Imatinib-induced platelet dysfunction and hypofibrinogenemia in chronic myeloid leukemia.

: We aim to present a case of chronic myeloid leukemia (CML) in chronic phase, in major molecular response for 5 years of treatment with imatinib 400 mg OD. He presented with recurrent melena for one and a half years, requiring 11 U of packed red cell transfusion since then. Various causes of bleeding in CML, such as thrombocytopenia, disease progression related to accelerated phase/blast crisis or imatinib-induced cytopenia were ruled out. His investigations revealed reduced plasma fibrinogen (150 mg/ml; range 200-450 mg/ml). The platelet count, prothrombin time, activated partial thromboplastin time and thrombin time were 314 × 10/l, 13 s (control 13 s), 31 s (control 30 s) and 16 s (control 16 s), respectively. Platelet aggregometry revealed normal platelet aggregation with adenine-di-phosphate, epinephrine and ristocetin, and reduced response with arachidonic acid (30%). Bleeding subsided with transfusion of fresh frozen plasma. Moreover, his medication was changed to nilotinib 300 mg BD. Thereafter, his subsequent repeat investigations were normal. Platelet function defects in CML both pretherapy and on tyrosine kinase inhibitors has been described in the literature. However, concomitant hypofibrinogenemia has rarely been reported.

TKI-Related Platelet Dysfunction Does Not Correlate With Bleeding in Patients With Chronic Phase-Chronic Myeloid Leukemia With Complete Hematological Response.

Bleeding has been reported in patients with chronic myeloid leukemia (CML) using tyrosine kinase inhibitors (TKIs). In this study, we aimed to evaluate platelet functions and associated bleeding symptoms in patients with CML using TKIs. A standardized questionnaire that was developed for inherited bleeding disorders (ISTH/SSC Bleeding Assessment Tool) was used to score bleeding symptoms in 68 chronic phase patients with CML receiving imatinib (n = 47), dasatinib (n = 15), or nilotinib (n = 6). Light transmission aggregometry was used for platelet function testing. None of the patients had major bleeding (score > 3). Minor bleeding was observed in 25.6% and 20% of the patients in imatinib and dasatinib treatment groups. Impaired/decreased platelet aggregation was observed in 29.8% of imatinib treatment group, 50% of nilotinib group, and 40% of dasatinib group. A secondary aggregation abnormality compatible with the release defect was observed in 26% of patients with CML; 25.5%, 33.3%, and 16.7% of patients receiving imatinib, dasatinib, and nilotinib, respectively. No correlation was found between bleeding symptoms and the impaired platelet function. We can conclude that TKIs may impair in vitro platelet aggregation but this impairment is not associated with bleeding diathesis.

Platelet aggregation response in immune thrombocytopenia patients treated with romiplostim.

The thrombopoietin receptor agonist romiplostim is used for the long-term treatment of chronic immune thrombocytopenia (ITP). ITP patients have an increased thrombotic risk, which could be exacerbated if romiplostim increased platelet hyperreactivity or caused spontaneous platelet aggregation. To investigate this possibility, this study examined platelet function in romiplostim-treated ITP patients and healthy subjects. Light transmission platelet aggregometry utilizing arachidonic acid, collagen, epinephrine, ristocetin, ADP, and saline (to assess spontaneous aggregation) was performed for each subject. In addition, the ADP AC50 (ADP concentration that induced half-maximal aggregation) was determined for each patient as a sensitive measurement of altered platelet reactivity. Fifteen ITP patients and 7 healthy subjects entered the study. All ITP patients had active disease and were receiving weekly romiplostim as the sole ITP-directed therapy. Platelet aggregation in response to the strong agonists arachidonic acid, collagen, and ristocetin was not significantly different between ITP patients and healthy subjects (P = 0.2442, P = 0.0548, and P = 0.0879, respectively). Platelet aggregation in response to weak agonists was significantly reduced in ITP patients compared with that in healthy subjects: median (range) aggregation to ADP, 45% (15-84%) versus 89% (70-95%) (P = 0.0010), and epinephrine, 21% (1.6-90%) versus 88% (79-94%) (P = 0.0085). The median AC50 of ADP was threefold higher in ITP patients versus that in healthy subjects (6.3 µM vs 2.1 µM) (P = 0.0049). Significant spontaneous aggregation was not observed in any patient. Platelets from romiplostim-treated ITP patients do not show evidence for spontaneous aggregation or hyperreactivity, but instead have a modestly reduced aggregation response to ADP and epinephrine.

Failure of the Platelet Function Assay (PFA)-100 to detect antiplatelet agents.

