TROMBOSITOPENIA PADA PENGOBATAN DENGAN HEPARIN

Heparin induced thrombocytopenia (HIT), a well known side effect of heparin therapy, occurs in 1–5% of adults exposed to heparin.Unlike other drug induced thrombocytopenia, HIT does not usually cause bleeding, but instead cause thrombosis about 50% of HIT.The thrombosis in HIT can lead to limb gangrene or even death. The Importance to know the HIT is the wide use of heparin led tothe increasing recognition of untoward complications including HIT, relatively uncommon but severe side effect of heparin therapy,unpredictable, and difficulty in diagnosing and treating HIT. HIT is mediated by an antibody that recognizes an epitope on the plateletfactor (PF4)-heparin complex. The platelet factor (PF4)-heparin complex binds to FcgRII receptor on the platelet surface and crosslinksthereceptors.Thisinducesintenseplateletactivationandaggregationandsimultaneouslyactivatesbloodcoagulationpathways,thesechangesareprobablythebasisofthethrombosiseventsinHIT.HITwasclassifiedintotype1and2baseonthepathogenesisandtheseverityofHIT.RegularplateletcountmonitoringisbestsuitedforearlydiagnosisofHIT.Functional(serotoninrelease,plateletaggregationtest)andantigenassays(solidphaseenzymeimmunoassay,fluidphase,andparticlegelimmunoassay)areavailabletoconfirmHIT.HITwasmadebaseontheclinicalfindingandlaboratoryexamination.OnceHITisclinicallysuspected,heparinshouldbestoppedimmediatelyandtreatmentwithanalternativeanticoagulant,waitingforlaboratoryconfirmationmaybecatastrophic.Earlydiagnosisof HIT will decrease the morbidity and mortality.

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Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation

Hematology ◽

10.1182/asheducation-2009.1.225 ◽

2009 ◽

Vol 2009 (1) ◽

pp. 225-232 ◽

Cited By ~ 14

Author(s):

Thomas L. Ortel

Keyword(s):

Platelet Count ◽

Heparin Therapy ◽

Severe Thrombocytopenia ◽

Drug Induced ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Immune Mediated ◽

Number Of Patients ◽

Increased Risk ◽

Antibody Levels

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of ~50 to 60 × 109 platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

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Testing for Heparin Induced Thrombocytopenia in Hospitalized Patients: In Line with Evidence?

Blood ◽

10.1182/blood-2021-153637 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1957-1957

Author(s):

Udhayvir Singh Grewal ◽

Shiva Jashwanth Gaddam ◽

Sahith Reddy Thotamgari ◽

Tyiesha Brown ◽

Kavitha Beedupalli ◽

...

Keyword(s):

Conflicts Of Interest ◽

Heparin Therapy ◽

Hospitalized Patients ◽

Antibody Testing ◽

Drug Induced ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Clinical Probability ◽

Test Probability ◽

4T Score

Abstract Background: Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. Both clinical probability and laboratory testing are needed for establishing a diagnosis of HIT. The 4Ts clinical scoring system, due to a very high negative predictive value when low, offers a robust means to exclude a diagnosis of HIT. However, these strategies are under-employed in clinical practice and limited evidence indicates a high prevalence of over-testing for HIT. Methods: This retrospective analysis was conducted to identify patients who underwent heparin/PF4 antibody testing over a period of 12 months. The testing was performed using an ELISA-based IgG anti-heparin/PF4 antibody assay and an optical density (OD) of 0.4 was used as a cut-off for a positive value. Electronic medical records were reviewed for 4T score documentation, anti-PF4 results, SRA testing and 4T scores were retrospectively calculated for all the patients. SAS v9.4 (Cary, NC) was used for statistical analysis. Results: A total of 105 patients who underwent anti-PF4 antibody testing were included for analysis. Majority of the patients in our cohort were admitted in an intensive care unit setting (75/105,71.4%). On chart review, only 17 patients (16.2%) were noted to have documentation of 4T score. Based on the retrospectively calculated 4T scores, 60 patients (57.1%) had low pre-test probability, 41 (39%) had intermediate pre-test probability and 4 (3.8%) patients were noted to have high pre-test probability. Anti-PF4/heparin antibodies were positive in 9 patients, of which 5 (55.5%) patients did not undergo concomitant SRA testing. Out of 9, 4 (44.4%) had weakly positive (0.4-1.0 OD units), 2 (21.1%) had strongly positive (1.0-2.0 OD units) and 2 (21.1%) patients had very strongly positive (>2 OD units) anti-PF4 antibody titers. Out of 105 patients, SRA was tested in 11 patients (10.5%) and was noted to be positive in 1 (0.95%). Overall, 2 patients were diagnosed and treated for HIT, out of which the diagnosis was not confirmed with SRA in 1 patient (due to high pre-test probability and very strong anti-PF4 titers). In the remaining patients, sepsis (48, 46.6%) and drug-induced thrombocytopenia (29, 28.2%) emerged as the most common possible causes of thrombocytopenia. Conclusion: Among hospitalized patients, over-testing for HIT is common. Practices to promote 4T score documentation and evidence-based anti-PF4 testing may help prevent unnecessary costs associated with serological testing and costly alternate anticoagulants. To improve overall outcomes, clinicians should also attempt to identify and treat other more likely causes of thrombocytopenia, especially in patients with low pre-test probability for HIT. Disclosures No relevant conflicts of interest to declare.

