Platelet-activating anti-PF4 disorders: An overview

Platelet factor 4 (PF4) is a highly cationic tetrameric protein that can be targeted by platelet-activating anti-PF4 antibodies of immunoglobulin G (IgG) class. Certain features of PF4, including its multivalent nature (duplicate antigen sites per tetramer), the ability of many PF4 tetramers to undergo close approximation through charge neutralization, and the dimeric binding of IgG molecules, results in formation of IgG-containing immune complexes in situ on platelets, neutrophils, and monocytes, resulting in Fcγ receptor-mediated pancellular activation that also activates hemostasis (potential for disseminated intravascular coagulation). This review discusses 4 anti-PF4 disorders: classic heparin-induced thrombocytopenia ([HIT]; triggered by heparin and certain other polyanionic pharmaceuticals, featuring predominantly heparin-dependent antibodies), autoimmune HIT (aHIT; severe subtype of HIT that features both heparin-dependent and heparin-independent platelet-activating antibodies), and spontaneous HIT (non-heparin triggers such as knee replacement surgery and infection; predominantly heparin-independent platelet-activating antibodies). Most recently, a novel fourth anti-PF4 disorder, vaccine-induced immune thrombotic thrombocytopenia (VITT), was identified as an ultrarare complication of adenovirus vector vaccines. VITT is characterized by thrombocytopenia, disseminated intravascular coagulation, a high frequency of thrombosis—including in unusual sites (cerebral veins, splanchnic veins)—and highly pathogenic anti-PF4 antibodies with heparin-independent platelet-activating properties.     

Delayed-onset heparin-induced thrombocytopenia

Delayed-onset heparin-induced thrombocytopenia is a syndrome in which thrombocytopenia and thrombosis begin several days after heparin discontinuation. Delayed-onset heparin-induced thrombocytopenia is caused by immunoglobulin G antibodies that are reactive against the heparin-platelet factor 4 complex in the absence of circulating heparin. We describe 2 patients with delayed-onset heparin-induced thrombocytopenia who presented to the emergency department. An 88-year-old man and a 62-year-old man experienced thrombocytopenia and thrombosis 9 or more days after heparin cessation and demonstrated a further decrease in platelet count on reexposure to heparin. Delayed-onset heparin-induced thrombocytopenia should be included in the differential diagnosis of a patient with recent heparin exposure who presents with thrombosis or thrombocytopenia.     

Delayed-onset HIT caused by low-molecular-weight heparin manifesting during fondaparinux prophylaxis

Heparin-induced thrombocytopenia (HIT) is a prothrombotic condition caused by platelet-activating antibodies that react with platelet factor 4 (PF4)/heparin complexes. Delayed-onset HIT occurs after heparin is stopped. Fondaparinux, a synthetic pentasaccharide, is thought to be a safe alternative anticoagulant in HIT. We describe a patient with delayed-onset HIT triggered by low-molecular-weight heparin (LMWH) which occurred during fondaparinux prophylaxis and which was complicated by microangiopathic hemolytic anemia. Patient serum contained high-titer anti-PF4/heparin antibodies demonstrating heparin-dependent platelet activation with serial dilutions. Confirmed delayed-onset HIT with LMWH has not been previously reported. Low dose fondaparinux does not necessarily prevent thrombotic complications of HIT.     

Heparin-induced thrombocytopenia

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

Heparin-induced thrombocytopenia: association with a platelet aggregating factor and arterial thromboses.

Eleven patients with heparin-induced thrombocytopenia were studied. Thrombocytopenia appeared 3-16 days following the initiation of prophylactic or therapeutic doses of heparin. The mean lowest platelet count recorded was 48,000/mm3. When heparin was stopped, recovery from thrombocytopenia began within 24 hours and was complete by ten days. Two patients developed fatal thromboses, and two others had myocardial infarctions while thrombo-cytopenic. In the serum of seven patients, including three of the four with arterial thrombosis, a heparin-dependent platelet aggregating factor was present. The factor caused release of platelet 14C serotonin but did not lyse platelets. It was present in the globulin fraction of all positive sera, and in one serum studied it was isolated in the IgG/IgA immunoglobulin fraction. The factor was not present in 16 normal sera or in the sera of 15 nonthrombocytopenic patients receiving heparin. Our observations suggest that heparin-induced thrombocytopenia is common and that, in some patients it may be accompanied by severe arterial thrombosis. In vivo platelet aggregation is a possible explanation for the thrombocytopenia and the thrombosis in this disorder.     

Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: a nested cohort study

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating, heparin-dependent IgG antibodies (HIT-IgG). Although HIT is known to predispose the patient to thrombosis, the relationship between the formation of HIT-IgG and various other unusual clinical sequelae putatively linked with the HIT syndrome, such as heparin-induced skin lesions and acute anaphylactoid reactions following treatment with an IV heparin bolus, is not clear. METHODS: We used data from a clinical trial of postoperative heparin prophylaxis to compare the frequency of one or more predefined unusual clinical sequelae developing in 20 patients who formed platelet-activating HIT-IgG with 80 control patients who did not form HIT-IgG (nested cohort study). RESULTS: Five of the 20 patients in whom HIT-IgG developed had one or more unusual clinical sequelae, compared with none of 80 control patients (25% vs 0%, respectively; odds ratio, infinity; 95% confidence interval, 4.3 to infinity; p < 0.001). The unusual complications included heparin-induced erythematous or necrotic skin lesions (n = 4), an anaphylactoid reaction following IV heparin bolus use (n = 1), and warfarin-associated venous limb ischemia (n = 1). Thrombocytopenia, as it is conventionally defined (ie, platelet count fall to < 150 x 10(9) cells/L) developed in only one of these five patients. CONCLUSIONS: Certain unusual clinical sequelae, such as heparin-induced skin lesions, are strongly associated with the formation of HIT-IgG and should be considered as manifestations of the HIT syndrome, even in the absence of thrombocytopenia as conventionally defined.     

A spontaneous prothrombotic disorder resembling heparin-induced thrombocytopenia

Background

Antibodies against the “self” protein, platelet factor 4 (PF4), bound to heparin—the cause of immune heparin-induced thrombocytopenia—are believed invariably to be triggered by preceding heparin therapy. We describe a novel syndrome, spontaneous heparin-induced thrombocytopenia, in which clinical and serologic features characteristic of this adverse drug reaction develop in patients despite the absence of preceding heparin therapy.

Methods

Three patients met the study criteria (clinical and serologic features of heparin-induced thrombocytopenia without preceding heparin exposure), of whom 2 patients were identified among 225 patients (0.89%, 95% confidence interval, 0.11%-3.17%) with serologically confirmed heparin-induced thrombocytopenia recognized during an 18-year period at 1 hospital. The platelet serotonin-release assay was used to detect heparin-dependent immunoglobulin G-induced platelet activation, and 2 enzyme immunoassays were used to detect antibodies against PF4/heparin.

Results

Two patients presented with thrombocytopenia and multiple arterial thrombosis, and 1 patient presented with anaphylactoid reactions after 2 subcutaneous injections of low-molecular-weight heparin. All 3 patients had high levels of platelet-activating anti-PF4/heparin antibodies of immunoglobulin G class at presentation despite the absence of previous heparin exposure. However, each patient did have a preceding infectious or inflammatory event; 1 patient had concomitant antiphospholipid antibodies.

Conclusion

Circumstances other than heparin use can trigger a spontaneous disorder that closely mimics heparin-induced thrombocytopenia, further supporting the autoimmune nature of this adverse drug reaction.     

Characterization of the humoral immune response in heparin-induced thrombocytopenia

Recent reports indicate that antibodies associated with heparin-induced thrombocytopenia and thrombosis (HITP) are specific for complexes formed between heparin and the heparin-binding, platelet alpha granule protein, platelet factor 4 (PF4). As with other disorders mediated by immune complexes (IC), the characteristics of the involved immunoglobulins could affect the ability of IC to cause symptoms. We therefore studied the class, subclass, and potency of antibodies specific for heparin:PF4 complexes formed by two groups of patients: one with severe thrombocytopenia, with or without thrombosis, and a positive serotonin release assay (SRA) (Group 1) and another with mild or absent thrombocytopenia, absence of thrombosis, and a negative SRA despite having formed antibodies reactive with heparin:PF4 complexes (Group 2). IgG antibodies were more common in the Group 1 patients (100%) than in Group 2 (46%), whereas IgM antibodies were more common in Group 2 (81%) than in Group 1 (42%) (P = 0.009). About half of each group formed IgA antibodies. In each group, the IgG antibodies were predominantly IgG1 (82%); 42% were IgG3. Only one IgG2 antibody was identified in a total of 52 antibody formers. Antibodies of the IgG class were consistently of higher titer in Group 1 patients than in Group 2 patients (P < 0.001). Recent reports suggest that the H131 form of the FcγRII receptor, which binds preferentially to IgG2 Fc, is found with greater than expected frequency in patients with HITP. Identification of only one IgG2 antibody among 38 antibodies of the IgG class argues against a unique role for antibodies of this subclass in the pathogenesis of HITP. The finding that titers of antibodies in Group 1 patients were a significantly higher titer than in Group 2 patients suggests that development of the full-blown HITP syndrome may require the formation of antibodies of unusually high titer. Am. J. Hematol. 54:196–201 © 1997 Wiley-Liss, Inc.     

