Specific Binding of Paraprotein to Platelet Receptors as a Cause of Platelet Dysfunction in Monoclonal Gammopathies

Đjunić, Irena; Elezović, Ivo; Vučić, Miodrag; Srdiċ-Rajiċ, Tatjana; Konić-Ristić, Aleksandra; Ilic, Vera; Milić, Nataša; Bila, Jelena; Suvajdzic-Vukovic, Nada; Virijevic, Marijana; Vidovic, Ana; Tomin, Dragica

doi:10.1159/000345418

Cited by 13 publications

(15 citation statements)

References 16 publications

(20 reference statements)

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“…Binding of IgA to the platelet FcαRI receptor has also been demonstrated to stimulate release of pro‐inflammatory cytokines, interleukin (IL)‐1β and tissue factor 63 . The finding of PAIg in subsets of patients with SM/MM, and PAIg in patients with MGUS with relatively low paraprotein levels, supports reports that disease‐specific changes affect paraprotein specificity or aggregation to facilitate PAIg 60,64,65 . Various mechanisms for PAIg may be involved and could be assessed in future work.…”

Section: Discussionmentioning

confidence: 55%

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Platelet hyperactivation in multiple myeloma is also evident in patients with premalignant monoclonal gammopathy of undetermined significance

et al. 2020

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Thrombotic events are common in patients with multiple myeloma (MM), smouldering myeloma (SM) and monoclonal gammopathy of undetermined significance (MGUS). Previous studies have indicated platelet hyperactivation as a feature of thrombotic risk in MM, but there is a dearth of data in MGUS. In the present study, multiparameter analysis of platelet activation and responsiveness was investigated by flow cytometry in patients with MGUS, SM/MM and healthy controls (HCs). The median platelet surface CD63 levels, annexin V and PAC-1 antibody (specific for activated integrin aIIbb3) binding were significantly elevated in patients with MGUS versus the HCs. These markers were also elevated in SM/MM, but not significantly. In all, 74% of MGUS and 38% of SM/MM patients had one or more elevated marker of platelet activation, compared to 19% of the HCs. Marker-specific hyporesponsiveness of platelets to agonist [adenosine diphosphate (ADP), thrombin receptor-activating peptide 6] stimulation in vitro was observed, with significantly reduced surface levels of Pselectin in response to ADP in patients with MGUS. Platelet-leucocyte aggregates were not altered in patients, while platelet-associated immunoglobulins were elevated in a subset of patients. Overall, we found that platelet hyperactivation is prevalent in both MGUS and SM/MM patients and is potentially related to hyporesponsiveness. These observations suggest that further investigation of the predictive and prognostic value of platelet hyperactivation in such patients is warranted.

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Section: Discussionmentioning

confidence: 55%

“…50 This may be attributed to blockade of specific surface receptors by paraproteins, hindering agonist-receptor interactions. 60 Paraprotein binding may also trigger receptor signalling that contributes to platelet hyperactivation. Our present finding of hyperactivation in these patients may involve Fc receptor signalling.…”

Section: Figmentioning

confidence: 99%

Platelet hyperactivation in multiple myeloma is also evident in patients with premalignant monoclonal gammopathy of undetermined significance

et al. 2020

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“…19,20 Although this method was questioned for a lack of sensitivity to detect certain types of platelet disorders (eg, secretion or granula defects), these defects are not typically found in MM. 7 In MM and PCD, interference of paraproteins with the platelet VWF receptor (GPIb, CD42b) and collagen binding sites (GPVI, CD36) 21,22 has been shown to cause a disturbed interplay of platelet cytoadhesive receptors and their ligands. In addition, paraproteins with specificity for GPIIIa have been found and resulted in a significant bleeding diathesis.…”

Section: Discussionmentioning

confidence: 99%

Disease progression and defects in primary hemostasis as major cause of bleeding in multiple myeloma

