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Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.

ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia. We now show that platelet factor 4 binds to monocytes and forms antigenic complexes with their surface GAG side chains more efficiently than on platelets likely due to differences in GAG composition. Binding to monocytes is enhanced when the cells are activated by endotoxin. Monocyte accumulation within developing arteriolar thrombi was visualized by situ microscopy. Monocyte depletion or inactivation in vivo attenuates thrombus formation induced by photochemical injury of the carotid artery in a modified murine model of HIT while paradoxically exacerbating thrombocytopenia. These studies demonstrate a previously unappreciated role for monocytes in the pathogenesis of arterial thrombosis in HIT and suggest that therapies targeting these cells might provide an alternative approach to help limit thrombosis in this and possibly other thrombotic disorders that occur in the setting of inflammation.

SUBMITTER: Rauova L

PROVIDER: S-EPMC3012595 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.

Rauova Lubica L Hirsch Jessica D JD Greene Teshell K TK Zhai Li L Hayes Vincent M VM Kowalska M Anna MA Cines Douglas B DB Poncz Mortimer M

Blood 20100819 23

Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening thrombotic disorder that develops after exposure to heparin, often in the setting of inflammation. We have shown previously that HIT is associated with antibodies to complexes that form between platelet factor 4 and glycosaminoglycan (GAG) side chains on the surface of platelets. However, thrombosis can occur in the absence of thrombocytopenia. We now show that platelet factor 4 binds to monocytes and forms antigenic complexe ...[more]

PMID: 20724543

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Project description:BackgroundDiagnosis of heparin-induced thrombocytopenia (HIT) is challenging. This study aimed to compare the diagnostic performance of HIT expert probability (HEP) and 4T scores, and to evaluate the inter-observer reliability for the 4T score in a clinical setting.MethodsThis prospective study included HIT-suspected patients between 2016 and 2018. Three hematologists assessed the HEP and 4T scores. Correlations between scores and anti-platelet factor 4 (anti-PF4)/heparin antibodies were evaluated. Receiver operating characteristic curves and area under the curve (AUC) were used to assess the predictive accuracy of these two scoring models. The intraclass correlation coefficient (ICC) was used to assess the inter-observer agreement of 4T scores between residents and hematologists.ResultsOf the 89 subjects included, 22 (24.7%) were positive for anti-PF4/heparin antibody. The correlations between antibody titer and either HEP or 4T scores were similar (r?=?0.392, P?<?0.01 for the HEP score; r?=?0.444, P?<?0.01 for the 4T score). No significant difference in the diagnostic performance was displayed between these two scores (AUC for the HEP score: 0.778 vs. AUC for the 4T score: 0.741, P?=?0.357). Only 72 4T scores were collected from the residents, with a surprisingly low percentage of observers (43.1%) presenting the four individual item scores which made up their 4T score. The AUC of 4T score assessed by residents and hematologists was 0.657 (95% confidence interval [CI]: 536-0.765) and 0.780 (95% CI: 0.667-0.869, P?<?0.05), respectively. The ICC of 4T score between residents and hematologists was 0.49 (95% CI: 0.29-0.65, P?<?0.01), demonstrating a fair inter-observer agreement.ConclusionsThe HEP score does not display a better performance for predicting HIT than the 4T score. With the unsatisfactory completion rate, the inter-observer agreement of 4T score in a tertiary hospital is fair, underscoring the necessity for continuing education for physicians.

Project description:BackgroundThis is a review article on heparin-induced thrombocytopenia, an adverse effect of heparin therapy, and vaccine-induced immune thrombotic thrombocytopenia, occurring in some patients administered certain coronavirus vaccines.Main body/textImmune-mediated thrombocytopenia occurs when specific antibodies bind to platelet factor 4 /heparin complexes. Platelet factor 4 is a naturally occurring chemokine, and under certain conditions, may complex with negatively charged molecules and polyanions, including heparin. The antibody-platelet factor 4/heparin complex may lead to platelet activation, accompanied by other cascading reactions, resulting in cerebral sinus thrombosis, deep vein thrombosis, lower limb arterial thrombosis, myocardial infarction, pulmonary embolism, skin necrosis, and thrombotic stroke. If untreated, heparin-induced thrombocytopenia can be life threatening. In parallel, rare incidents of spontaneous vaccine-induced immune thrombotic thrombocytopenia can also occur in some patients administered certain coronavirus vaccines. The role of platelet factor 4 in vaccine-induced thrombosis with thrombocytopenia syndrome further reinforces the importance the platelet factor 4/polyanion immune complexes and the complications that this might pose to susceptible individuals. These findings demonstrate, how auxiliary factors can complicate heparin therapy and drug development. An increasing interest in biomanufacturing heparins from non-animal sources has driven a growing interest in understanding the biology of immune-mediated heparin-induced thrombocytopenia, and therefore, the development of safe and effective biosynthetic heparins.Short conclusionIn conclusion, these findings further reinforce the importance of the binding of platelet factor 4 with known and unknown polyanions, and the complications that these might pose to susceptible patients. In parallel, these findings also demonstrate how auxiliary factors can complicate the heparin drug development.

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Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.

Publications

Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia.

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