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Selected mechanisms of drug induced thrombocytopenia in cancer. Examples of implicated drugs are given for each mechanism. HDAC, histone deacetylase.
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Cancer patients have varying incidence, depth and duration of thrombocytopenia. The mainstay of managing severe chemotherapy-induced thrombocytopenia (CIT) in cancer is the use of platelet transfusions. While prophylactic platelet transfusions reduce the bleeding rate, multiple unmet needs remain, such as high residual rates of bleeding, and antica...
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There are no standard treatments to prevent or hasten the recovery from severe conditioning-regimen-induced thrombocytopenia occurring after autologous hematopoietic cell transplantation (autoHCT). We conducted an open-label, single-arm pilot study of romiplostim, a thrombopoietin receptor agonist, to enhance platelet recovery in patients with mult...
Citations
... In contrast, most single Vwf-tdTomato − HSCs replenish all lympho-myeloid lineages upon transplantation (multilineage HSCs (multi-HSCs)), typically in a lineage-balanced or lymphoid-biased manner 9 . the bone marrow (BM), resulting in transient but critical reductions in short-lived platelets and granulocytes, which can lead to considerable morbidity, hospitalization and transfusion burden 4 . In addition to hemostasis and thrombosis 5 , platelets have important roles in immune responses 6,7 . ...
... In addition to hemostasis and thrombosis 5 , platelets have important roles in immune responses 6,7 . Substantial efforts have been made toward enhancing platelet replenishment following therapeutic and physiological challenges, but success has been limited 4 . ...
Rare multipotent stem cells replenish millions of blood cells per second through a time-consuming process, passing through multiple stages of increasingly lineage-restricted progenitors. Although insults to the blood-forming system highlight the need for more rapid blood replenishment from stem cells, established models of hematopoiesis implicate only one mandatory differentiation pathway for each blood cell lineage. Here, we establish a nonhierarchical relationship between distinct stem cells that replenish all blood cell lineages and stem cells that replenish almost exclusively platelets, a lineage essential for hemostasis and with important roles in both the innate and adaptive immune systems. These distinct stem cells use cellularly, molecularly and functionally separate pathways for the replenishment of molecularly distinct megakaryocyte-restricted progenitors: a slower steady-state multipotent pathway and a fast-track emergency-activated platelet-restricted pathway. These findings provide a framework for enhancing platelet replenishment in settings in which slow recovery of platelets remains a major clinical challenge.
... Coagulopathy in leukemia can result from thrombocytopenia, factor deficiencies, hypofibrinogenemia and/or enhanced fibrinolysis [2,3]. This constellation can result in mild to severe lifethreatening bleeds [1,4]. ...
... Sixty-two patients were enrolled with a median age of 5.5 years (Q1-Q3, [3][4][5][6][7][8][9][10][11], and predominant diagnosis of ALL (91.9 %). Table 1 describes the presenting clinical characteristics and diagnoses. ...
... Thrombocytopenia may thus last several weeks or months, increasing the risk of bleeding. Thrombocytopenia due to anticancer therapy occurs via various mechanisms that can be divided into two groups: bone marrow suppression and effects on circulating platelets [72]. Alkylating agents, cyclophosphamide, cisplatin, and proteasome inhibitors inhibit pluripotent stem cells, act on later megakaryocyte progenitors, and decrease platelet shedding by megakaryocytes. ...
... Gemcitabine and mitomycin C cause thrombotic microangiopathy, while venetoclax and cisplatin increase platelet apoptosis. Kinase inhibitors inhibit platelet kinase activity [72]. Thrombocytopenia does not protect from VTE but significantly increases the risk of bleeding, mostly when using anticoagulants [70]. ...
Simple Summary
People with cancer are at an increased risk of developing blood clots. Both cancer and anti-cancer treatment are responsible for this risk. In some types of cancer, such risk is higher than in others. There are different types of blood thinners also known as anticoagulants. Blood thinners prevent the recurrence of deep venous thrombosis (a blood clot in the limbs) or pulmonary embolism (a blood clot in the lungs) in people with cancer. In some clinical situations and, specifically, in patients with active cancer, injectable blood thinners are safer than tablets to be taken orally and work just as well.