BACKGROUND: Antiplatelet therapy is a complicating factor in patients with traumatic brain injuries (TBI), as well as those with hemorrhagic cerebrovascular accidents (CVAs). Platelet Function Assay (PFA)-100 is a coagulation device that can detect platelet dysfunction caused by aspirin and adenosine diphosphate inhibition. Our retrospective study reviewed the effectiveness of PFA-100 in detecting platelet dysfunction caused by aspirin and clopidogrel and determined its clinical importance. METHODS: All patients with PFA-100 tests from January 2013 to February 2014 were collected. Diagnoses indicative of a TBI or CVA were chosen for analysis. Patients with a normal PFA-100 indicating no platelet dysfunction but with documented aspirin and/or clopidogrel use were selected. An extensive chart review was performed to determine the relevance to their clinical care. RESULTS: A total of 475 patients were evaluated with a PFA-100 from January 2013 to February 2014. PFA-100 detected platelet dysfunction as the result of pre-injury use of antiplatelet agents in TBI and CVA patients with a sensitivity of only 48.6% and a specificity of 74.8%. Had these antiplatelet medications been known during initial workup, these patients would have had a change in management that may have impacted their outcomes. CONCLUSION: Despite its common usage, the PFA-100 is an unreliable tool to assist in the management of TBI and CVA patients. Additional investigation into alternative methods for detecting platelet dysfunction is warranted.

Comparison of the safety of seven iodinated contrast media.

We aimed to determine the characteristic adverse events (AEs) of iodinated contrast media (IOCM) and to compare the safety profiles of different IOCM. This study used the database of AEs reports submitted by healthcare professionals from 15 Regional Pharmacovigilance Centers between June 24, 2009 and December 31, 2010 in Korea. All reports of IOCM, including iopromide, iohexol, iopamidol, iomeprol, ioversol, iobitridol and iodixanol, were analyzed. Safety profiles were compared between different IOCM at the system organ level using the proportional reporting ratio (PRR) and 95% confidence interval (95% CI). Among a total of 48,261 reports, 6,524 (13.5%) reports were related to the use of IOCM. Iopromide (45.5%), iohexol (16.9%), iopamidol (14.3%) and iomeprol (10.3%) were identified as frequently reported media. 'Platelet, bleeding & clotting disorders' (PRR, 29.6; 95%CI, 1.9-472.6) and 'urinary system disorders' (PRR, 22.3; 95% CI, 17.1-29.1) were more frequently reported for iodixanol than the other IOCM. In conclusion, the frequency of AEs by organ class was significantly different between individual media. These differences among different IOCM should be considered when selecting a medium among various IOCM and when monitoring patients during and after its use to ensure optimum usage and patient safety.

Drugs that affect platelet function.

Drugs represent the most common cause of platelet dysfunction in our overmedicated society. While acetylsalicylic acid (aspirin), adenosine diphosphate receptor antagonists (clopidogrel and prasugrel), and integrin αIIbß3 (GPIIb-IIIa) receptor blockers (abciximab, eptifibatide, and tirofiban) are well-known prototypes of antiplatelet drugs, other widely used agents such as nonsteroidal anti-inflammatory drugs, antibiotics, cardiovascular and lipid-lowering drugs, selective serotonin reuptake inhibitors, and volume expanders can also impair platelet function and thus cause or aggravate hemorrhages in certain clinical settings. Therefore, induction of a bleeding diathesis remains a significant concern. This is especially relevant in patients with preexisting hemostatic defects of any kind, which may remain compensated as long as platelet function (and/or coagulation) is not inhibited pharmacologically. Identification of individual patients with preexisting hemostatic defects remains crucial (1) to prevent otherwise unexpected bleeding complications, (2) to manage hemorrhagic symptoms adequately, (3) to minimize the risk from invasive procedures, and (4) to avoid unnecessary patient exposure to blood products. This article provides a review of the large variety of agents that have not been designed for antiplatelet therapy but nevertheless interfere with platelet reactivity or induce platelet inhibition. In particular, drug interactions and mechanisms by which these agents can trigger or cause platelet dysfunction are detailed.

Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy.

BACKGROUND: Tumour necrosis factor-alpha (TNF-α) is an important mediator of the molecular cascade leading to chronic inflammation. TNF-α inhibitors have proven their safety and efficacy in the treatment of inflammatory diseases. AIM: To review the non-malignant haematological adverse events, such as thrombocytopaenia, neutropaenia, hypercoagulability, pancytopaenia and aplastic anaemia in patients receiving TNF-α inhibitors. METHODS: We reviewed the literature by searching MEDLINE and EMBASE databases as well as references of all retrieved articles for the following terms: anti-tumour necrosis factor, anti-TNF, infliximab, adalimumab, certolizumab, etanercept, haematological complications, thrombocytopaenia, neutropaenia, anaemia, bone marrow and thrombosis. RESULTS: Thombocytopaenia is a very rare phenomenon and was associated with no serious adverse events. However, transient neutropaenia developed in up to 16% of cases. Patients with a previous history of neutropaenia on other therapies or baseline neutrophil count <4 × 10(9) /L are at a particularly higher risk. The association between anti-TNF-α therapy and thrombosis is very nebulous due to the multitude of potential confounders. Only one case of primary eosinophilia has been reported with anti-TNF-α therapy. CONCLUSION: Regular monitoring of the white blood cell count at baseline and with each infusion is recommended for patients on anti-TNF-α. Further studies to elucidate their interaction with the immune system are warranted.

