Heparin‐induced thrombocytopenia: pathogenesis and management

Heparin-induced thrombocytopenia (HIT) is a transient prothrombotic disorder initiated by heparin. Its central feature is thrombocytopenia caused by antibody-mediated platelet activation. HIT can be viewed as an acquired hypercoagulability disorder, with increased thrombin generation in vivo, and increased risk for arterial and, especially, venous thrombosis. The pathogenic HIT antibodies are directed against neoepitopes on a ‘self’ protein, platelet factor 4 (PF4), that are expressed when PF4 is bound to heparin or certain other polyanions. This review focuses on studies published since 1990, and summarizes the pathogenesis, laboratory testing, frequency and clinical picture of HIT. Two treatment situations are reviewed critically: management of thrombosis complicating HIT and treatment of ‘isolated HIT’ (HIT recognized because of thrombocytopenia alone). There is potential for medicolegal risk, particularly if inappropriate therapy contributes to patient harm. Heparin-induced thrombocytopenia (HIT) can be defined as any clinical event best explained by platelet factor 4 (PF4)/heparin-reactive antibodies (‘HIT antibodies’) in a patient who is receiving, or who has recently received, heparin (or another polyanion implicated in this syndrome). Thrombocytopenia is the most common ‘event’ in HIT and occurs in at least 90% of patients, depending upon the definition of thrombocytopenia. A high proportion of patients with HIT develop thrombosis. Alternative (non-heparin) anticoagulant therapy reduces the risk of subsequent thrombosis. The diagnosis of HIT should be based upon: (a) the occurrence of one or more HIT-associated clinical events, and (b) detection of HIT antibodies in patient serum or plasma (Warkentin et al, 1998; Warkentin, 2002a) (Table I). By thus viewing HIT as a clinicopathological disorder, it follows that a patient who develops HIT antibodies during heparin treatment but who neither manifests thrombocytopenia nor other adverse events does not have HIT, but rather HIT antibody seroconversion alone. It also follows that a patient who may appear on clinical grounds to have HIT, but in whom sensitive tests for HIT antibodies are negative, also does not have HIT. Indeed, the high negative predictive value of current assays has led to recognition of various HIT-mimicking disorders (‘pseudo-HIT’) (Warkentin, 2001a). Table II lists terms used to describe HIT and its complications (Warkentin, 2001b). In this review, ‘heparin-induced thrombocytopenia’ (HIT) will be used. Figure 1 summarizes the pathogenesis of HIT. The central concept is heparin-induced generation of pathogenic antibodies of immunoglobulin (Ig)G class that recognize multimolecular complexes of PF4 and heparin (Amiral et al, 1992) on platelet surfaces, leading to platelet activation in vivo and associated thrombin generation. There is evidence that endothelial cells and monocytes can also be activated by HIT antibodies. Pathogenesis of HIT: a central role for thrombin generation. PF4/heparin complexes that can express multiple neoepitope sites bind to platelet surfaces. HIT-IgG antibodies recognize neoepitope sites on PF4, leading to formation of multimolecular PF4/heparin/IgG complexes on the platelet surface. The IgG Fc regions bind and crosslink the platelet FcγIIa receptors, resulting in platelet activation, including formation of procoagulant, platelet-derived microparticles, which provide altered membrane surfaces that support coagulation reactions. Activated platelets release additional PF4 from α-granules, leading to a vicious cycle of progressive platelet and coagulation activation. PF4 also can bind to endothelial heparan sulphate, leading to endothelial cell immunoinjury, with tissue factor expression. Monocytes also can bind PF4/heparin-IgG immune complexes, potentially leading to tissue factor expression on these cells. Ultimately, there results marked thrombin generation in vivo, which helps explain the strong association between HIT and thrombotic events. Figure adapted from Greinacher, A. & Warkentin, T.E. (2001) Treatment of heparin-induced thrombocytopenia: an Overview. In: Heparin-induced Thrombocytopenia, 2nd edn. (ed. by T.E. Warkentin & A. Greinacher) Marcel Dekker, New York, used