Spontaneous heparin-induced thrombocytopenia syndrome without any proximate heparin exposure,infection, or inflammatory condition: Atypical clinical features with heparin-dependent platelet activating antibodies

Recent studies suggest that a thromboembolic disorder resembling heparin-induced thrombocytopenia (HIT), so-called spontaneous HIT syndrome, can occur in patients without any history of heparin exposure. It is likely due to anti-platelet factor 4 (PF4)/polyanion antibodies induced by other polyanions, such as bacterial surfaces and nucleic acids. We describe an atypical case of spontaneous HIT syndrome. A 70-year-old man suddenly presented with acute cerebral sinus thrombosis (CST). Soon after the initiation of unfractionated heparin (UFH) for the treatment of CST, his platelet count fell precipitously and he developed deep vein thrombosis, a clinical picture consistent with rapid-onset HIT but without any proximate episodes of heparin exposure, infection, trauma, surgery, or other acute illness. Antigen assays and a washed platelet activation assay indicated that the patient already possessed anti-PF4/heparin IgG antibodies with heparin-dependent platelet activation properties on admission. Cessation of UFH and initiation of argatroban resulted in prompt recovery of his platelet count without further thromboembolic events. We identified two similar cases in the literature. However, these patients do not meet the recently proposed criteria for spontaneous HIT syndrome. Even in atypical cases, however, inappropriate or delayed diagnosis of HIT appears to be associated with worse outcomes. We propose that these atypical cases should be included in the category of spontaneous HIT syndrome.     

Prevalance of heparin-dependent platelet-activating antibodies in preterm newborns after exposure to unfractionated heparin.

Heparin is frequently used in preterm infants to prolong the patency of intravascular catheters. The aim of this study was to evaluate the prevalence of heparin-dependent platelet-activating antibodies in newborns. A cross-section of all preterm newborn infants expected to require heparin to maintain patency of a central venous access line were enrolled. A blood sample was obtained soon after birth before heparin exposure to exclude the possibility of placental transfer of maternal heparin-dependent platelet-activating antibodies. A second sample was obtained at termination of heparin use (mean duration of heparin exposure was 23 +/- 13 days; range, 6-67). Paired samples, at birth and after heparin use, were available for 42 infants with a mean gestational age of 27.8 +/- 2.2 weeks and birth weight of 1036 +/- 267 g. Thrombocytopenia developed in 57% (24/42) of the infants. None of these infants had clinical suspicion of thrombosis during the study period. The etiology of thrombocytopenia was confirmed sepsis in six, presumed sepsis in three, necrotizing enterocolitis in one, and unclear in 14 infants. Anti-heparin/platelet factor 4 antibodies measured using the standard assays for heparin-induced thrombocytopenia (two commercially available enzyme-linked immunosorbent assay tests and the functional platelet serotonin release assay) were negative on all infants. Although it could be related to the poor ability of these infants to mount an immunologic response, further research is necessary to fully understand this lack of response to heparin and to elucidate further the reasons for thrombocytopenia in very-low-birth-weight infants.     

Heparin-induced skin lesions

Six patients who developed heparin-induced skin lesions were tested for the presence of heparin-dependent, platelet-activating IgG irrespective of whether they developed thrombocytopenia. All six patients' sera contained potent heparin-dependent, platelet-activating IgG. However, only two of the six patients developed thrombocytopenia, and both of these patients developed thrombotic complications. One of the four patients who developed skin lesions without thrombocytopenia also developed a characteristic complication of heparin-induced thrombocytopenia (adrenal haemorrhagic infarction). These observations indicate that formation of heparin-dependent, platelet-activating IgG is a consistent feature of patients who develop heparin-induced skin lesions irrespective of whether thrombocytopenia occurs.     

Platelet activation induced by human antibodies to interleukin-8

Some cases of heparin-induced thrombocytopenia (HIT) have been reported to be associated with antibodies against interleukin-8 (IL-8), a chemokine related to platelet factor 4. We found that sera from 5 HIT patients containing immunoglobulin G (IgG) or IgM antibodies to IL-8, as evidenced using surface plasmon resonance spectroscopy, were able to trigger IL-8-dependent activation of washed platelets, leading to procoagulant activity. This activation occurred at IL-8 concentrations achievable in vivo and was facilitated by heparin (0.1 U/mL). Activation was also induced by affinity-purified anti-IL-8 IgG and involved FcgammaRIIa. In the 2 patients who could be followed up, antibodies were no longer detectable 4 months after heparin withdrawal. One additional patient with paraneoplastic recurrent thrombosis without thrombocytopenia was found to have platelet-activating anti-IL-8 IgM, but in this case heparin was inhibitory. This is another example of potentially pathogenic platelet activation by antibodies.     

