
Regardless of their turn-around-time or cost-effectiveness, all the antigen (immunologic) tests are considered technically simpler to perform than the functional assays, and off course the ELISA can be readily automated. Antigen tests can be batched and performed in large test volumes, and being commercially available, and perhaps widely standardized between the laboratories.
 
TREATMENT OF HIT
7Recent consensus guidelines recommend that when HIT is suspected, all heparins should be discontinued immediately and alternative anticoagulation should be initiated.3,25 The use of non-heparin anticoagulant in patients with, or at high risk of, HIT may reduce the risk of poor outcome. Although patients with a past history of HIT do not invariably have recurrent HIT upon heparin re-exposure, it is considered prudent to avoid future exposures to heparin, if at all possible, in these “at risk” patients.4,12 Warfarin is not recommended in acute HIT because it is associated with the development of venous limb gangrene.26 The LMWHs are not recommended because they cross-react with HIT antibodies, hence worsening the progression of HIT.25 Although danaparoid sodium, a heparinoid, has been used successfully in the past in HIT patients,27 but a recent report suggest that it can also cross-react with HIT antibodies,28 and currently is unavailable worldwide (e.g. in the US, where there is a strong desire/recommendations underway to make this agent available).
 
Emerging Therapeutic Roles of DTIs in HIT
It is abundantly becoming clearer now that alternative (non-heparin) anticoagulation is necessary to treat HIT, to reduce the risk of HIT in patients at risk of HPF4 antibody formation, and to prevent seroconversion in patients with hematologic and cardiovascular diseases. Currently available alternative anticoagulants include the direct thrombin inhibitors (DTI), namely argatroban (Novastan®, GlaxoSmithKline, Research Triangle Park, NC, USA), bivalirudin or hirulog (Angiomax®, The Medicines Company, Parsippany, NJ, USA), and hirudin (Refludan®, Berlex Laboratories, Inc., Montville, NJ, USA). These DTIs by and large neither cross-react with HIT antibodies nor potentiate HIT pathogenesis. Hirudin and argatroban are indicated for the treatment of HIT, and argatroban is indicated for patients with HIT undergoing percutaneous coronary intervention (PCI). Prospective studies indicate that argatroban29,30 and hirudin31,32 improve the outcomes and reduce TE complications in HIT. It is, however, important to note that among clinical concerns regarding hirudin, it is renally excreted and should therefore be used with extreme caution in renal insufficiency.33 Approximately 50 percent of patients exposed to hirudin form hirudin-binding antibodies that can alter the agent's pharmacokinetics and increase bleeding risk, and anaphylactic deaths are reported.32 Below we are providing with some specific details of the currently available alternative anticoagulants for the prophylaxis/treatment of HIT patients.
8Argatroban is a synthetic DTI derived from L-arginine, which inhibits free and clot-bound thrombin without need of a cofactor and exerts dose-dependent anticoagulant effects that are rapidly active and rapidly reversible (elimination half-life, 39-51 min). Argatroban provides predictable parenteral anticoagulation and is well tolerated with an acceptably low bleeding risk in a variety of clinical settings including HIT, acute ischemic stroke (AIS), PCI, and hemodialysis.34 It exerts anticoagulant effects without the need of a cofactor by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation, activation of factors V, VIII and XIII, and platelet aggregation. The anticoagulant effects of argatroban are monitored routinely using the activated partial thromboplastin time (aPTT) or, at higher levels of anticoagulation, the activated clotting time (ACT).35,36 Argatroban also exerts dose-dependent effects on other clot-based assays, including the prothrombin time (PT)/ international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). As soon as argatroban infusion is initiated, plasma argatroban concentrations and anticoagulant effects begin increased. Steady-state levels of drug and effect are usually attained within 1-3 hours, or sooner if a loading dose is given, and maintained until dose adjustment or infusion cessation. Plasma argatroban increases proportionally with doses up to 40 μg/kg/min and is correlated well with steady-state anticoagulant effects. When the infusion is stopped, drug levels and anticoagulant effects return to pretreatment values in concert.35
Two multicenter, prospective studies (ARG-911 and ARG-915) have demonstrated the efficacy and safety of argatroban therapy in patients having HIT with or without thrombosis.29,30 In each study, patients with HIT (isolated thrombocytopenia) or HIT with thrombosis (HITTS) received IV argatroban starting at 2 mg/kg/min (or lower in the presence of hepatic impairment), adjusted to maintain aPTTs 1.5-3.0 times the baseline value. Treatment was given 5-7 days, on average, using mean argatroban doses of 1.7-2.0 mg/kg/min. Most patients underwent 3 or fewer dosage adjustments over the entire course of their therapy, with the incremental adjustment typically being 0.5 mg/kg/min.37 The primary efficacy endpoint was a composite of all-cause death, all-cause amputation, or new thrombosis over 37 days. Overall, in these studies, argatroban therapy improved clinical outcomes, particularly reducing new thrombosis and death due to thrombosis, without increasing bleeding. 9Interestingly, argatroban therapy did not generate any detectable antibody that could alter its anticoagulant activity in patients with HIT.38
