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.

Platelet Dysfunction and Intracerebral Hemorrhage in a Patient Treated with Empiric Piperacillin-Tazobactam in the Neurocritical Care Unit.

BACKGROUND: Piperacillin-tazobactam is common empiric antibiotic therapy. Hematologic laboratory test abnormalities were documented but rare in premarketing studies, and whether these alterations are of clinical significance has been studied little. Very few cases of piperacillin-induced bleeding, thrombocytopenia, or both have been reported; aberrations in platelet function have not been implicated. CASE DESCRIPTION: A 55-year old Vietnamese man with hypertension presented for treatment of an Intracranial hemorrhage. Platelet function assays (PFAs) at the time of external ventricular drain and quad-lumen bolt placement were normal, and imaging showed no hemorrhage after placement. The patient was later started on empiric piperacillin-tazobactam due to high suspicion for aspiration pneumonia. After removal of the quad-lumen bolt and external ventricular drain on separate days, both follow-up computed tomography scans showed new hematomas in the devices' tracts, with significant intraventricular hemorrhage. Repeat PFAs were abnormally prolonged, representing a distinct change from baseline. A trend toward normalization of PFAs was observed 6 hours after discontinuation of piperacillin-tazobactam with progression toward baseline thereafter. CONCLUSIONS: This is unique in that the significant bleeding that occurred was attributable to platelet dysfunction rather than thrombocytopenia. This is the first reported case of intracranial (periprocedural) hemorrhage potentially related to piperacillin-tazobactam; further research into this drug's impact upon qualitative platelet function is needed.

Role of coagulopathy in glucocorticoid-induced osteonecrosis of the femoral head.

The two major theories of glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) are apoptosis and ischaemia. The traditional theory implicates ischaemia as the main aetiological factor because the final common pathway of ONFH is interruption of blood supply to the bone. The most common causes of interruption of blood supply include fat embolism and coagulation disorders. GCs can directly or indirectly lead to coagulation disorders, producing a hypercoagulable state, followed by poor blood flow, ischaemia, and eventually ONFH. This review summarizes the existing knowledge on coagulation disorders in the context of GC-induced ONFH, including hypofibrinolysis and thrombophilia, endothelial cell dysfunction and damage, endothelial cell apoptosis, lipid metabolism, platelet activation, and the effect of anticoagulant treatment.

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.

Platelet dysfunction in thrombosis patients treated with vitamin K antagonists and recurrent bleeding.

BACKGROUND: Recurrent bleeding can complicate the treatment of thrombosis patients with vitamin K antagonists (VKA), even at a well-regulated level of anticoagulation. In this proof-of-principle study, we investigated whether alterations in platelet function or von Willebrand factor (vWf) contribute to a bleeding phenotype in these patients. METHODS: In this case-control study 33 well-regulated patients without bleeding events (controls) and 33 patients with recurrent bleeding (cases) were retrospectively included. Thrombin generation and vWf were determined in plasma. Platelet function was assessed by light transmission aggregometry and flow cytometry using a validated panel of agonists. RESULTS: Thrombin generation was similarly reduced in controls and cases, in comparison to normal plasma. Plasma vWf level was above the normal range in 85% of controls and 67% of the cases. vWf activity was similarly increased in all patients in comparison to healthy volunteers. Platelet aggregation was in the normal range for almost all patients irrespective of the type of agonist. However, in response to a low collagen dose, platelets from 21% of controls and 27% of cases showed diminished responses. Agonist-induced secretion of alpha- and dense-granules or integrin αIIbß3 activation were affected in platelets from neither controls nor cases. CONCLUSION: Recurrent bleeding in well-controlled patients on VKA therapy is not explained by anti-hemostatic changes in platelet or vWf function.

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.

Sub-chronic toxicity study of the methanol root extract of Cnestis ferruginea.