Hinterleitner

Pecher

Kreißelmeier

et al. 2019

European J of Haematology

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Background and objectives In patients with multiple myeloma (MM), unexpected bleeding complications remain a major issue. Since routine coagulation parameters are often inconspicuous, diagnosis and treatment of the underlying coagulation disorders are challenging. Patients and methods In our single‐center observational study, we analyzed 164 patients with MM for coagulation disorders and bleeding complications. Results Prolonged closure times (CTs), measured by PFA‐100, were the most common, abnormal coagulation test, found in 66% of bleeding patients vs 5% in non‐bleeding, followed by qualitative defects of von Willebrand factor (VWF:CB/VWF:Ag ratios), found in 34% vs 1% in the non‐bleeding group. Increased serum free light chains (SFLC) and SFLC ratios were significantly associated with prolonged CTs and acquired von Willebrand syndrome (AVWS). Prolonged CTs and AVWS were associated with disease progression, determined by dynamics of SFLC ratios (P < .001), serum creatinine level (P = .013), Beta‐2 microglobulin (P = .03), LDH (P = .016), and bone marrow infiltration (P < .001). Of note, response to myeloma therapy was frequently correlated with normalization of coagulation parameters. Conclusions Bleeding complications in MM are predominantly caused by defects in primary hemostasis and associated with disease progression. In a peri‐interventional workup, determination of CTs and VWF:CB/VWF:Ag ratios are of significant importance to assess bleeding risk.

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“…Certain drugs 9,10 and procedures 11,12 that can affect platelet function need to be considered in these complicated patients (Table 1), but removal of the paraprotein is generally effective in improving platelet function and helps in correcting the bleeding diathesis. Djunic et al 13 showed that paraproteins bind to specific platelet receptors such as the platelet vWF receptor GPIb and platelet collagen receptor GPVI (decreased CD42b and CD36 expression on flow cytometry, respectively. On addition of paraprotein to platelet-rich plasma from normal healthy donors), thereby affecting their function.…”

Section: Discussionmentioning

confidence: 99%

“…On addition of paraprotein to platelet-rich plasma from normal healthy donors), thereby affecting their function. 13 New generation instruments such as multiplate multiple electrode aggregrometry using whole blood impedancemetry allow multiple functional studies to be performed on platelets using agonists (such as ADP test, RISTO test, COL test among others) using the help of multiple channels on the analyzer. 14 In paraprotein associated aVWD, the laboratory reports will show a normal PT and prolonged APTT which corrects on mixing.…”

Section: Discussionmentioning

confidence: 99%

Acquired Platelet Dysfunction as a Cause of Bleeding Diathesis: Two Case Studies

Khan¹

2017

HTIJ

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The aims are to highlight the importance of recognizing that clinically significant platelet dysfunction can develop in the background of known causes of bleeding disorders. In this paper, we discuss two patients who developed acquired platelet dysfunction due to eosinophilia with underlying mild Hemophilia A and IgA paraproteinemia that complicated a clinical picture of acquired von Willebrand disease.Case 1: An 8-yr-old boy with known mild haemophilia A presented with abdominal pain and gross haematuria that partially response to Factor VIII concentrate and cryoprecipitate. Tests revealed significant peripheral eosinophilia (AEC 3200/mm 3 ), prolonged bleeding time >15seconds, FVIIIc 31%, normal vWF: Ag and RICOF assays. Functional platelet studies were abnormal and a diagnosis of Acquired Platelet Dysfunction with Eosinophilia (APDE) was made. His symptoms resolved with standard treatment of eosinophilia with anti-histamines, diethylcarbamazine and albendazole.Case 2: A 57-year-old lady was admitted with malena following commencement of oral prednisolone for recently diagnosed Sjogrens syndrome. UGI showed multiple gastric erosions with no response to standard treatment. She was a known diabetic and treated for carcinoma breast 4years ago. A year before this admission, she had her first bleeding episode with epistaxis following septoplasty (APTT prolonged at 40s, not investigated). She finally responded to fresh frozen plasma and cryoprecipitate. Investigations showed APTT 55sec, protein electrophoresis/immune fixation-small spike with IgA lambda and normal SFLC ratio. The mucosal bleeds with partial response to cryoprecipitate and FFP was suggestive of aVWD. Functional platelet studies were abnormal and a diagnosis of paraprotein associated acquired platelet dysfunction was made. She responded to rituximab with reduction in IgA levels and no further bleeds and remains on bortezomib. Identification of acquired platelet dysfunction and knowledge of how that may affect bleeding risk with existing complex autoimmune/hematological disorders are important in optimizing patient care.

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Specific Binding of Paraprotein to Platelet Receptors as a Cause of Platelet Dysfunction in Monoclonal Gammopathies

Cited by 13 publications

References 16 publications

Platelet hyperactivation in multiple myeloma is also evident in patients with premalignant monoclonal gammopathy of undetermined significance

Platelet hyperactivation in multiple myeloma is also evident in patients with premalignant monoclonal gammopathy of undetermined significance

Disease progression and defects in primary hemostasis as major cause of bleeding in multiple myeloma

Acquired Platelet Dysfunction as a Cause of Bleeding Diathesis: Two Case Studies

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