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Platelet Factor 4 (PF4) Antigenic Complexes on the Macrophage Surface: Implications for the Pathogenesis of Heparin Induced Thrombocytopenia (HIT).

Blood ◽

10.1182/blood.v108.11.94.94 ◽

2006 ◽

Vol 108 (11) ◽

pp. 94-94

Author(s):

Lubica Rauova ◽

Douglas B. Cines ◽

Mortimer Poncz

Keyword(s):

Host Protein ◽

Thrombin Inhibitors ◽

Direct Thrombin Inhibitors ◽

Igg Antibody ◽

Drug Induced ◽

Platelet Factor ◽

Platelet Surface ◽

Heparin Induced Thrombocytopenia ◽

Heparan Sulfates ◽

Bell Shaped Curve

Abstract HIT is the most frequent antibody-mediated drug-induced thrombocytopenia and is unique in the associated prevalence of thrombosis. HIT is caused by antibodies to a normal host protein, PF4, complexed to heparin or cellular glycosaminoglycans (GAGs). We have shown that binding of HIT antibodies and a monoclonal HIT-like antibody KKO to platelet surface chondroitin sulfate (CS) follows a bell-shaped curve with respect to PF4 concentration. At external PF4 concentrations below the peak value of <50 μg/mL, heparin dissociates PF4 and thereby decreases surface antigenicity, whereas at PF4 concentrations >50 μg/mL, heparin initially increases antigenicity. Surface GAGs on macrophages differ from those on platelets in several ways, including having a higher affinity for PF4. In addition, the binding of HIT-IgG elicits the elaboration of tissue factor. Therefore, we characterized the binding of HIT IgG antibody to macrophages exposed to different concentrations of PF4. Binding of PF4 to the surface of human/murine macrophages also followed a bell-shaped curve with peak antigenicity at the same PF4 concentration as seen on platelets. However, HIT antigenticity persisted at lower PF4 concentrations. For example at a PF4 concentration of 6 μg/mL, six times as much KKO bound to macrophages as to platelets. PF4-coated monocytes were also more resistant to the abrogation of KKO binding by heparin. At therapeutic concentrations of heparin, HIT antigenicity actually increased on macrophages exposed to optimal concentrations of PF4, while platelet surface antigenicity was nearly eliminated. Enzymatic removal of surface GAGs showed that unlike platelet surfaces, where CS is the major GAG involved in HIT antigenicity, a more complex pattern was seen on macrophages that included heparan sulfates, CS and likely dermatan sulfates. Thus, these studies show that expression of surface HIT antigenic complexes on macrophages develop at much lower concentrations of PF4 than platelets and that these complexes are more resistant to removal by heparin. The enhanced avidity of macrophages for PF4/GAG complexes may also contribute to the persistent risk of thrombosis for at least several days after heparin exposure has been stopped. Whether measurement of antigenic complexes on macrophages would identity patients at higher risk of thrombosis and whether reduction in the risk of thrombosis requires measures directed at the integrity of these complexes in addition to use of direct thrombin inhibitors are under investigation.

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Monocytes Are a Particularly Favorable Target for Surface Platelet Factor 4 (PF4) Antigenic Complex Formation in Heparin-Induced Thrombocytopenia: New Insights into the Thrombotic Risk in HIT

Blood ◽

10.1182/blood.v112.11.271.271 ◽

2008 ◽

Vol 112 (11) ◽

pp. 271-271

Author(s):

Lubica Rauova ◽

Gowthami M Arepally ◽

Douglas B. Cines ◽

Mortimer Poncz

Keyword(s):

