Challenges in the Monitoring of Therapeutic Plasma Exchange during Acute Heparin-Induced Thrombocytopenia in Adults under ECMO.

Therapeutic plasma exchange (TPE) has been proposed to remove heparin-induced thrombocytopenia (HIT) antibodies before planned thoracic surgery in patients with acute HIT and to allow brief re-exposure to heparin during surgery. In patients on extracorporeal membrane oxygenation (ECMO), simultaneous administration of TPE and alternative nonheparin anticoagulant therapies is challenging. We report 2 patients on ECMO with acute HIT who underwent repeated TPE to enable cardiothoracic surgery with the use of heparin. In both cases, serial monitoring of HIT antibody titer and heparin-induced platelet activation assay (HIPA) was performed. The effect of adding exogenous platelet factor 4 (PF4) in the HIPA was also tested. Negative anti-PF4/H IgG levels were achieved after 5 and 3 TPE sessions, respectively and patients could beneficiate from surgery with brief heparin re-exposure without any thrombotic complication. Negative HIPA results were obtained before negative anti-PF4/H IgG in one patient but remained positive in the other despite very low antibody titers. The addition of PF4 in HIPA led to more contrasted results for the two patients. Serial HIT screening including immunological and functional assays is necessary to closely monitor TPE in acute HIT patients on ECMO who require surgery. The addition of PF4 in HIPA could help detect clinically relevant platelet-activating antibodies and guide re-exposure to heparin.

Monoclonal Gammopathy of Thrombotic Significance.

The current review provides an overview of the thrombotic risk observed in patients with MG who do not otherwise require treatment. We discuss clinical and biomarker studies that highlight the heterogenous hemostatic profile observed in these patients and how knowledge has evolved over the past 20 years. Biomarker studies suggest shared biologic features between multiple myeloma and monoclonal gammopathy of undetermined significance (MGUS), which involves both hypercoagulability and platelet activation. Hemostatic abnormalities identified in MGUS patients cannot be translated into clinical practice as they lack correlation to clinical events. The prothrombotic phenotype of MGUS patients has not been ascertained yet, but novel data on coagulation markers are promising. We also review rare conditions associated with the thrombogenic properties of the monoclonal protein that predispose to arterial, venous or microthrombotic events and demonstrate that the M-protein can be linked to clinically significant thrombotic events. Cryoglobulinemia, cryofibrinogenemia, cryo-crystaloglobulinemia and MG-related antiphospholipid syndrome are reviewed. We propose the new umbrella term "monoclonal gammopathy of thrombotic significance" (MGTS) to refer to significant, recurrent thrombotic events in patients with MGUS that provide a rationale for targeting the underlying plasma cell clone. Identifying MGUS patients at high risk for thrombotic events is currently a challenge.

Multiple Sites of Arterial Thrombosis in A 35-Year Old Patient after ChAdOx1 (AstraZeneca) Vaccination, Requiring Emergent Femoral and Carotid Surgical Thrombectomy.

BACKGROUND: Vaccine Induced Thrombotic Thrombocytopenia (VITT) is a rare complication following ChAdOx1 (AstraZeneca) vaccination. Venous thrombosis in unusual sites such as splachnic or intracranial thrombosis, is the commonest manifestation. CASE REPORT: We report a 35-year-old male patient who presented with acute left leg ischemia and thrombocytopenia 11-days after vaccination requiring emergent thrombectomy. During work-up, a localized thrombus was detected in the left carotid bifurcation mandating carotid thrombectomy. Localized right iliac thrombus causing a non-limiting flow stenosis was treated conservatively. The platelet aggregating capacity of patient's plasma was confirmed in a functional assay, thereby establishing VITT. CONCLUSION: To the best of our knowledge this is the first case presenting multiple arterial thromboses requiring surgical treatment after ChAdOx1 vaccination.

Heparin-induced Thrombocytopenia Diagnosis: A Retrospective Study Comparing Heparin-induced Platelet Activation Test to 14 C-serotonin Release Assay.