by permission. Heparin is a glycosaminoglycan (GAG), i.e. it consists of linear polymers of repeating disaccharide subunits (Fig 2) that vary in chain length and grade of sulphation. Binding of PF4 to heparin is independent of its antithrombin-catalysing pentasaccharide region. Non-specific role of heparin and other polyanions that lead to neoepitope formation on PF4. The disaccharide units of heparin consist of alternating 1→4-linked residues of hexuronic acid (either d-glucuronic or l-iduronic acid) and d-glucosamine. The predominant disaccharide (comprising 75–90% of heparin) occurs when both ‘X’ and ‘Y’ are SO3–, i.e. the trisulphated disaccharide: [→ 4)-O-α-l-iduronic acid-2-sulphate (1→4)-O-α-d-glucosamine-2, 6-disulphate (1 →]. Heparin, the four polyvinyl structures and pentosan polysulphate are all good at causing neoepitope(s) on PF4 that are recognized by HIT antibodies. In contrast, when PF4 binds to polystyrene sulphonate, only some HIT antibodies react weakly. This may be caused by the greater distance between the negative charge (SO3–) and the carbon backbone in polystyrene sulphonate, compared with the other molecules shown (Visentin et al, 2001). PF4 is a 70-amino acid (7780 Da), platelet-specific member of the C-X-C subfamily of chemokines (Fig 3). Four PF4 molecules self-associate to form compact tetramers of globular structure (∼31 000 Da). PF4 is rich in the basic amino acids, lysine and arginine (32 and 12 residues per tetramer respectively), which form a ‘ring of positive charge’, providing the interface between the PF4 tetramer and heparin (Fig 3). PF4 is stored in platelet α-granules, where it is bound to the GAG, chondroitin sulphate. Under normal conditions, only trace levels of PF4 (∼3 ng/ml) are found in human plasma. However, heparin infusion increases PF4 levels about 15- to 30-fold for several hours, by displacing PF4 from endothelial cell surfaces. Relation of primary and secondary structure of PF4 in relation to HIT neoepitopes. (Top) A 3-dimensional representation of the PF4 tetramer is shown, indicating the two neoepitope sites identified by Li et al (2002). The ‘ring of positive charge’, formed by the lysine residues in the C-terminus of PF4 (light blue) and other lysine and arginine residues (dark blue), is also shown. (Bottom) The linear sequence of the 70-amino acid polypeptide of a single PF4 molecule is shown. Four such polypeptides combine to form the PF4 tetramer. PF4 is classified as a member of the C-X-C subfamily of chemokines, because of its cysteine10–leucine11–cysteine12 sequence. Figure adapted from Li, Z.Q., Liu, W., Park, K.S., Sachais, B.S., Arepally, G.M., Cines, D.B. & Poncz, M. (2002) Defining a second epitope for heparin-induced thrombocytopenia/thrombosis antibodies using KKO, a murine HIT-like monoclonal antibody. Blood, 99, 1230–1236. Copyright American Society of Hematology, used by permission. The immune response against PF4/heparin complexes is polyspecific, i.e. antibodies are directed against multiple neoepitope sites (Suh et al, 1998; Ziporen et al, 1998; Newman & Chong, 1999; Li et al, 2002). Suh et al (1998) showed that heparin must be in a flexible, relatively unconstrained state to react with PF4 and the neoepitopes. Li et al (2002) identified two neoepitopes recognized by HIT antibodies (Fig et al HIT antibodies from patients, and showed that greater of HIT-IgG antibodies with for PF4/heparin complexes or one against PF4 alone. studies are with clinical studies that only a of IgG are platelet but that HIT occurs only in patients with relatively high of IgG (Suh et al, Warkentin et al, The of HIT-IgG for PF4/heparin complexes is between that of relatively and and respectively), the potential for both of HIT-IgG to recognize neoepitopes on the multimolecular PF4/heparin complexes & Chong, role in HIT, its to neoepitopes on PF4 is Indeed, two pentosan polysulphate to (Fig 2) and chondroitin can lead to formation of thrombocytopenia and thrombosis et al, et al, the polyvinyl (Fig which has neither nor also neoepitope formation on PF4 (Visentin et al, 2001). of polyanions that support neoepitope formation of negative charge at and a length to at least of the of the PF4 tetramer its of positive complexes are used to HIT antibodies in a complexes bind to platelets by