Summary
Fcγ receptors have critical roles in the pathophysiology of heparin-induced thrombocytopenia (HIT), a severe immune-mediated complication of heparin treatment. Activation of platelets, ...monocytes and neutrophils by platelet-activating anti-PF4/heparin IgG antibodies results in thrombocytopenia, hypercoagulability and thrombosis in susceptible patients, effects that depend on FcγRIIA. In addition, FcγRIIIA receptors probably contribute to clearance of platelets sensitised by HIT immune complexes. FcγRI has also been reported to be involved in monocyte activation by HIT IgG antibodies and synthesis of tissue factor. This review focuses on the role of these FcγRs in HIT pathophysiology, including the potential influence of several gene variations associated with variable risk of HIT and related thrombosis. In particular, the 276P and 326Q alleles of CD148, a protein tyrosine phosphatase that regulates FcγRIIA signalling, are associated with a lower risk of HIT, and platelets from healthy donors expressing these alleles are hyporesponsive to anti-PF4/H antibodies. It was also recently demonstrated that the risk of thrombosis is higher in HIT patients expressing the R isoform of the FcγRIIA H131R polymorphism, with HIT antibodies shown to activate RR platelets more efficiently, mainly explained by an inhibitory effect of normal IgG2, which bound to the FcγRIIA 131H isoform more efficiently. Environmental risk factors probably interact with these gene polymorphisms affecting FcγRs, thereby increasing thrombosis risk in HIT.
Heparin‐induced thrombocytopenia (HIT) is a common adverse effect of unfractionated heparin (UFH) therapy. In contrast, only a few patients have been reported with HIT following low‐molecular‐weight ...heparin (LMWH) therapy (LMW‐HIT). To define the clinical and biological characteristics of LMW‐HIT, 180 patients treated for suspected HIT at 15 French centres were investigated. Clinical history was recorded and HIT was confirmed in 59 patients with positive serotonin release assay results: 57 of them had high levels of antibodies (Abs) to heparin–platelet factor 4 complexes (H/PF4) and two had Abs to interleukin 8. Eleven patients were treated exclusively with LMWH (LMW‐HIT) and 48 with UFH either alone (UF‐HIT, n = 34) or combined with LMWH (UF/LMW‐HIT, n = 14). The LMW‐HIT and UF‐HIT groups were similar with respect to sex, age, platelet count before heparin therapy, frequency of bleeding and occurrence of disseminated intravascular coagulation. The interval to onset of HIT was longer in LMW‐HIT patients compared with UF‐HIT patients (P = 0·03). Severe thrombocytopenia (platelets < 15 × 109/l) was more frequent in the LMW‐HIT group (P = 0·04). Thrombosis occurred in three of 11 LMW‐HIT patients, i.e. as frequently as in UF‐HIT patients. LMW‐HIT is potentially severe and may be observed after longer heparin treatment compared with UF‐HIT. It is highly recommended, therefore, that platelet counts be monitored carefully whenever LMWH is administered.
Background
Heparin‐induced thrombocytopenia (HIT) is a severe adverse reaction to heparin caused by heparin‐dependent, platelet‐activating anti‐platelet factor 4 (PF4)/heparin antibodies. Heparin is ...a cornerstone of treatment in critically ill COVID‐19 patients. HIT antibodies can be detected by antigen tests and functional tests. Often strong reactivity in the antigen test is used as a surrogate marker for the presence of clinically relevant, platelet‐activating antibodies. We observed an unexpectedly high percentage of COVID‐19 patients, clinically suspected to have HIT, with high titer anti‐PF4/heparin antibodies, but a negative functional test.
Objective
We investigated whether in COVID‐19 patients a serum‐derived factor inhibits the heparin‐induced platelet activation test (HIPA).
Methods and Results
Twelve COVID‐19 patients with suspected HIT were tested. Three samples tested negative in all assays; nine samples tested positive by antigen tests, among which only three tested also positive by HIPA. When we spiked COVID‐19 serum or control serum with the human HIT antibody like monoclonal antibody 5B9, reactivity of 5B9 remained the same. Also, the purified IgG fractions of COVID‐19 sera testing strongly positive in the PF4/heparin antigen test but negative in the functional test did not show increased reactivity in the functional test in comparison to the original serum. Both results make a functionally inhibitory factor in the serum/plasma of COVID‐19 patients highly unlikely.
Conclusion
COVID‐19 patients often present with strong reactivity in PF4/heparin antigen tests without the presence of platelet‐activating antibodies. Diagnosis of HIT requires confirmation of heparin‐dependent, platelets activating antibodies to avoid overdiagnosis and overtreatment with non‐heparin anticoagulants.
The rare vaccine-induced immune thrombotic thrombocytopenia that may follow adenovirus-based Covid-19 vaccination resembles heparin-induced thrombocytopenia, but rapid assays for anti-PF4 antibodies ...used to diagnose HIT may be negative in patients with VITT. The PF4–serotonin release assay appears to detect the IgG antibodies to PF4–PVS that mediate this condition.
Abstract
BACKGROUND
Dual antiplatelet therapy (DAPT) associating aspirin + clopidogrel is commonly utilized in neurovascular interventions despite unpredictable clopidogrel efficacy with 4% to 50% of ...patients considered nonresponders. Ticagrelor is an antiplatelet agent with low resistance rates but unknown efficacy and safety in neurovascular patients.