Complex Formation ◽

Platelet Factor 4 ◽

Drug Induced ◽

Platelet Factor ◽

Platelet Surface ◽

Thrombotic Risk ◽

Heparin Induced Thrombocytopenia ◽

Antigenic Complex

Abstract Monocytes are a Favored Target for Surface Platelet Factor 4 (PF4) Antigenic Complex Formation in Heparin-Induced Thrombocytopenia: New Insights into the Thrombotic Risk in HIT Lubica Rauova, Gowthami Arepally, Douglas Cines and Mortimer Poncz HIT is a drug-induced autoimmune thrombocytopenia caused by antibodies to heparin/PF4 complexes that predispose to thrombotic complications. The studies described below examine how monocytes (Mo) may contribute to the thrombotic risk. We demonstrated previously that glycosaminoglycans (GAG) on the surface of platelets bind PF4, forming complexes that are recognized by HIT antibody, leading to platelet activation via the platelet FcγRIIA receptor in vitro and thrombocytopenia/thrombosis in vivo. However, heparin not only induces antibodies to develop against the PF4/GAG surface antigenic complexes, but also rapidly removes the same PF4/GAG complexes from the platelet surface, which may limit the likelihood of developing HIT and help limit its duration. This led us to study the involvement of Mo, which are a rich potential source of tissue factor and are known to be activated in HIT. Moreover, unlike platelets, which are coated with GAG composed almost entirely of chrondroitin sulfate (CS), Mo also express heparan sulfate, which has the capacity to bind PF4 with greater avidity and be resistant to the effect of plasma heparin. We found that Mo bind PF4 with greater avidity than platelets and higher concentrations of UFH are needed to remove PF4/GAG complexes and reduce the binding of a HIT monoclonal antibody KKO. In contrast to platelets, dissociation of PF4/GAG complexes from monocytes requires heparinases in addition to chondroitinases. In addition, macrophages GAG undergo hypersulfation during inflammation. Because clinical studies have shown inflammation predisposes to HIT, we examined the binding of KKO to unstimulated and bacterial lipopolysaccharide (LPS, E. coli serotype 011) stimulated cultured macrophages. Macrophages were derived from primary human Mo or murine bone marrow, cultured in the presence of M-CSF and stimulated with 0–500 ng/mL of LPS for 72 hrs. LPS increased KKO binding in the presence of PF4 2.7±0.7-fold compared to unstimulated cells (p<0.002) and the stimulated cells required ~2-fold higher concentrations of heparin to remove surface PF4/GAG complexes. Addition of [35S]sulfate during the last 24 hrs of incubation lead to a 4.1±0.1-fold increase in the incorporation of 35S into surface GAG after LPS stimulation (p<0.0001). These results provide important insights into the potential role of Mo in the prothrombotic sequelae of HIT. Compared to platelets, Mo are relatively resistant to “antigen down-regulation” by heparin and are more likely to bind anti-PF4/GAG HIT antibodies and become activated. The relative resistance of Mo to the dissociation PF4/GAG complexes from the cell surface also suggest a role in the development of Delayed-Onset HIT after heparin withdrawal.

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Diagnosis and treatment of heparin-induced thrombocytopenia

Perfusion ◽

10.1191/0267659103pf637oa ◽

2003 ◽

Vol 18 (1) ◽

pp. 47-53 ◽

Cited By ~ 6

Author(s):

William J DeBois ◽

Junli Liu ◽

Leonard Y Lee ◽

Leonard N Girardi ◽

Charles Mack ◽

...

Keyword(s):

New York ◽

Platelet Inhibition ◽

Heparin Therapy ◽

Serotonin Release ◽

Antibody Detection ◽

Thrombin Inhibitor ◽

Heparin Infusion ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Life Threatening

Heparin-induced thrombocytopenia (HIT) is a major side effect secondary to the administration of heparin. This syndrome is serious and potentially life threatening. This response is the result of antibodies formed against the platelet factor 4 (PF4)/heparin complex. The incidence of this immune-mediated syndrome has been estimated to be 1-3% of all patients receiving heparin therapy. The occurrence of HIT in patients requiring full anticoagulation for cardiopulmonary bypass (CPB), therefore, presents a serious challenge to the cardiac surgery team. The diagnosis of HIT should be based on both clinical and laboratory evidence. While functional assays, platelet aggregation tests, and the serotonin release assay can be used to support the diagnosis, the negative predictive value of these tests is generally less than 50%. In contrast, although non-functional antibody detection assays are more sensitive, they have a low specificity. HIT can be treated in several ways, including cessation of all heparin and giving an alternative thrombin inhibitor, platelet inhibition followed by heparin infusion, and the use of low molecular weight heparins. In this presentation, the pathology and current diagnostic tests, as well as the successful management of patients with HIT undergoing CPB at New York Presbyterian Hospital, are reviewed.