the negative charge of the heparin et al, & of PF4/heparin complexes, and thus platelet activation by occurs when PF4 and heparin are in an from to a PF4/heparin of about (Visentin et al, & such as and not support the of PF4 and HIT antibodies to the platelet in high these molecules activation of platelets by HIT-IgG et al, This that with PF4 to some and in PF4 from the platelet to the activation to PF4 release from and may risk of HIT, by greater risk or by of HIT-IgG & platelet activation by HIT-IgG the is because PF4 from platelets can form additional immune complexes Newman & Chong, HIT-IgG recognize PF4 bound to in the of heparin et al, Newman & Chong, 1999; et al, and platelets in heparin (Amiral et al, Warkentin & 2001a). Indeed, HIT neoepitopes are on PF4 (Fig and HIT can be a The of HIT-IgG to platelets in the of heparin explain the of thrombocytopenia and thrombosis several HIT’ (Warkentin & 2001a). The sequence of events by which HIT-IgG platelets recently by Newman and using HIT-IgG and platelet of heparin to plasma led to the release of of PF4 that bound to platelet surfaces. of HIT-IgG bound to platelets in with progressive platelet Fc monoclonal antibody platelet activation by it not of HIT-IgG to platelet activation by HIT-IgG heparin in to PF4, i.e. the for antibody in an This that the platelet the as PF4 is during progressive platelet activation. This is with a of formation on platelet surfaces of the PF4/heparin/IgG immune complexes, rather in plasma. of platelet FcγIIa by PF4/heparin/IgG immune complexes to and events that and review 2001). levels of which activation of platelet This the of using the during platelet in certain assays for HIT platelet during thus high of the platelets to activation by HIT-IgG the of et al, A of platelet activation by HIT-IgG is the formation of procoagulant, platelet-derived (Warkentin et al, et al, et al, Warkentin and have shown that HIT-IgG and other platelet IgG monoclonal an greater platelet response platelet such as and that platelet activation occurs in vivo in patients with HIT on platelets et al, and increased of platelet-derived (Warkentin et al, is by to its The resulting complexes have a and thus can be in plasma to thrombin generation in Two studies complexes in HIT patients, with of greater 4 ng/ml) (Warkentin et al, et al, also in patients with thrombosis to HIT. thrombin generation is a feature of hypercoagulability disorders such as or that increased risk for venous thrombosis. antibodies of and class are also in patients with HIT, it these antibody HIT in the of HIT-IgG antibodies. In studies of HIT antibody formation found IgG antibodies in all patients identified with HIT (Warkentin et al, In contrast, et al only antibodies in 12 of patients with HIT, with However, as can clinical HIT it in that HIT can be caused by or antibodies. be IgG antibodies against other chemokines (Amiral et al, of the four HIT-IgG can be identified in HIT some more with more one in patients et al, Suh et al, in clinical of HIT in relation to IgG or the of or class antibodies has The class of found on platelets has for IgG review 2001). these bind HIT-IgG only PF4/heparin/IgG complexes have formed on platelet surfaces, as immune complexes be by FcγIIa a that platelet activation by human that this risk for HIT. However, has The et al, of the patients with HIT-associated leading the to that of immune complexes by the to greater platelet activation and risk of thrombosis. is a found on endothelial cell surfaces that is heparin. HIT antibodies of both IgG and class recognize PF4 bound to heparan on leading to that high levels of PF4 during HIT to the (Visentin et al, and endothelial with immunoglobulin platelet and endothelial cells in from patients with HIT. Two that HIT-IgG can monocytes in the of PF4 & et al, 2001). these activated monocytes expressed tissue factor and Heparin is not for PF4 to which is by such as chondroitin sulphate. heparin et al found that PF4/heparin complexes cells from patients with HIT. However, evidence for immune in HIT. HIT antibodies an of HIT (Warkentin & 2001b). HIT antibodies are not when such a patient with HIT is to heparin et al, and, if antibodies are are not formed more (Warkentin & et al, have for HIT review Warkentin, one by et al several clinical