Successful use of reduced doses of argatroban in combination with platelet glycoprotein IIb/IIIa receptor antagonist in patient with HIT undergoing PCI has also been described.39 For special clinical circumstances, various case reports are available describing successful argatroban anticoagulation during renal stent implant,40 carotid stent implant,41 and extracorporeal membrane oxygenation42,43 in patients with HIT, and successful sequenced intravenous and intra-arterial thrombolysis and argatroban anticoagulation in a patient with suspected HIT and AIS.44 Although there are case reports of successful argatroban anticoagulation in patients with HIT undergoing off-pump coronary artery bypass surgery45-48 and cardiopulmonary bypass49 and in a patient with a history of HIT undergoing vascular surgery,50 a safe, effective argatroban dose to support cardiovascular surgery remains to be established in clinical trial.51 A small but growing body of literature exists on argatroban use in pediatric patients with or at risk for HIT,52,53 and a study is ongoing in the United States to evaluate argatroban anticoagulation in pediatric patients in whom heparin use is problematic.54
Bivalirudin is also a specific and reversible DTI whose active substrate is a synthetic 20 amino acid peptide with a MW of 2,180 Da (anhydrous free base peptide). It is a short-acting, bivalent DTI indicated for angioplasty in patients with unstable angina (UA). This agent is a synthetic analog of hirudin, which has some potential advantages for use in HIT, which may include: less reliance on renal metabolism (80% of circulating bivalirudin is cleared from plasma by proteoplytic cleavage) and a relatively short half-life of ∼25 min.55 This agent binds with high affinity to thrombin bivalently. It is rapidly cleaved by thrombin, leaving a weakly bound fragment that is soon displaced from the thrombin molecule by other substrate—this results in an essentially reversible mechanism of action. The recommended dosage of bivalirudin is an IV bolus dose of 1.0 mg/kg followed by a 4 h IV infusion at a rate of 2.5 mg/kg/h. After completion of the initial 4 h infusion, an additional IV infusion of bivalirudin may be initiated at a rate of 0.2 mg/kg/h for up to 20 h, if needed. Bivalirudin, compared with heparin, has been shown to afford benefits in PCI;56 similar data on the use of bivalirudin in HIT patients undergoing PCI is limited.57 A few prospective studies are currently underway to compare the use of bivalirudin with other DTIs as anticoagulable therapy for patients with clinical HIT. 10These studies are aimed to provide some insight on the rates of all-cause mortality, hospital length of stay, incidence of bleeding complications, time to platelet recovery, and percentage of patients with therapeutic aPTT between patient groups, which is often influenced by the patient's own clinical status.
Hirudin (also known as lepirudin in its recombinant form) is a potent natural anticoagulant protein derived from medicinal leeches. Hirudin has the distinction of being the first DTI approved by the FDA in 1998 for the anticoagulation/treatment of HIT-associated thrombosis. To date, hirudin has the most extensive clinical data of any HIT treatment compared to any other DTIs. It binds bivalently and irreversibly to thrombin, and is excreted renally with a half-life of ∼80 min. Hirudin inhibits both clot-bound and free thrombin, thereby inhibiting platelet aggregation and the formation of new thromboses.58 Currently recommended dosages are 0.4 mg/kg as a bolus followed by 0.15 mg/kg/h adjusting the dose to achieve an aPTT of 1.5 to 3 times the baseline value.4 For hirudin monitoring, the aPTT shows considerable variability between patients, particularly at higher plasma levels where aPTT curve flattens (values >70 sec). Therefore, for higher hirudin dosages (e.g. during cardiopulmonary bypass surgery), the ECT test should be used.59 There is no antidode available for hirudin. In a meta-analysis of three prospective multi-center trials with laboratory confirmed acute HIT treated with hirudin, Lubenow et al60 found that the incidence of the combined end-point of death, new TE complications and limb amputation was significantly lower in the hirudin-treated patients than in a contemporaneous control group not treated with hirudin.
Ximelagatran is a new DTI in late-stage clinical trials with advantages for treatment of VTE including oral administration and fixed dosing, making it convenient for long-term treatment.61 A phase III trial demonstrated that ximelagatran was superior to placebo for preventing recurrent thrombosis in patients who had undergone 6-months of standard anticoagulant therapy for venous thromboembolism. The superior role of this oral DTI, if any, in the treatment of HIT patients is yet to be determined.
Fondaparinux (Arixtra®; Organon Sanofi-Synthelabo LLC, West Orangem NJ, USA) is a novel synthetic heparin pentasaccharide, which does not cross-react with HIT antibodies.62,63 This heparin pentasaccharide selectively inhibits factor Xa. Although this anticoagulant is FDA-approved primarily for prophylaxis of DVT in orthopedic patients, its use in HIT patients is rather limited. HIT antibody seroconversion occurred in patients treated with fondaparinux following knee- and hip-replacement surgery at a rate similar to patients treated with a LMWH enxoparin.64 11However, no thrombocytopenia indicating clinical HIT was observed in the fondaparinux-treated patients. Most recently, emerging evidence suggest that this agent can be successfully used for the treatment of patients with HIT.65,66 Additional controlled and systematic clinical studies are required to further evaluate the safety and efficacy of this novel agent in the treatment of patients with HIT.
 