Heparin-dependent and -independent anti-platelet factor 4 autoantibodies in patients with systemic lupus erythematosus

Objective. Antibodies that recognize complexes formed by platelet factor 4 (PF4) and heparin are involved in the pathogenesis of heparin-induced thrombocytopenia (HIT). This study was undertaken to investigate the prevalence and clinical correlations of anti-PF4 autoantibodies in patients with SLE. Methods. We studied 118 patients with SLE, 78 with primary immune thrombocytopenia (ITP), 27 with primary APS, 2 with HIT (as positive controls) and 47 healthy controls. Heparin-dependent and -independent anti-PF4 antibodies were measured with an ELISA. Antibody binding was confirmed to be heparin-dependent when inhibited by the presence of a high concentration of heparin. Pathogenic anti-PF4 antibody was assessed by serotonin-release assay. Results. Heparin-dependent anti-PF4 antibodies were detected in 11 SLE (9%) and 2 primary ITP (3%) patients, but at much lower levels than in HIT patients. In serotonin-release assays, only the HIT sera induced platelet activation in vitro. Heparin-independent anti-PF4 antibodies were detected in 17 SLE patients (14%). There was no correlation between the levels of heparin-dependent and -independent anti-PF4 antibodies. Cross-reactivity between these two antibodies was not detectable by ELISA competitive assay. Heparin-dependent anti-PF4 antibodies were associated with thrombocytopenia and IgM aCLs (P?=?0.007 for both comparisons), while heparin-independent anti-PF4 antibody levels were correlated with SLE disease activity index (P?=?0.0005). None of the SLE patients with anti-PF4 antibodies had previous heparin exposure. Conclusion. PF4 is an autoimmune target in SLE patients. Heparin-dependent and -independent anti-PF4 autoantibodies may be involved in different aspects of pathophysiology of SLE.     

Heparin-induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases

Heparin-induced thrombocytopenia and/or thrombosis (HITT) are serious complications of heparin treatment. The incidence, as previously reported, varies widely and, in consequence, is not precisely known. Moreover, most reports only concern clinically defined heparin-induced thrombocytopenia. Therefore we carried out a prospective study of the incidence of serologically confirmed HITT.
All patients admitted to the Departments of Cardiology and Neurology of our institution with an indication for treatment with therapeutic-dose intravenous unfractionated heparin were enrolled in the study. The patients were examined daily for the occurrence of thromboembolic complications. Regular platelet counts and tests for the presence of heparin-dependent antibodies were carried out using two different tests: a quantitative platelet factor 4/heparin (PF4/hep) Elisa, and a functional test, the heparin-induced platelet activation assay (HIPAA). HITT was defined as a rapidly occurring (within 5 d) decrease of the platelet count from normal values of >120 ×10⁹ l to <60 ×10⁹ l or to <100 ×10⁹ l if there was a rapid fall of >50% of starting value or >30% with concomitant acute thrombosis.
The observed incidence of HITT was 1/358 patients (0.3%, 95% confidence limits 0.01–1.5%). However, Elisa PF4/hep specific IgG antibodes were demonstrated in nine (2.5%) and IgM antibodies in seven (2.0%) of 358 patients. 30/358 patients (8.4%) had platelet activating antibodies in the HIPAA.
We conclude that the incidence of serologically confirmed HITT in this study is very low (0.3%) in patients with cardiac and neurologic diseases treated with intravenous unfractionated heparin. The frequency of heparin-dependent antibodies without concomitant occurrence of thrombocytopenia is much higher.     

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

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

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.     