and laboratory of HIT. a murine i.e. with platelets human and human PF4 platelet receptors, and murine PF4 is not recognized by HIT these with a HIT-mimicking murine monoclonal antibody that and the thrombocytopenia and in multiple including the a of patients who form HIT antibodies develop thrombocytopenia or other of HIT (Amiral et al, Warkentin et al, assays that are more sensitive at HIT antibodies are for clinical HIT, if have high for antibodies. for HIT antibodies can be classified as platelet activation assays and assays (Table I). platelet assays used to HIT antibodies review Warkentin, 2001b). However, greater and is using A platelet can of platelets as in the of patient plasma and heparin et al, Warkentin & Greinacher, 2001). However, this is relatively for clinical HIT et al, Warkentin & Greinacher, 2001). to multiple assays as relatively and can be can from such as that a patient in platelet in the of HIT antibodies (Warkentin & Greinacher, 2001). activation using that are and in have increased and for HIT compared with is as platelet to HIT-IgG normal (Warkentin et al, A of platelet activation can be including release of (Warkentin et al, of platelet et al, or generation of platelet-derived by et al, The assays are in of can be This of conditions, platelet activation at various heparin in the of platelet Fc monoclonal antibody and which HIT antibodies a activation at heparin that the activation at and by Fc monoclonal antibody. platelet activation assays are and et al, is that about of patient immune complexes or human and i.e. platelet activation occurs at all heparin Two are that antibodies of the immunoglobulin against PF4 bound to heparin (Amiral et al, 1992) or polyvinyl (Visentin et al, 2001). The PF4, the PF4 from that have the to antibodies of the IgG which increases for clinical HIT by detection of and antibodies et al, 2001). a has et al, that to have between the and a platelet activation et al, Newman et al (1998) a that the of in This may a of and, is for of HIT-IgG against heparin and In is when HIT is In this platelet activation assays and assays have high for diagnosis of HIT. Indeed, negative by two sensitive and assays and platelet activation HIT (Warkentin, is using platelet et al, is greater with the platelet activation assays compared with as the are more to antibodies (Warkentin et al, The of the of HIT with the of used and its a the of HIT (Warkentin & a platelet activation is associated with a for HIT a for a patient with a of HIT of about the associated from about to results are of HIT (Warkentin & 2001a). Figure a the between platelet activation thrombocytopenia and HIT-associated thrombosis & Warkentin, 2001). This is with the only a of antibodies have (Amiral et al, Warkentin et al, platelet activation assays have greater for clinical HIT and thrombosis is not associated with HIT antibody formation that does not in a platelet (Warkentin et al, the between HIT antibodies by platelet activation release thrombocytopenia and HIT-associated thrombosis. the is more sensitive for HIT it is for clinical HIT is the platelet activation of HIT. The risk of HIT antibody formation and for HIT upon the of heparin and the patient heparin. adapted from & Warkentin, T.E. (2001) of heparin-induced thrombocytopenia. In: Thrombocytopenia, 2nd edn. (ed. by T.E. Warkentin & A. Greinacher) Marcel Dekker, New York, used by permission. Figure also the heparin and patient the frequency of HIT. and other are in Table A of four in the showed that heparin from more to HIT heparin from & Warkentin, 2001). a by et al found that also more to be associated with HIT antibody formation chain length and of of heparin explain its HIT is more common with In in patients heparin is about more to be associated with formation of HIT-IgG antibodies and also about more to thrombocytopenia when HIT-IgG are i.e. is about more to HIT (Warkentin et al, Warkentin & 2002). In a of and et al also HIT more with HIT antibodies formed more in patients compared with et al, 2002). HIT is common in and patients in patients & Warkentin, 2001). et al (2001) that of HIT during of HIT in of patients who This that the patients heparin for et al (2001) HIT with and (2001) reviewed the that HIT in or with in between and of This the for to heparin. In