Laboratory confirmation of heparin-induced thrombocytopenia (HIT) is of crucial importance and remains challenging and relies on platelet functional assays highlighting the presence of heparin-dependent platelet-activating antibodies in patient serum or plasma. Platelet functional assays using washed platelets include the 14 C-serotonin release assay (SRA), usually described as the gold standard, and the heparin-induced platelet activation assay (HIPA). Since its first comparison with SRA there has been no additional published study regarding HIPA diagnostic performances compared with SRA. Aim of our retrospective study was to compare the concordance between HIPA and SRA in HIT suspected-patients with positive anti-PF4/heparin antibodies between October 2010 and October 2015. Fifty-five HIT-suspected patients who beneficiated from both HIPA and SRA were included. Positive and negative percent agreements were 83.8% (95% CI 68.0-93.8%) and 66.7% (95% CI 41.0-86.7%), respectively. Overall percent agreement was 78.2% (95% CI 65.0-92.2%). Agreement was higher in patients who underwent cardiopulmonary bypass with extracorporeal circulation circuit for cardiac surgery. We also confirm that the use of a minimum of 2 platelet donors to establish positive HIT diagnosis and 4 platelet donors to exclude HIT diagnosis allows obtaining a good agreement with SRA. Although HIPA and SRA were performed with different platelet donors and in different laboratories, HIPA had a good positive agreement with SRA for HIT diagnosis, showing that HIPA is a useful functional assay that does not require radioactivity and could be developed worldwide to improve HIT diagnosis.

Correction of Severe Myelofibrosis, Impaired Platelet Functions and Abnormalities in a Patient with Gray Platelet Syndrome Successfully Treated by Stem Cell Transplantation.

Gray platelet syndrome (GPS) is an inherited disorder. Patients harboring GPS have thrombocytopenia with large platelets lacking α-granules. A long-term complication is myelofibrosis with pancytopenia. Hematopoietic stem cell transplant (HSCT) could be a curative treatment. We report a male GPS patient with severe pancytopenia, splenomegaly and a secondary myelofibrosis needing red blood cells transfusion. He received an HSCT from a 10/10 matched HLA-unrelated donor after a myeloablative conditioning regimen. Transfusion independence occurred at day+21, with a documented neutrophil engraftment. At day+ 180, we added ruxolitinib to cyclosporine and steroids for a moderate chronic graft versus host disease (GVHD) and persistent splenomegaly. At day+240 GVHD was controlled and splenomegaly reduced. Complete donor chimesrism was documented in blood and marrow and platelets functions and morphology normalized. At day+ 720, the spleen size normalized and there was no evidence of marrow fibrosis on the biopsy. In GPS, HSCT may be a curative treatment in selected patients with pancytopenia and myelofibrosis.

Prospective Evaluation of a Rapid Functional Assay for Heparin-Induced Thrombocytopenia Diagnosis in Critically Ill Patients.

OBJECTIVES: Overdiagnosis of heparin-induced thrombocytopenia remains an unresolved issue in the ICU leading to the unjustified switch from heparin to alternative anticoagulants or delays in anticoagulation. Platelet function assays significantly improve the specificity of heparin-induced thrombocytopenia diagnosis, but they are not readily available, involve technical difficulties and have a long turnaround time. We evaluated the performance of a rapid and easy to perform functional assay for heparin-induced thrombocytopenia diagnosis in ICU patients, known as "heparin-induced multiple electrode aggregometry." DESIGN: In this observational prospective study patients were tested with the immunoglobulin G enzyme-linked immunosorbent assay, the serotonin release assay and heparin-induced multiple electrode aggregometry. Heparin-induced multiple electrode aggregometry was assessed against heparin-induced thrombocytopenia diagnosis (clinical picture in favor, serotonin release assay, and immunoglobulin G enzyme-linked immunosorbent assay positive) and serotonin release assay. SETTING: Medical or surgical ICU of 35 medical centers. PATIENTS: Patients suspected for heparin-induced thrombocytopenia hospitalized in medical or surgical ICU from January 2013 to May 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Heparin-induced thrombocytopenia diagnosis was retained in 12 patients (14%). Using heparin-induced thrombocytopenia diagnosis as reference, heparin-induced multiple electrode aggregometry showed an excellent negative predictive value and sensitivity, at 98% and 92% respectively. Its positive predictive value and specificity were 100%. Receiver operating characteristic analysis with the serotonin release assay as reference showed an optimal heparin-induced multiple electrode aggregometry cut-off at 1,300 AU × minutes (specificity, 100%; sensitivity, 90%; area under the curve, 0.98; 95% CI, 0.95-1.0). The Kappa coefficient between heparin-induced multiple electrode aggregometry and the serotonin release assay was at 0.90%. CONCLUSIONS: Heparin-induced multiple electrode aggregometry performed very well in heparin-induced thrombocytopenia diagnosis in ICU patients and agreed with the gold standard test for heparin-induced thrombocytopenia diagnosis, the serotonin release assay. Heparin-induced multiple electrode aggregometry is a reliable and rapid platelet functional assay that could decrease heparin-induced thrombocytopenia overdiagnosis in the ICU setting.