Acquired disorders of platelet function.

Platelet dysfunction is commonly acquired due to medications, procedures, medical conditions, and underlying hematologic disease. These issues are presented, the data reviewed, and recommendations given herein. Many medications and dietary supplements have platelet-inhibitory effects in vitro, although the clinical effects on bleeding risks are unclear for many. Platelet-inhibitory drugs are key in the treatment of vascular disease. Data are available to aid in the management of these medications to prevent hemorrhagic complications. Bleeding in patients with renal failure has decreased with improved dialysis and the use of erythropoietin, but remains a challenge. Platelet dysfunction accompanies cardiac valvular disease and use of cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation. Hematologic disorders including myeloproliferative disorders (MPDs), myelodysplasia, paraproteinemias, and immune thrombocytopenia (ITP) can also be associated with hemorrhagic complications due to platelet dysfunction. Knowledge of which factors affect bleeding risk and how to treat individuals with acquired platelet dysfunction are important in optimizing patient care.

Complications in oral and maxillofacial surgery: management of hemostasis and bleeding disorders in surgical procedures.

Oral and maxillofacial surgeons perform a wide variety of surgical procedures. One of the major complications of these various surgical techniques is uncontrolled bleeding. The best management of perioperative hemorrhage is prevention. This includes proper preoperative patient evaluation, knowledge of the various bleeding disorders, and the characterization of the correct methods of management. This article evaluates various causes of bleeding, and identifies both local and systemic and pathways. Considerations of treatment for patients with these various disorders are discussed regarding the best management options for adequate hemostasis.

The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects.

P2Y12, the G(i)-coupled platelet receptor for adenosine diphosphate (ADP), plays a central role in platelet function. Patients with congenital P2Y12 defects display a mild to moderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and post-traumatic blood loss. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥ 10 µM), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid. The most important drawback of clopidogrel is its inability to inhibit adequately P2Y12-dependent platelet function in approximately one-third of patients who are therefore not protected from major cardiovascular events. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y12 in the majority of patients, proved to be more efficacious than clopdidogrel in preventing major cardiovascular events. Although they increase the incidence of major bleedings, the net clinical benefit is in favor of the new P2Y12 inhibitors.

Modified thromboelastography evaluation of platelet dysfunction in patients undergoing coronary artery surgery.

OBJECTIVE: Anti-platelet therapy is associated with increased perioperative bleeding. Although current guidelines call for its caessation 5-10 days prior to cardiac surgery, this could constitute an increased risk of preoperative myocardial infarction. The optimal safe period from discontinuation of anti-platelet therapy to surgery is as yet unknown for the individual patient. We investigated whether preoperative thromboelastography (TEG) with platelet mapping could predict bleeding tendency in patients (on recent anti-platelet therapy) undergoing coronary artery bypass grafting (CABG). METHODS: We prospectively evaluated 59 patients on aspirin and clopidogrel therapy who underwent CABG. Of them, 25 patients received aspirin alone. TEG with platelet mapping was performed immediately prior to surgery in all 59 patients. RESULTS: During the first 24h post-surgery, 9/59 patients bled excessively (1216 + or - 310 ml in excessive bleeding vs 576 + or - 155 ml in non-bleeding patients). Of the patients bled excessively, eight received clopidogrel treatment prior to surgery. However, 26 of the remaining 34 patients receiving clopidogrel did not bleed significantly. Clopidogrel-induced platelet dysfunction diagnosed by platelet mapping discerned between patients who demonstrated excessive bleeding and those who did not (78% - sensitivity, 84% - specificity, p=0.004). Aspirin-induced platelet dysfunction did not reflect a bleeding tendency. Of all patients, 85% did not respond to a standard dose of clopidogrel, whereas 44% did not respond to aspirin. CONCLUSIONS: TEG with platelet mapping is able to predict excessive postoperative blood loss among patients who underwent CABG and recent anti-platelet therapy. The prevalence of non-responsiveness to anti-platelet therapy, including clopidogrel, is higher in patients undergoing coronary artery bypass grafting than in the general population. In this study, aspirin-induced platelet dysfunction did not influence postoperative blood loss.

Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia.