HIT is not as and platelet activation assays have not used in this Warkentin and (2002) found that are more to develop HIT: more to form HIT more to develop HIT when antibodies because formed levels of it is that heparin therapy increases the subsequent risk of HIT, evidence this et al, Indeed, patients with a of HIT can heparin the of HIT antibodies The only between heparin and risk of HIT is the of in which a to heparin an platelet if heparin is to of the antibodies (Warkentin & et al, Thrombocytopenia is the central feature of HIT: the platelet is about (Fig In at least of patients, the platelet (Warkentin, In the patients, HIT is recognized because of a in the platelet or or because of clinical events, such as thrombosis or at heparin that to HIT platelet et al, Warkentin, of thrombocytopenia and thrombotic complications in HIT. patients positive for HIT antibodies by patients a or greater in the platelet by who as HIT based upon thrombotic events, heparin-induced or heparin The used to this from Warkentin and that venous thrombosis arterial thrombosis in HIT. Figure of HIT: and HIT (Warkentin & et al, 2002). In about of patients, HIT is recognized because of a platelet that a of levels may not be of HIT In all patients, is by heparin during with levels of HIT antibodies about HIT develops or in the because of HIT antibodies by heparin to In about of patients, HIT is recognized because of an in platelet upon the of heparin patients have heparin the and the thrombocytopenia is explained by heparin to a patient who has levels of HIT antibodies. the heparin may have or in the heparin & Warkentin, HIT several the patient heparin a single heparin has to thrombocytopenia and thrombosis about 1 (Warkentin & HIT is associated with thrombosis (Table the from 12 to depending upon the definition of thrombocytopenia (Warkentin, et al, of all patients with HIT are recognized only HIT-associated thrombosis (Warkentin & thrombosis HIT more arterial thrombosis (Warkentin & et al, Indeed, is more common all the arterial thrombotic events thrombosis most with thrombotic and but thrombotic venous thrombosis as and progressive and thrombosis as or such as or from the of thrombosis et al, not to an increased risk of thrombosis HIT patients et al, Heparin-induced at heparin from to are a feature of the HIT only of patients develop HIT antibodies are (Warkentin, thrombocytopenia and thrombosis a heparin has because of an heparin. of patients who an heparin at a when have HIT antibodies develop or such as or transient (Table (Warkentin et al, et al, Warkentin, or the heparin and are by an in the platelet coagulation increased thrombin generation is a feature of HIT, defined as or an in the occurs in only of patients (Warkentin, may be more common in HIT, as platelet activation occurs in the of heparin (Warkentin & 2001a). of the by of thrombin Table lists four to the of HIT (Warkentin & a high is when the of of thrombocytopenia is with heparin-induced in the of another thrombocytopenia with a diagnosis such as et al, Warkentin 2001a). disorders HIT on clinical with and with (Warkentin, 2001a). The high negative predictive value of sensitive assays for HIT antibodies HIT to be in these disorders (Warkentin, 2001a). complicating HIT treatment with an HIT is by thrombosis there is on heparin with an anticoagulant when HIT is because of thrombocytopenia & Warkentin, et al, 2001). Table lists treatment of HIT (Warkentin, to be heparin with are (Warkentin & and potentially venous (Warkentin et al, platelet are relatively in HIT. is to HIT risk of its frequency of causing this et al, of anticoagulant are for HIT, when of thrombosis is A recently recognized is that to heparin is an to during in patients with HIT antibodies have et al, Warkentin & 2001b). various treatment to medicolegal risk if but are & Warkentin, 2001). have for treatment of HIT-associated thrombosis. are the and two thrombin and (Table have not compared in a of and found for treatment of HIT-associated with greater risk with et al, 2001). The to a should be based upon in or and or treatment of HIT-associated thrombosis with one of these there a frequency of thrombosis (Table The frequency of an is greater if the and This that and other patient are when therapy with an anticoagulant is some