Abstract
Cancer-associated thrombosis (CAT) is a leading cause of death among patients with cancer. CAT can manifest itself as venous thromboembolism (VTE), in the form of deep vein thrombosis or pulmonary embolism, or arterial thromboembolism. The pathophysiology of CAT is complex and depends on cancer-, patient-, treatment- and biomarkers-related factors. Treatment of VTE in patients with cancer is complex and includes three major classes of anticoagulant agents: heparin and its derivatives, e.g., low molecular weight heparins, direct oral anticoagulants (DOACs), and vitamin K inhibitors. Given the tremendous heterogeneity of clinical situations in patients with cancer and the challenges of CAT, there is no single universal treatment option for patients suffering from or at risk of CAT. Initial studies suggested that patients seemed to prefer an anticoagulant that would not interfere with their cancer treatment, suggesting the primacy of cancer over VTE, and favoring efficacy and safety over convenience of route of administration. Recent studies show that when the efficacy and safety aspects are similar, patients prefer the oral route of administration. Despite this, injectables are a valid option for many patients with cancer.
... [11] Increased risk for spontaneous bleeding occurs with platelet counts <20,000/µL, and a threshold platelet count of >10,000/ µL is recommended for prophylactic platelet transfusion in patients receiving therapy for hematologic malignancies. [26,36] Higher platelet counts of >20,000/µL are recommended in the setting of hemorrhage as well as in settings of expectant invasive procedures. [36] reshold platelet counts 40-50,000/µL are recommended before performing any major invasive procedure and platelet counts >100,000/µL before neurosurgery. ...
Background
Surgical decompression for the treatment of chronic subdural hematomas (cSDHs) is irrefutably effective; however, its utility in managing cSDH in patients with comorbid coagulopathy remains controversial. The optimal threshold for platelet transfusion in cSDH management is <100,000/mm ³ , according to guidelines from the American Association of Blood Banks GRADE framework. This threshold may be unachievable in refractory thrombocytopenia, though surgical intervention may still be warranted. We present a patient with symptomatic cSDH and transfusion-refractory thrombocytopenia successfully treated with middle meningeal artery embolization (eMMA). We also review the literature to identify management approaches for cSDH with severe thrombocytopenia.
Case Description
A 74-year-old male with acute myeloid leukemia presented to the emergency department with persistent headache and emesis following fall without head trauma. Computed tomography (CT) revealed a 12 mm right-sided, mixed density SDH. Platelets were <2000/mm ³ initially, which stabilized to 20,000 following platelet transfusions. He then underwent right eMMA without surgical evacuation. He received intermittent platelet transfusions with platelet goal >20,000 and was discharged on hospital day 24 with resolving SDH on CT.
Conclusion
High-risk surgical patients with refractory thrombocytopenia and symptomatic cSDH may be successfully treated with eMMA without surgical evacuation. A platelet goal of 20,000/mm ³ before and following surgical intervention proved beneficial for our patient. Similarly, a literature review of seven cases of cSDH with comorbid thrombocytopenia revealed five patients undergoing surgical evacuation following initial medical management. Three cases reported a platelet goal of 20,000. All seven cases resulted in stable or resolving SDH with platelets >20,000 at discharge.
... In China, recombinant human thrombopoietin (rhTPO) is a standard treatment for chemotherapy-induced thrombocytopenia, but it is not available elsewhere (31,32). rhTPO use is associated with the generation of antibodies against endogenous thrombopoietin, which results in refractory thrombocytopenia (33). ...
... Thrombocytopenia is one of the most frequent consequences of anticancer therapy (45) and because polyphenols are often used in cancer therapy, we decided to first test the effects of compounds 1-14 that have been isolated as a result of previous research (3,4) on platelet viability ( Figure 10A). Among them, only compound 1 concentration-dependently decreased platelet viability ( Figure 10B). ...
Fourteen hexane-soluble polyphenolic secondary metabolites were previously isolated as individual compounds from Empetrum nigrum L. and identified as three bibenzyls, four 9,10-dihydrophenanthrenes, two chalcones, four dihydrochalcones and one flavanone. In this study, the mass-spectra and retention indexes (RI) of compounds 1-14 without prior derivatization were obtained and the resulting fragmentation pathways rationalized in accordance with literary data and the compounds structures. Preliminary differences in metabolite composition were assessed by comparative profiling using GC-MS chromatography combined with multivariate data analysis for a limited amount of E. nigrum n-hexane extracts obtained from plants growing in three different geographic locations. To characterize antioxidant capacity of isolated compounds 1-14 we used our well-established model based on reactive oxygen species (ROS) production by activated human platelets and showed that most of the examined polyphenols act as antioxidants by inhibition of ROS production.
... Chemotherapy-induced thrombocytopenia (CIT) is one of the most common complications of tumor treatment and is a common clinically hematological toxic reaction (Kuter, 2015;Weycker et al., 2019;Leader et al., 2021). The occurrence of CIT can lead to reduced chemotherapeutic drug dosage, delayed chemotherapy, and even chemotherapy termination. ...