Dasatinib is associated with increased risk of bleeding among patients with chronic myeloid leukemia, even in the absence of thrombocytopenia, suggesting the presence of a hemostatic defect. We tested platelet aggregation in 91 patients with chronic myeloid leukemia in chronic phase either off-therapy (n = 4) or receiving dasatinib (n = 27), bosutinib (n = 32), imatinib (n = 19), or nilotinib (n = 9). All but 3 patients simultaneously receiving imatinib and warfarin had normal coagulation studies. All 4 patients off therapy had normal platelet aggregation. Impaired platelet aggregation on stimulation with arachidonic acid, epinephrine, or both was observed in 70%, 85%, and 59% of patients on dasatinib, respectively. Eighty-five percent of patients on bosutinib, 100% on nilotinib, and 33% on imatinib had normal platelet aggregation. Dasatinib 400 nM induced rapid and marked prolongation of closure time to collagen/epinephrine in normal whole blood on the PFA-100 system. In conclusion, dasatinib and, to some extent, imatinib produce abnormalities in platelet aggregometry testing.

Platelet-dense granule deficiency causes postoperative hemorrhage in patients receiving enoxaparin: a novel observation with dramatic clinical implications.

BACKGROUND: Inherent hemorrhage risk has impeded the universal adoption of low-molecular-weight heparin (LMWH) for venous thromboembolic prophylaxis in surgical patients. Coagulation pathway parameters and platelet numbers routinely are evaluated preoperatively; scant attention has been directed toward evaluation of platelet function. We hypothesized that administration of LMWH may unmask latent platelet dysfunction and result in postoperative hemorrhage. METHODS: Postoperative hemorrhage occurred in 15 (3.5%) of 423 consecutive patients undergoing laparoscopic gastric bypass. All patients received LMWH (enoxaparin, 40 mg) preoperatively. Hematologic evaluation included measurement of von Willebrand's factor level and activity, factor VIII level, and electron microscopic enumeration of platelet-dense granules. RESULTS: All patients had normal preoperative platelet counts and coagulation profiles. Ten patients underwent hematologic evaluation: coagulation pathway parameters were normal in all; however, all patients had a markedly decreased number of platelet-dense granules. CONCLUSIONS: Platelet-dense granule deficiency may cause postoperative hemorrhage in patients receiving LMWH.

Prevalence of platelet dysfunction and abnormal coagulation: results of a population-based study.

The prevalence of impairments in the hemostatic process is unknown in acutely ill people. Data on hemostasis (PFA 100) and the coagulation cascade of 1015 people are presented here, establishing a cohort of unselected emergency patients in a population-based approach. A high prevalence of reduced platelet function (38%) was found, which was more frequent than expected. In contrast, there was a lower prevalence (20%) of abnormal plasmatic coagulation, which was almost always explained by medication, whereas medication could not predict abnormal platelet function. Moreover, a history of disproportionate bleeding did not correlate well with abnormal platelet or coagulation factor function and could not substitute for a screening in this setting. The effect of acetylsalicylic acid (ASA) on PFA-closure time was frequently missing (34%), indicating a considerable prevalence of ASA nonresponse among the study population. These data should be applicable in similar settings. The high prevalence of unexpectedly abnormal platelet function in acute illness as well as the high prevalence of possible ASA nonresponders suggests a functional platelet assay to be effective in screening certain subpopulations of emergency patients.

Is platelet adhesion assay able to quantify drug-induced platelet dysfunction?

The platelet adhesion assay (PADA) is an innovative method for the detection of both normal, pathologically increased or decreased platelet adhesiveness. Adhesion is the first important phase of platelet activation, followed by shape change and aggregation. Adhesion is triggered by glycoproteins (GP) on the platelet surface, mainly by GPIIb/IIIa, and to a lesser extent also by GPIb/V/IX. Since fibrinogen serves as adhesive protein for GPIIb/IIIa receptors, and since the PADA uses polymer particles that become coated with fibrinogen, the PADA is able to monitor GPIIb/IIIa receptor antagonists and to detect overdosing, potentially leading to bleeding complications. Ex vivo, citrated whole blood from healthy volunteers and patients was spiked with increasing GPIIb/IIIa inhibitor concentrations and PADA was measured. Comparing these results with GPIIb/IIIa receptor occupancy, determined by FACS, a basic consistency of the data was shown. Via intracellular signaling, the adenosine diphosphate (ADP) receptor mechanism is closely involved in the activation of GPIIb/IIIa receptors so that also ADP receptor antagonists of the thienopyridine type, especially clopidogrel, can be quantitatively determined by the PADA. In patients under clopidogrel therapy, the therapeutic effect was monitored and also individual dose adjustments were realized. Furthermore, patients having partial or full clopidogrel resistance were identified. Overdoses can be detected as well.