CONTEXT: Cnestis ferruginea (CF) Vahl ex DC (Connaraceae) is a shrub abundant in West Africa. Root preparations are used in traditional medicine to treat diverse conditions. OBJECTIVE: To evaluate the sub-chronic toxicological effects of the methanol root extract of CF. MATERIALS AND METHODS: Groups of adult rats of both sexes were treated daily with distilled water (DW) and CF at doses of 80 (sub-therapeutic dose), 400 (therapeutic dose), and 1000 (supra-therapeutic dose) mg/kg orally for 90 days. Animals were weighed weekly and observed for behavioral and morphological changes. At the end, rats were sacrificed and blood samples collected for hematological and biochemical analysis. Vital organs were harvested, weighed, and assessed for in vivo antioxidants and histopathological changes. Sperm analysis and reversibility study were done, and mortality was recorded. RESULTS: CF at the therapeutic dose did not produce any significant irreversible deleterious effects on the weight of animals and vital organs, in vivo antioxidants, histopathological presentation, hematological, biochemical, and sperm parameters. Platelet anomaly was elicited as a delayed effect. Effects at the sub- and supra-therapeutic doses were similar but with delayed anemia in females and weight reduction and sterility in males as possible side effects. CF generally showed a potential to induce in vivo antioxidants. DISCUSSION AND CONCLUSION: Findings suggest that CF given over an extended period possess the potential to cause induction of in vivo antioxidants especially in the ovary. Possible side effects identified with CF, which necessitate caution, include delayed platelet anomaly and anemia in females, weight reduction, and sterility in males.

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.

Paracetamol and cyclooxygenase inhibition: is there a cause for concern?

Paracetamol is recommended as first-line therapy for pain associated with osteoarthrosis and is one of the most widely used over-the-counter analgesic drugs worldwide. Despite its extensive use, its mode of action is still unclear. Although it is commonly stated that paracetamol acts centrally, recent data imply an inhibitory effect on the activity of peripheral prostaglandin-synthesising cyclooxygenase enzymes. In this context paracetamol has been suggested to inhibit both isoforms in tissues with low levels of peroxide by reducing the higher oxidation state of cyclooxygenase enzymes. Two recent studies have also demonstrated a preferential cyclooxygenase 2 (COX-2) inhibition by paracetamol under different clinically relevant conditions. This review attempts to relate data on paracetamol's inhibitory action on peripheral cyclooxygenase enzymes to the published literature on its anti-inflammatory action and its hitherto underestimated side-effects elicited by cyclooxygenase inhibition. As a result, a pronounced COX-2 inhibition by paracetamol is expected to occur in the endothelium, possibly explaining its cardiovascular risk in epidemiological studies. A careful analysis of paracetamol's cardiovascular side-effects in randomised studies is therefore strongly advised. On the basis of epidemiological data showing an increased gastrointestinal risk of paracetamol at high doses or when co-administered with classic cyclooxygenase inhibitors, paracetamol's long-term gastrointestinal impact should be investigated in randomised trials. Finally, paracetamol's fast elimination and consequently short-lived COX-2 inhibition, which requires repetitive dosing, should be definitely considered to avoid overdosage leading to hepatotoxicity.

Measurement of shear-activated platelet aggregate formation in non-anticoagulated blood: utility in detection of clopidogrel-aspirin-induced platelet dysfunction.

We studied the ability of a new instrument, the PlaCor PRT that measures shear-induced platelet aggregation in fingerstick, non-anticoagulated blood without added agonists, to detect platelet dysfunction ex vivo. Platelet reactivity time (PRT) and whole blood aggregation (WBA) were measured in 160 healthy volunteers, before and after aspirin and in 170 participants with established vascular disease or risk factors thereof treated with aspirin ± clopidogrel. Pretreatment PRT and WBA were significantly correlated (collagen r = -.63; arachidonate r = -.65; P < .0001). Following aspirin, the mean PRT increased from 82 to 142 seconds (P < .0001), and in participants treated with clopidogrel-aspirin, the mean PRT (286 seconds, n = 65) was significantly longer than with aspirin alone (166 seconds, n = 105; P < .001). Only 13% of PRTs of participants treated with clopidogrel and aspirin were within the normal range. We conclude that the PlaCor PRT is a simple, rapid, point-of-care instrument that compares favorably with published descriptions of other platelet function instruments.