patients or when thrombosis is by is a of anticoagulant heparan and It is (Table and with to in a clinical (Table et al, 2001). does not the and has a which it for venous complicating HIT, where to is is HIT-associated thrombosis or HIT et al, Warkentin, by has the can be two or is a to thrombosis complicating HIT. It complexes with Its is about which increases in (Table in patients with or is relatively The is by an infusion of for a activated of However, when thrombosis is it may be to the and to a Greinacher, this has risk of and and has risk of the may be to using the of the normal for the is used during or one is to or of the by 2001). et al the studies for treatment of HIT-associated which also as a et al, (Table and studies clinical have with greater et al, et al, a from the of antibodies that lead to in a of patients et al, from of It is that antibodies explain which has in patients Greinacher, the is a thrombin associated with a thrombotic event in studies of both thrombosis complicating HIT and HIT et al, The infusion of used in both The is the must be in is for treatment of HIT and thrombosis complicating HIT in the and the and a during upon the used to the should be used et al, 2001). The is for during There is of using this for HIT et al, is in the for during in patients with or HIT et al, 2002). is an pentasaccharide for This does not with HIT antibodies (Amiral et al, and should be for HIT, its can thrombin generation in HIT. class of can lead to thrombosis when used to HIT-associated resulting in as venous (Warkentin et al, have a which a for in factor (Warkentin, of in HIT (Warkentin et al, who develop venous in HIT not have in the anticoagulant that HIT is a risk factor for complications of (Warkentin, has during therapy of with or and has when the thrombin during thrombocytopenia et al, et al, should be of thrombocytopenia in patients with HIT et al, 2001). This also reduces risk for with or because of from to is to with or has in these of can be in HIT patients with platelet activation by HIT-IgG in et al, and may platelet in HIT. In are for HIT to studies have a high risk of thrombosis in patients with HIT of heparin with or by (Table In the the risk of thrombosis from to and the from to in and of patients in two A high of thrombosis has when patients with HIT HIT-associated thrombosis is not when heparin is because of detection of HIT platelet et al, thrombin generation heparin contributes to the thrombotic this that platelet of patients lead to only if heparin is by an anticoagulant (Warkentin, is in the for the of HIT-associated thrombosis. In a of HIT, thrombosis by compared with as the event of and et al, 2001). for this in to for HIT in thrombosis in only of patients and with the in of patients et al, A of thrombosis also in a of patients for HIT et al, in and of patients with and et al, et al, should be in when used for thrombosis in patients with HIT et al, Warkentin the of HIT, and the evidence for the of using or treatment of HIT is & Warkentin et al, 2001). is to for thrombosis by in the treatment et al, patients in whom HIT antibodies are it is to heparin at the to & Warkentin, are HIT antibodies are not or not appear for at least et al, Warkentin & 2001b). patients who have HIT or HIT, two treatment are can be during such as et al, Warkentin et al, & or with its for and of an patients develop et al, of the to using the et al, risk for during and of has for and predominant rather and it is for this (Warkentin & Greinacher, A second is to heparin with an such as et al, or et al, have used but is the of against this because of heparin should be when is because of a risk of HIT & Warkentin, et al, HIT occurs with compared with in patients, and is associated with a risk of HIT or HIT antibody formation in situations such as and treatment of venous thrombosis et al, 1999; et al, 2002). detection of HIT by platelet has not shown to HIT-associated because heparin to thrombosis. on heparin with an anticoagulant when HIT is has increased the of platelet The of HIT in various clinical situations that of platelet should the risk of HIT in a (Warkentin, The for this and to and for in the The the of and Society on and in a that clinical and laboratory to HIT.

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