OBJECTIVE
To evaluate frequency of ischemic and hemorrhagic events in patients treated with aspirin and ticagrelor when associated with perioperative heparin bolus for unruptured aneurysms treated with intracranial stents.
METHODS
One hundred fifty-four consecutive patients with unruptured intracranial aneurysms treated by stent procedures (113 = flow diverter stent FDS, 41 = stent-assisted coiling) were retrospectively analyzed. All patients received aspirin and ticagrelor without platelet function testing. Patients were separated in 2 groups following perioperative heparin dose: group I = 70 U/kg; group II = 50 U/kg. FDS versus stent-assisted coiling procedures were also separately analyzed.
RESULTS
Nine patients (5.8%) presented symptomatic neurological complications poststenting (3 ischemic, 6 hemorrhagic): 8 patients received 70 U/kg of heparin (11.1%) and 1 patient received 50 U/kg (1.2%; P < .009). Four patients died (2.6%) during the 3-mo follow-up period—all deaths were correlated to intracranial hemorrhage: 3 at group I and 1 at group II (P < .251). No difference in complications or death was observed considering separately FDS and stent-assisted coiling procedures.
CONCLUSION
This study did not find more neurological complications than in previous neurointerventional reports using DAPT with aspirin + ticagrelor or aspirin + clopidogrel. Overall number of neurological complications was lower when a lower dose of heparin was administered. Neurovascular studies comparing clopidogrel to ticagrelor and different doses of heparin are necessary to demonstrate which association is more efficient with lower complication rates.
Summary
Retinal vein occlusion (RVO) is a multifactorial disease involving vessel damage, stasis, viscosity and thrombosis. Conflicting findings on hereditary thrombophilic risk factors have been ...reported and their impact on RVO features remains to be defined. The aim of the present study was to evaluate the prevalence of hereditary thrombophilic risk factors (HTRF) and characteristics of RVO in patients with or without HTRF. The design of the study was a prospective, observational case series. Two hundred and thirty-four patients with RVO were included consecutively. A French healthy population of the same region was studied as control group. The HTRF studied were protein C (PC), protein S (PS) and antithrombin (AT) deficiencies, factor V Leiden (FVL) and factor II 20210A polymorphisms. Chi-Square was used for comparison with the healthy subjects and between RVO patient with and without HTRF according to localisation (branch vs. central), type of RVO (ischemic or non-ischemic), recurrence, age at first event and classical vascular risk factors. Twenty-two patients had HTRF (12 FV Leiden heterozygotes, 9 FII 20210A heterozygotes and 1 PS deficiency). No AT or PC deficiency was detected. Frequencies of PS deficiency, FVL and FII 20210A allele were similar to the reference population as well as to published data in the general caucasian population. Eighty-six patients experienced their first episode before the age of 60 years. Systemic hypertension, glaucoma and angina were significantly less frequent in patients with RVO before 60 years. Fourteen of the 22 patients with one HTRF (64%) experienced their first episode of RVO before the age of 60 years compared to 72 of 212 without HTRF (34%) (
p = 0.006
). Heterozygote status for FV Leiden was significantly more frequent in patients who had experienced their first episode of RVO before 60 years (
p = 0.027
). In conclusion, this study suggests a role of FV Leiden in the occurrence of RVO in patients younger than 60 years who exhibit fewer acquired vascular risk factors than in older patients.
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 FcγRIIa. 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.
Introduction: Auricular chondritis has been occasionally described in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Materials and methods: We report the case ...of a woman with a previous history of APS who presented with auricular chondritis with onset of SLE symptoms during the postpartum period. Conclusion: SLE and APS should be taken into consideration in the differential diagnosis of auricular chondritis.
Abstract
Background
Heparin-induced thrombocytopenia (HIT) is typically caused by platelet-activating immunoglobulin G (IgG) antibodies (Abs) against platelet factor 4 (PF4) complexed with heparin ...(H). Much less frequent “autoimmune” HIT is distinguished from typical HIT by platelet activation without heparin and the presence of both anti-PF4/H and anti-PF4 IgG. We developed three murine monoclonal anti-PF4 Abs with a human Fc-part, 1E12, 1C12, and 2E1, resembling autoimmune HIT Abs.
Objectives
To characterize 1E12, 1C12, and 2E1 in comparison to the heparin-dependent monoclonal anti-PF4/H Abs 5B9 and KKO, and polyclonal Abs from patients with typical HIT (group-2) and autoimmune HIT (group-3).
Methods
Interactions of Abs with PF4 and PF4/H were studied by enzyme-linked-immunosorbent assay, single-molecule force spectroscopy, isothermal titration calorimetry, and dynamic light scattering. Serotonin release assay and heparin-induced platelet activation assay were used to assess platelet activation. The binding sites of monoclonal Abs on PF4 were predicted in silico (MAbTope method).
Results
1C12, 1E12, and 2E1 displayed higher affinity for PF4/H complexes than 5B9 and KKO, comparable to human group-3 Abs. Only 1C12, 1E12, 2E1, and group-3 Abs formed large complexes with native PF4, and activated platelets without heparin. The predicted binding sites of 1C12, 1E12, and 2E1 on PF4 differed from those of KKO and 5B9, but were close to each other. 2E1 exhibited unique bivalent binding, involving its antigen recognition site to PF4 and charge-dependent interactions with heparin.
Conclusion
1C12, 1E12, and 2E1 are tools for studying the pathophysiology of autoimmune HIT. 2E1 provides evidence for a new binding mechanism of HIT Abs.
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