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Defining a second epitope for heparin-induced thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like monoclonal antibody

Blood ◽

10.1182/blood.v99.4.1230 ◽

2002 ◽

Vol 99 (4) ◽

pp. 1230-1236 ◽

Cited By ~ 87

Author(s):

Zhong Q. Li ◽

Weiyi Liu ◽

Kwang S. Park ◽

Brue S. Sachais ◽

Gowthani M. Arepally ◽

...

Keyword(s):

Monoclonal Antibody ◽

Binding Site ◽

Binding Sites ◽

Heparin Therapy ◽

Common Complication ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

The Third ◽

N Terminus ◽

A Site

Heparin-induced thrombocytopenia/thrombosis (HIT/T) is a common complication of heparin therapy that is caused by antibodies to platelet factor 4 (PF4) complexed with heparin. The immune response is polyclonal and polyspecific, ie, more than one neoepitope on PF4 is recognized by HIT/T antibodies. One such epitope has been previously identified; it involves the domain between the third and fourth cysteine residues in PF4 (site 1). However, the binding sites for other HIT/T antibodies remain to be defined. To explore this issue, the binding site of KKO, an HIT/T-like murine monoclonal antibody, was defined. KKO shares a binding site with many HIT/T antibodies on PF4/heparin, but does not bind to site 1 or recognize mouse PF4/heparin. Therefore, the binding of KKO to a series of mouse/human PF4 chimeras complexed with heparin was examined. KKO recognizes a site that requires both the N terminus of PF4 and Pro34, which immediately precedes the third cysteine. Both regions lie on the surface of the PF4 tetramer in sufficient proximity (within 0.74 nm) to form a contiguous antigenic determinant. The 10 of 14 HIT/T sera that require the N terminus of PF4 for antigen recognition also require Pro34 to bind. This epitope, termed site 2, lies adjacent to site 1 in the crystal structure of the PF4 tetramer. Yet sites 1 and 2 can be recognized by distinct populations of antibodies. These studies further help to define a portion of the PF4 tetramer to which self-reactive antibodies develop in patients exposed to heparin.

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Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia

Blood ◽

10.1182/blood-2004-04-1544 ◽

2005 ◽

Vol 105 (1) ◽

pp. 131-138 ◽

Cited By ~ 188

Author(s):

Lubica Rauova ◽

Mortimer Poncz ◽

Steven E. McKenzie ◽

Michael P. Reilly ◽

Gowthami Arepally ◽

...

Keyword(s):

Electron Microscopy ◽

Platelet Activation ◽

Low Molecular Weight Heparin ◽

Heparin Therapy ◽

Low Molecular Weight ◽

Dependent Manner ◽

Fondaparinux Sodium ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Autoantibody Formation

Abstract Heparin-induced thrombocytopenia and thrombosis (HITT) is a severe complication of heparin therapy caused by antibodies to complexes between unfractionated heparin (UFH) and platelet factor 4 (PF4) that form over a narrow molar range of reactants and initiate antibody-induced platelet activation. We observed that UFH and tetrameric PF4 formed ultralarge (> 670 kDa) complexes (ULCs) only over a narrow molar range with an optimal ratio of PF4 to heparin of approximately 1:1. These ULCs were stable and visible by electron microscopy, but they could be dissociated into smaller complexes upon addition of heparin. ULCs formed inefficiently when PF4 was incubated with low-molecular-weight heparin, and none formed with the pentasaccharide fondaparinux sodium. In addition, mutation studies showed that formation of ULCs depended on the presence of PF4 tetramers. The ULCs were more reactive as determined by their capacity to bind to a HITT-like monoclonal antibody and showed greater capacity to promote platelet activation in an antibody- and FcγRIIA-dependent manner than were the smaller complexes. The capacity of PF4 to form ULCs composed of multiple PF4 tetramers arrayed in a lattice with several molecules of UFH may play a fundamental role in autoantibody formation, antibody-dependent platelet activation, and the propensity for thrombosis in patients with HITT.

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A New Approach in the Study of the Molecular and Cellular Events Implicated in Heparin-induced Thrombocytopenia

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615969 ◽

2001 ◽

Vol 85 (06) ◽

pp. 1090-1096 ◽

Cited By ~ 30

Author(s):

Mahnouch Khairy ◽

Dominique Lasne ◽

Brigitte Brohard-Bohn ◽

Martine Aiach ◽

Francine Rendu ◽

...