Eltrombopag to Treat Thrombocytopenia During Last Month of Pregnancy in a Woman With MYH9-Related Disease: A Case Report.

MYH9-related disease (MYH9-RD) is an inherited rare autosomal dominant macrothrombocytopenia. Patients with MYH9-RD have giant platelets and leukocyte inclusion bodies caused by mutations in the MYH9 gene encoding the non-muscle myosin heavy chain II-A. Before identification of the causative gene, patients were diagnosed as Epstein or Fechtner or Sebastian syndromes or May-Hegglin anomaly. As with other inherited thrombocytopenias, the risk of increased bleeding during perioperative period or delivery is a major concern. We report here the first successful cesarean delivery of a woman with MYH9-RD treated with eltrombopag during the last month of pregnancy.

Mutations of the integrin αIIb/ß3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α-granules.

Rare gain-of-function mutations within the ITGA2B or ITGB3 genes have been recognized to cause macrothrombocytopenia (MTP). Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, ß3D723H. In silico analysis shows how the two mutated amino acids directly modify the salt bridge linking the intra-cytoplasmic part of αIIb to ß3 of the integrin αIIbß3. For all affected patients, the bleeding syndrome and MTP was mild to moderate. Platelet aggregation tended to be reduced but not absent. Electron microscopy associated with a morphometric analysis revealed large round platelets; a feature being the presence of abnormal large α-granules with some giant forms showing signs of fusion. Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips. Interestingly, this study revealed that in addition to the classical phenotype of patients with αIIbß3 intracytoplasmic mutations there is an abnormal maturation of α-granules. It is now necessary to determine if this feature is a characteristic of all mutations disturbing the αIIb R995/ß3 D723 salt bridge.

Rapid detection of D-Dimers with mLabs® whole blood method for venous thromboembolism exclusion. Comparison with Vidas® D-Dimers assay.

BACKGROUND: Easy to use point of care assays for D-Dimers measurement in whole blood from patients with clinical suspicion of venous thromboembolism (VTE) will facilitate the diagnostic strategy in the Emergency Department (ED) setting. We prospectively evaluated the diagnostic performance of the point-of-care mLabs® Whole Blood D-Dimers test and we compared it with the Vidas® D-Dimers assay. METHODS: As part of the diagnostic algorithm applied in patients with clinical suspicion of VTE, the VIDAS® D-Dimers Test was prescribed by the emergency physician in charge. The mLabs® Whole Blood D-Dimers Test was used on the same samples. All patients had undergone exploration with the recommended imaging techniques for VTE diagnosis. RESULTS: Both assays were performed, on 99 emergency patients (mean age was 65 years) with clinical suspicion of VTE. In 3% of patients, VTE was documented with a reference imaging technique. The Bland and Altman test showed significant agreement between the two methods. Both assays showed equal sensitivity and negative predictive value for VTE. CONCLUSIONS: The mLabs whole blood assay is a promising point of care method for measurement of D-Dimers and exclusion of VTE diagnosis in the emergency setting which should be validated in a larger prospective study.

[The usefulness of platelet function evaluation in clinical practice]. / L'exploration fonctionnelle plaquettaire: intérêts en pratique clinique.

Platelets play a pivotal role in the regulation of both thrombosis and haemostasis. Functional testing of platelet response has been exclusively used in the diagnosis and management of bleeding disorders. Recent advances of light transmission aggregometry and development of more useful devices have demonstrated the clinical utility to enlarge platelet function testing in patients with cardiovascular disease. The ex vivo measurement of residual platelet response seems, with some assays, predictive of adverse clinical events. Still a debate, it represents an emerging area of interest for both the clinician and the basic scientist. Heparin-induced thrombocytopenia diagnosis is also difficult and a functional assay is now available for an easier and rapid method to rule out such a life-threatening situation. This review article will describe the available methods of measuring platelet response and will discuss both the limitations and emerging data supporting the role of platelet function studies in clinical practice.