... The occurrence of CIT can lead to reduced chemotherapeutic drug dosage, delayed chemotherapy, and even chemotherapy termination. It may also increase the risk of bleeding in patients, endanger their life and health, affect the therapeutic effect, and increase the medical costs (Kuter, 2015;Weycker et al., 2019;Leader et al., 2021). Patients with severe CIT are at significant risk of bleeding events (Slichter et al., 2010;Stanworth et al., 2015). ...
... The mainstay for the prophylactic or therapeutic treatment of CIT includes platelet transfusion (Stanworth et al., 2015;Schiffer et al., 2018). Platelet transfusion can decrease the rate of World Health Organization (WHO) grade ≥2 bleeding (Wandt et al., 2012;Stanworth et al., 2013), but several issues cannot be managed by transfusion, including bleeding despite platelet transfusion, delayed chemotherapy or reduced dosage, and refractoriness to platelet transfusion (Stanworth et al., 2013;Juskewitch et al., 2017;Leader et al., 2021). Therefore, plateletstimulating growth factors, such as recombinant human interleukin 11 (rhIL-11) and recombinant human thrombopoietin (rhTPO), can be indicated to manage CIT (Leader et al., 2021). ...
Objective: To explore the effect and safety of avatrombopag for chemotherapy-induced thrombocytopenia (CIT).
Methods: This multicenter, open-label, single-arm trial enrolled CIT patients in eight centers from October 2020 to April 2021. The participants received avatrombopag tablets 60 mg once a day for 5–10 days. The main endpoint was the proportion of patients with platelet count ≥100×10 ⁹ /L or increased by ≥ 50×10 ⁹ /L or increased by ≥ 100% in the cycle after the start of treatment.
Results: Seventy-four participants were enrolled with a mean age of 59.8 ± 11.62.2% were males. The cumulative effective rate (any criteria) was 70.3% at 4 weeks. 42 (56.8%) achieved platelet count ≥100×10 ⁹ /L, 44 (59.5%) increased by ≥ 50×10 ⁹ /L, and 27 (36.5%) increase by ≥ 100% from baseline. The duration of grade III and IV platelet reduction was 4.2 ± 5.3 days. The time of PLT recovery to ≥75×10 ⁹ /L was 9.4 ± 6.6 days. The time of PLT recovery to ≥100×10 ⁹ /L was 10.2 ± 6.4 days. The platelet count nadir was 57.9 ± 45.3×10 ⁹ /L. The most common adverse events were nausea (8.1%), fatigue (5.4%), and abdominal pain (1.4%). There were no cases of fever, headache, or peripheral edema.
Conclusion: Although it was a single-arm trial without a control group, the application of avatrombopag in patients with CIT can increase the platelet count of the patients compared with baseline. Avatrombopag is safe and tolerable.
Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04609891?term=04609891&draw=2&rank=1 , identifier [NCT04609891]
... Retrospective, 72 phase 2 studies (including 1 randomized phase 2 study 73 ) and 1 phase 3 trial 74 have investigated TPO-RAs for the treatment and secondary prevention of chemotherapy-induced TP in solid tumors. 75 The majority of evidence comes from studies of subcutaneous romiplostim given once weekly at doses titrated up to 10 µg/ kg/wk according to platelet counts. In the largest retrospective study to date (n = 173 [153 solid tumor and 20 lymphoma or myeloma]), 71% of patients receiving romiplostim achieved a platelet response, and 89% avoided platelet transfusions. ...
... 74 As summarized in a recent review, the rate of thrombotic complications in cancer patients who received romiplostim was between 5% and 15% in phase 2 and retrospective cohort studies (most without comparison groups), which is comparable to expected rates in cancer patients. 75,76 Most of the events were VTE and only a small number of arterial events were reported. The placebo-controlled study of avatrombopag for chemotherapy-induced TP did not raise any thrombotic safety signals; thromboembolic events occurred in 2 (2%) patients receiving avatrombopag and in 1 (3%) patient receiving placebo. ...
... Both romiplostim and eltrombopag have been studied in patients with myelodysplastic syndrome (MDS), acute myeloid leukemia, and postallogeneic HSCT. 75 Romiplostim showed a potential benefit in patients with grade 4 TP related to low-risk MDS 79 and postallogeneic HSCT. 80 Similar results have been shown with eltrombopag in patients with low-risk MDS or postallogeneic HSCT. ...
