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Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia.

ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder initiated by antibodies to complexes between platelet factor 4 (PF4) and heparin. The risk of recurrent thromboembolism persists after heparin is cleared and platelet activation leading to release of PF4 has dissipated. We asked whether antigenic complexes between polyphosphates and PF4 released from activated platelets might intensify or sustain the prothrombotic phenotype of HIT. PF4 forms stable, ultralarge complexes with polyphosphates of various sizes, including those released from platelets, which are recognized by the HIT-like monoclonal KKO, an immunoglobulin G2b? monoclonal heparin/PF4 binding antibody, and by human HIT antibodies. KKO helps to protect PF4/polyphosphate complexes from degradation by phosphatases. Complement is activated when HIT antibodies bind to PF4/polyphosphate complexes and PF4 reverses the inhibition of complement by polyphosphates. Polyphosphates and PF4 are stored primarily in separate granules in resting platelets, but they colocalize when the cells are activated. Platelets activated by subaggregating doses of thrombin receptor activating peptide release polyphosphates and PF4, which form antigenic complexes that allow KKO to further activate platelets in the absence of heparin and exogenous PF4. These studies suggest that thrombin- or immune complex-mediated release of endogenous antigenic PF4/polyphosphate complexes from platelets may augment the prothrombotic risk of HIT and perpetuate the risk of thrombosis after heparin has been discontinued.

SUBMITTER: Cines DB

PROVIDER: S-EPMC5744055 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia.

Cines Douglas B DB Yarovoi Serge V SV Zaitsev Sergei V SV Lebedeva Tatiana T Rauova Lubica L Poncz Mortimer M Arepally Gowthami M GM Khandelwal Sanjay S Stepanova Victoria V Rux Ann H AH Cuker Adam A Guo Cecilia C Ocariza Linnette Mae LM Travers Richard J RJ Smith Stephanie A SA Kim Hugh H Morrissey James H JH Conway Edward M EM

Blood advances 20161122 1

Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder initiated by antibodies to complexes between platelet factor 4 (PF4) and heparin. The risk of recurrent thromboembolism persists after heparin is cleared and platelet activation leading to release of PF4 has dissipated. We asked whether antigenic complexes between polyphosphates and PF4 released from activated platelets might intensify or sustain the prothrombotic phenotype of HIT. PF4 forms stable, ultralarge complexes with polypho ...[more]

PMID: 29296696

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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.

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.

Dataset Information

Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia.

Publications

Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia.

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