Monitoring Issues
The DTIs differ in their ability to prolong the PT by virtue of their respective molar plasma concentrations required for clinical effect. Recent observations suggest that DTIs with a relatively low affinity for thrombin (e.g. argatroban) require high plasma concentrations to double the aPTT; these higher plasma concentrations, in turn, quench more of the thrombin generated in the PT, thereby more greatly prolonging the PT.67 Coumadin (warfarin) should not be used early or upopposed with HIT, and when appropriate, transition to coumadin must be done cautiously to avoid venous limb gangrene or central skin necrosis. Monitoring anticoagulation during a transition to coumadin is more difficult with hirudin or argatroban than with heparin. Normally a patient with thrombosis is started on heparin and coumadin is begun simultaneously. However, coumadin takes about 5-days to exert its effect. During this period, coumadin's impact is tracked by calculating the INR from the PT value. When the INR has been in the coumadin therapeutic range for 2 days, heparin is stopped. However, if argatroban or hirudin is used instead of heparin, this simple scheme does not work, because both of these DTIs can prolong the PT and/or INR. An INR of 2.0 might no longer signal a therapeutic coumadin level.
 
Adjunctive Therapies
In addition to the above described alternative therapeutic options for HIT patients, there are some adjunctive therapies that are often practiced in limited/select situations. These include: medical thrombolysis (i.e. the use of thrombolytic agents such as streptokinase, tissue plasminogen activator68), surgical thromboembolectomy, IV gammaglobulin (both intact IgG as well as Fc fragments), plasmapheresis (using plasma as a replacement fluid), and the use of antiplatelet agents (e.g. GPIIb/IIIa receptor antagonists, aspirin, dipyramole, etc.). Due the space limitations in this chapter, detailed account of these potentially adjunctive therapies for HIT is not provided at this time.
 
SYNOPSIS AND FUTURE PERSPECTIVES
12The number of patients exposed to heparin is rather large, including not only those undergoing orthopedic procedures and VDT prophylaxis or treatment, but also patients having heparin flushes or heparin-coated catheters in many cardiovascular/hematologic patients. HIT is one of the most serious immune-mediated adverse drug reactions that physicians face today. Unfortunately, HIT remains fairly under-recognized and under-diagnosed, often with devastating thromboembolic complications. While in the Western world, HIT has relatively been studied more systematically, the prevalence of symptomatic HIT and associated antibody characterization among Asian-Indians is rather limited.69 Continued educational initiatives are needed to promote its recognition, prompt diagnosis and appropriate treatment. Heparin cessation alone is inadequate treatment, rather alternative anticoagulation must be initiated to combat the ongoing “thrombin storm” of HIT.
HIT is a clinicopathologic syndrome and its diagnosis primarily remains a clinical one; however, the serologic confirmation is also a necessary part of the evaluation. The demonstration of antibodies directed against the HPF4 complex is one of the most important components of the laboratory diagnosis of HIT. Commercially used laboratory assays for HIT are ELISAs and rapid tests devices that measure the antibody against HPF4 complex. Functional (platelet activation) assays are gaining more recognition as it closely relates with the immunobiology of HIT pathogenesis. Regardless of the specificity/sensitivity magnitude of a given test, the HIT antibody test results should be interpreted in the appropriate context of the available clinical information of the patient.
Therapy for HIT is to discontinue all heparin and LMWHs and commence the anticoagulation with an alternative drug. The DTIs offer several theoretical advantages as an alternative parenteral anticoagulant: a predictable dose-response effect, rapidly active and rapidly reversible anticoagulant effects, and effective inhibition of free or bound thrombin, no dependence on a cofactor for activity, no cross-reactivity with HIT antibodies, and no induction of drug-specific antibodies. The DTIs improved clinical outcomes, including reducing thrombosis and its sequelae, without increasing bleeding risk in HIT, and hence provides an important therapeutic option where fewer choices currently exist. 13 Higher risk subgroups for poor outcomes in HIT include patients with more severe thrombocytopenia or a history of peripheral vascular surgery or renal impairment.
It is possible that these patients may benefit from additional targeted therapies as adjunct to DTIs. The role of DTI anticoagulation with adjunctive therapies, perhaps antiplatelet therapies, in the management of patients with HIT remains to be investigated. Additional studies to further evaluate the clinical utility of DTIs in other clinical settings where heparins are not recommended or may not be ideal, remain to be considered. While newer agents have clinical advantages over heparin, they carry a familiar drawback - expense, which many hospitals in developing countries like India can not afford yet. It is hoped that the transient nature of HIT antibodies and the role of immune memory in HIT will be elucidated, allowing refined identification of “at risk” patients who would benefit from alternative anticoagulation and treatment.
 
ACKNOWLEDGEMENT
SA gratefully acknowledges the partial funding support received from the American Heart Association (Florida-Puerto Rico Affiliate) in the form of a Grant-in-Aid Award.
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