Heparin-induced thrombocytopenia: a frequent complication after cardiac surgery

Thrombocytopenia is a common problem in cardiovascular patients, and heparin-induced thrombocytopenia (HIT) is therefore frequently suspected. Unfractionated heparin during cardiopulmonary bypass is particularly immunogenic as 25% to 50% post-cardiac surgery patients develop heparin-dependent antibodies but only 1 to 3% will develop HIT. These antibodies recognize a 'self protein', platelet factor 4 (PF4), bound to heparin. Antibodies associated with a high risk of HIT are mainly IgG1 which strongly activate platelets and coagulation, thereby causing thrombocytopenia and thrombosis. A biphasic evolution of platelet count with a secondary decrease after a previous increase following CPB or non-recovery of thrombocytopenia within 6 days post-operatively always requires screening for HIT antibodies. Both functional (platelet activation tests) and immunologic assays (antigen assays) are necessary in every patient to establish the diagnosis of HIT. When the clinical probability of HIT is high, the first requirement is to discontinue heparin, without waiting for results of laboratory investigations. An alternative anticoagulant such as danaparoid sodium (Orgaran) or lepirudin (Refludan) must then be administered since heparin withdrawal alone is insufficient to control the prothrombotic state associated with HIT. The risk of HIT will probably soon decrease due to the wider use of fondaparinux, which does not interact in vitro with PF4, but it could remain significant in patients undergoing cardiac surgery with CPB.     

HITlights: a career perspective on heparin-induced thrombocytopenia

Two decades of research into heparin-induced thrombocytopenia (HIT) permit a personal historical perspective on this fascinating syndrome. Previously, the frequency of HIT was unknown, although complicating thrombosis was believed to be rare and primarily arterial. The opportunity to apply a remarkable test for "HIT antibodies"--the (14) C-serotonin-release assay (SRA)--to serial plasma samples obtained during a clinical trial of heparin thromboprophylaxis, provided insights into the peculiar nature of HIT, such as, its prothrombotic nature--including its strong association with venous thrombosis (RR = 11.6 [95%CI, 6.4-20.8; P < 0.0001); its more frequent occurrence with unfractionated versus low-molecular-weight heparin; the "iceberg" model, which states that among the many patients who form anti-PF4/heparin antibodies during heparin therapy, only a minority whose antibodies evince strong platelet-activating properties develop HIT; and the characteristic HIT timeline, whereby serum/plasma antibodies are readily detectable at or prior to the HIT-associated platelet count fall. Applying the SRA also to patients encountered in clinical practice led to recognition of warfarin-induced venous limb gangrene (for which HIT is a major risk factor via its extreme hypercoagulability) and delayed-onset HIT (whereby thrombocytopenia begins or worsens following heparin discontinuation, due to the ability of HIT antibodies strongly to activate platelets even in the absence of heparin--so-called heparin-"independent" platelet activation). Recent concepts include the increasing recognition of HIT "overdiagnosis" (due to the low diagnostic specificity of the widely-applied PF4-dependent immunoassays), and the observation that HIT-associated consumptive coagulopathy is a risk factor for treatment failure with PTT-adjusted direct thrombin inhibitor therapy ("PTT confounding" secondary to HIT-associated coagulopathy).     

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

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

Unfractionated heparin compared with low-molecular-weight heparin as related to heparin-induced thrombocytopenia

PURPOSE OF REVIEW: Heparin-induced thrombocytopenia is a severe side effect of treatment with unfractionated heparin. The relation of low-molecular-weight heparin to heparin-induced thrombocytopenia is less well understood. This review will summarize what is known about the similarities and differences between thrombocytopenia induced by low-molecular-weight heparin and that induced by unfractionated heparin. RECENT FINDINGS: The pathophysiology of unfractionated heparin-induced thrombocytopenia, caused by the development of antibodies to heparin/platelet factor 4 complexes, holds true for low-molecular-weight heparin because the molecules of the latter are of the same saccharidic structure as those of unfractionated heparin. Owing to their smaller size, however, low-molecular-weight heparin does not interact with platelet factor 4 and platelets as efficiently as does unfractionated heparin. This translates to a two- to threefold lower risk of immune sensitization (antibody generation and occurrence of clinical heparin-induced thrombocytopenia). Low-molecular-weight heparin-induced thrombocytopenia antibodies are more often immunoglobulin A and immunoglobulin M, in contrast to the immunoglobulin G antibodies generated with unfractionated heparin-induced thrombocytopenia, which tend to be more often associated with clinical heparin-induced thrombocytopenia. The clinical expression of low-molecular-weight heparin-induced thrombocytopenia is generally similar to that of unfractionated heparin-induced thrombocytopenia but can have a slower onset, more severe thrombocytopenia, and slower platelet count recovery. Given that low-molecular-weight heparin, of itself, is linked with heparin-induced thrombocytopenia pathophysiology and it can interact with most preexisting heparin-induced thrombocytopenia antibodies generated after exposure to unfractionated heparin, treatment of heparin-induced thrombocytopenia patients with low-molecular-weight heparin is contraindicated. SUMMARY: The risk of the development of heparin-induced thrombocytopenia with low-molecular-weight heparin treatment is reduced relative to the frequency of unfractionated heparin-induced thrombocytopenia, but it is not eliminated, and platelet counts should be monitored with treatment.