In cancer patients, thrombocytopenia can result from bone marrow infiltration or from anticancer medications and represents an important limitation for the use of antithrombotic treatments, including anticoagulant, antiplatelet, and fibrinolytic agents. These drugs are often required for prevention or treatment of cancer-associated thrombosis or for cardioembolic prevention in atrial fibrillation in an increasingly older cancer population. Data indicate that cancer remains an independent risk factor for thrombosis even in case of thrombocytopenia, since mild-to-moderate thrombocytopenia does not protect against arterial or venous thrombosis. In addition, cancer patients are at increased risk of antithrombotic drug-associated bleeding, further complicated by thrombocytopenia and acquired hemostatic defects. Furthermore, some anticancer treatments are associated with increased thrombotic risk and may generate interactions affecting the effectiveness or safety of antithrombotic drugs. In this complex scenario, the European Hematology Association in collaboration with the European Society of Cardiology has produced this scientific document to provide a clinical practice guideline to help clinicians in the management of patients with cancer and thrombocytopenia. The Guidelines focus on adult patients with active cancer and a clear indication for anticoagulation, single or dual antiplatelet therapy, their combination, or reperfusion therapy, who have concurrent thrombocytopenia because of either malignancy or anticancer medications. The level of evidence and the strength of the recommendations were discussed according to a Delphi procedure and graded according to the Oxford Centre for Evidence-Based Medicine.
... 10,45 Given that patients with MM will often exhibit thrombocytopenia due to either bone marrow suppression or chemotherapy-induced thrombocytopenia, it is likely that the excess VWF seen in the plasma of patients with MM is of EC origin, though the effect of MM cells on EC VWF secretion has not been delineated thus far. 74 It is likely multifaceted including a combination of chronic endothelial activation and dysfunction, increased bone marrow angiogenesis, and disturbances in the VWF/ ADAMTS-13 axis, which may all contribute to elevated VWF/FVIII levels reported in patients with MM ( Figure 1). However, additional robust studies, incorporating patients on the newer anti-myeloma treatments, will be required to fully evaluate these effects and provide better mechanistic insights. ...
Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of thrombosis even in spite of widespread use of thromboprophylactic agents. The pathophysiology of thrombosis in MM is multifactorial and patients with MM appear to display a hypercoagulable phenotype with potential contributory factors including raised von Willebrand Factor (VWF) levels, activated protein C resistance, impaired fibrinolysis and abnormal thrombin generation. In addition to this, the toxic effect of anti‐myeloma therapies on the endothelium and contribution to thrombosis has been widely described. Elevated VWF/FVIII plasma levels have been reported in heterogeneous cohorts of patients with MM and other haematological malignancies. In specific studies, high plasma VWF levels have been shown to associate with VTE risk and reduced overall survival. While the mechanisms underpinning this remain unclear, dysregulation of the VWF and ADAMTS13 axis is evident in certain solid organ malignancies and correlates with advanced disease and thrombosis. Furthermore, thrombotic microangiopathic conditions arising from deficiencies in ADAMTS13 and thus an accumulation of prothrombotic VWF multimers have been reported in patients with MM, particularly in association with specific myeloma therapies. This review will discuss current evidence on the pathophysiological mechanisms underpinning thrombosis in MM and in particular summarise the role of VWF/FVIII in haematological malignancies with a focus on thrombotic risk and emerging evidence for contribution to disease progression.
... Although chemotherapy dose intensity is an element that is tried not to be compromised in adjuvant treatments, the prognostic benefit of providing optimal dose density for metastatic cases is clear. However, optimal dose density may cause fatal complications in patients with low bone marrow reserve (19). At this point, the clinician should not forget that the main goal of advanced chemotherapy is palliation and quality of life support. ...
Aim: Pancreatic adenocarcinoma (PA) is the seventh most common cause of cancer-related mortality. Our primary endpoint of study was to determine the relationship between albumin/globulin ratio (AGR) and progression-free and overall survival (PFS and OS) in second-line treatment after FOLFIRINOX. Our secondary endpoint was to assess treatment side effects and the relationship of treatment dose intensity with treatment type and AGR. Material and Method: PA patients who followed-up between January 2014 and January 2021 were evaluated retrospectively. Age, gender, ECOG score and AGR recorded at the beginning of the second-line treatment. Thrombocytopenia, neutropenia, chemotherapy type, chemotherapy dose intensity, PFS and OS were recorded during the second-line treatment. Results: Median age 64 (44-80), 72 (70.6%) male, 102 metastatic PA patients were evaluated. 76 (74.5%) patients were ECOG 0-1, 26 (25.5%) patients were ECOG 2. Of these patients in the second step, 68 (66.7%) received single-agent gemcitabine and 34 (33.3%) received Nab-paclitaxel + gemcitabine treatment. Progression and exitus events occurred in all cases. Median PFS was 166.8 days in the AGR>1.2 group, it was 80.7 days in the AGR1.2 group, it was 144 days in the AGR1.2 group, it was 71.3% in the AGR