Keyword(s):

Heparin Therapy ◽

Dependent Manner ◽

Common Complication ◽

Igg Antibodies ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

New Approach ◽

Cellular Events ◽

Healthy Donors ◽

Antigenic Complex

SummaryHeparin-induced thrombocytopenia (HIT), a relatively common complication of heparin therapy, results of platelet activation, via the receptor for the Fc domain of IgG (FcγRIIa), by heparin-dependentantibodies, commonly directed against the heparin-platelet factor 4 (H-PF4) antigenic complex. Our strategy was to use whole blood allowing the study of leukocyte-platelet interactions. Experiments were performed with blood from healthy donors incubated with HIT patients’ plasma and different concentrations of heparin. We showed that 75% of the HIT patients’ plasma induced the formation of leukocyteplatelet-aggregates in a heparin-dependent-manner. The formation of leukocyteplatelet-aggregates induced by HIT plasma in the presence of heparin was (i) independent of the healthy blood donor FcγRIIa polymorphism, (ii) correlated with the levels of anti H-PF4 IgG antibodies contained in the patients’ plasma, and to a lesser extent to anti H-PF4 IgM antibodies, and (iii) was mediated by P-selectin. This report opens new prospects in the study of the molecular and cellular events implicated in HIT.

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Heparin-induced thrombocytopenia: An Update

Cardiovascular Journal ◽

10.3329/cardio.v3i2.9189 ◽

1970 ◽

Vol 3 (2) ◽

pp. 187-199

Author(s):

LA Sayami ◽

M Ullah

Keyword(s):

Morbidity And Mortality ◽

Diagnosis And Treatment ◽

Significant Morbidity ◽

Drug Induced ◽

Heparin Induced Thrombocytopenia ◽

Recent Advances ◽

Immune Mediated

Heparin-induced thrombocytopenia (HIT) is the most important and most frequent drug-induced, immune-mediated type of thrombocytopenia. It is associated with significant morbidity and mortality if unrecognized. In this review, we briefly discuss the main features of heparin-induced thrombocytopenia, particularly analyzing the most recent advances in the pathophysiology, diagnosis and treatment of this syndrome. Keywords: Heparin; Thrombocytopenia DOI: http://dx.doi.org/10.3329/cardio.v3i2.9189 Cardiovasc. J. 2011; 3(2): 187-199

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Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4

Blood ◽

10.1182/blood.v83.11.3232.3232 ◽

1994 ◽

Vol 83 (11) ◽

pp. 3232-3239 ◽

Cited By ~ 246

Author(s):

JG Kelton ◽

JW Smith ◽

TE Warkentin ◽

CP Hayward ◽

GA Denomme ◽

...

Keyword(s):

Minimum Degree ◽

Equilibrium Dialysis ◽

Fluid Phase ◽

Platelet Factor 4 ◽

Minimum Size ◽

Sulfated Polysaccharides ◽

Platelet Factor ◽

Platelet Surface ◽

Heparin Induced Thrombocytopenia

Abstract Heparin-induced thrombocytopenia (HIT) is an important complication of heparin therapy. Although there is general agreement that platelet activation in vitro by the HIT IgG is mediated by the platelet Fc receptor, the interaction among the antibody, heparin, and platelet membrane components is uncertain and debated. In this report, we describe studies designed to address these interactions. We found, as others have noted, that a variety of other sulfated polysaccharides could substitute for heparin in the reaction. Using polysaccharides selected for both size and charge, we found that reactivity depended on two independent factors: a certain minimum degree of sulfation per saccharide unit and a certain minimum size. Hence, highly sulfated but small (< 1,000 daltons) polysaccharides were not reactive nor were large but poorly sulfated polysaccharides. The ability of HIT IgG to recognize heparin by itself was tested by Ouchterlony gel diffusion, ammonium sulfate and polyethylene glycol precipitation, and equilibrium dialysis. No technique demonstrated reactivity. However, when platelet releasate was added to heparin and HIT IgG, a 50-fold increase in binding of radio-labeled heparin to HIT IgG was observed. The releasate was then depleted of proteins capable of binding to heparin by immunoaffinity chromatography. Only platelet factor 4-immunodepleted releasate lost its reactivity with HIT IgG and heparin. Finally, to determine whether the reaction occurred on the surface of platelets or in the fluid phase, washed platelets were incubated with HIT IgG or heparin and after a wash step, heparin or HIT IgG was added, respectively. Reactivity was only noted when platelets were preincubated with heparin. Consistent with these observations was the demonstration of the presence of PF4 on platelets using flow cytometry. These studies indicate that heparin and other large, highly sulfated polysaccharides bind to PF4 to form a reactive antigen on the platelet surface. HIT IgG then binds to this complex with activation of platelets through the platelet Fc receptors.

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