Altered Fibrinolysis in Hematological Malignances.

Bleeding and thrombosis are well-known complications to hematological malignancies, and changes in fibrinolysis impact both these issues. In the present systematic review, we provide an overview and discussion of the current literature in regards to clinical manifestations, diagnosis, and treatment of altered fibrinolysis in patients suffering from hematological malignancies, beyond acute promyelocytic leukemia. We performed a systematic literature search employing the databases Pubmed, Embase, and Web of Science to identify original studies investigating fibrinolysis in hematological malignancies. Studies investigating fibrinolysis in acute promyelocytic leukemia or disseminated intravascular coagulation were excluded. We identified 32 studies fulfilling the inclusion criteria. A majority of the studies were published more than two decades ago, and none of the studies examined all available markers of fibrinolysis or used dynamic clot lysis assays. In acute leukemia L-asparaginase treatment induced a hypofibrinolytic state, and prior to chemotherapy there seemed to be little to no change in fibrinolysis. In studies examining fibrinolysis during chemotherapy results were ambiguous. Two studies examining multiple myeloma indicated hypofibrinolysis prior to chemotherapy, and in another plasma cell disease, amyloid light chain-amyloidosis, clear signs of hyperfibrinolysis were demonstrated. In myeloproliferative neoplasms, the studies reported signs of hypofibrinolysis, in line with the increased risk of thrombosis in this disease. Only one study regarding lymphoma was identified, which indicated no alterations in fibrinolysis. In conclusion, this systematic review demonstrated that only sparse, and mainly old, evidence exists on fibrinolysis in hematological malignancy. However, the published studies showed a tendency toward hypofibrinolysis in myeloproliferative disorders, an increased risk of hyperfibrinolysis, and bleeding in patients with AL-amyloidosis, whereas studies regarding acute leukemias were inconclusive except with regard to L-asparaginase treatment, which induced a hypofibrinolytic state.

Outcome of treatment with carfilzomib before and after treatment with daratumumab in relapsed or refractory multiple myeloma patients.

Real world evidence is important since most patients cannot be included in randomized clinical trials (RCTs). In a nationwide, cohort of relapsed/refractory multiple myeloma patients treated with daratumumab (N = 635), we retrospective studied patients treated with carfilzomib (N = 251). Data were collected by audit of medical records. We compared characteristics of patients treated with carfilzomib before daratumumab (Car-Da; N = 150) and after daratumumab (Da-Car; N = 101) with those not treated with carfilzomib (N = 384). Furthermore, we examined effectiveness and safety of carfilzomib. The group of patients treated with carfilzomib differed from patients not treated with carfilzomib in the following parameters: They were younger, more were treated up-front with high dose melphalan and autologous stem cell transplantation (HDM-ASCT)and had relapse within 18 months thereafter, and more had high-risk cytogenetic abnormalities (CA) and amplification 1q (amp1q). In patients treated with Car-Da, 30.3% had high-risk CA and 30.1% had amp1q and in Da-Car it was 43.3% and 41%, respectively. In the Car-Da cohort, 34.4% experienced early relapse after HDM-ASCT versus 47.4% in the Da-Car cohort. The percentage of patients with very good partial remission was higher in patients treated with Car-Da compared to Da-Car (31.7% vs. 17.4%). The median duration of treatment and time to next treatment (TNT) of Car-Da/Da-Car were 4.6/4.3 months and 7.1/4.3 months and only a trend toward superior TNT for Car-Da was found (p = 0.06). Toxicity of carfilzomib was the same as reported in RCT. A similar poor TNT of daratumumab was found when used before (5.6 months) or after carfilzomib (4.9 months). In this cohort of patients with sequential treatment with carfilzomib and daratumumab or vice versa, a high percentage of patients were high-risk by CA, amp1q, and early relapse after HDM-ASCT. Outcome of Car-DA and outcome of Da-Car were equally poor. These patients should be considered for new promising treatment strategies.

Once- versus twice-daily aspirin treatment in patients with essential thrombocytosis.

Insufficient platelet inhibition has been reported in up to 40% of aspirin-treated patients, including patients with essential thrombocytosis. To maintain sufficient platelet inhibition, a shorter dosing interval with aspirin has been suggested. We aimed to investigate the antiplatelet effect of low-dose aspirin given twice-daily compared to standard once-daily dosing in patients with essential thrombocytosis. We included 22 patients, who were treated for 7 days with standard once-daily aspirin (75 mg once-daily) followed by 7 days treatment of twice-daily aspirin (37.5 mg twice-daily). The two regimens were separated by 14 days aspirin washout. Blood samples were obtained 1h and 24h/12h after the last pill intake in each regimen. The effect of aspirin was evaluated by: (1) platelet aggregation measured by whole blood impedance aggregometry (Multiplate® Analyser) using arachidonic acid (ASPItest 0.5 mM) as agonist and (2) serum thromboxane B2 levels determined using an enzyme-linked immunosorbent assay. The difference in platelet aggregation from 1h to the end of the dosing interval (24h/12h) was used to compare the two regimens. We demonstrated a significantly smaller difference in platelet aggregation in the twice-daily regimen compared to the once-daily: mean of difference = 228 AU*min (95% confidence interval (CI): 92-363, p < 0.01). In addition, a significantly smaller difference in thromboxane B2 was demonstrated in the twice-daily regimen compared to the once-daily regimen: mean of difference = 16.3 ng/mL (95% CI: 9.9-22.7, p < 0.01). In conclusion, twice-daily dosing with low-dose aspirin provides a more consistent platelet inhibition compared with standard once-daily dosing in patients with essential thrombocytosis.

Impaired fibrinolysis and increased clot strength are potential risk factors for thrombosis in lymphoma.

Thrombosis and bleeding are significant contributors to morbidity and mortality in patients with hematological cancer, and the impact of altered fibrinolysis on bleeding and thrombosis risk is poorly understood. In this prospective cohort study, we investigated the dynamics of fibrinolysis in patients with hematological cancer. Fibrinolysis was investigated before treatment and 3 months after treatment initiation. A dynamic clot formation and lysis assay was performed beyond the measurement of plasminogen activator inhibitor 1, tissue- and urokinase-type plasminogen activators (tPA and uPA), plasmin-antiplasmin complexes (PAP), α-2-antiplasmin activity, and plasminogen activity. Clot initiation, clot propagation, and clot strength were assessed using rotational thromboelastometry. A total of 79 patients were enrolled. Patients with lymphoma displayed impaired fibrinolysis with prolonged 50% clot lysis time compared with healthy controls (P = .048). They also displayed decreased clot strength at follow-up compared with at diagnosis (P = .001). A patient with amyloid light-chain amyloidosis having overt bleeding at diagnosis displayed hyperfibrinolysis, indicated by a reduced 50% clot lysis time, α-2-antiplasmin activity, and plasminogen activity, and elevated tPA and uPA. A patient with acute promyelocytic leukemia also displayed marked hyperfibrinolysis with very high PAP, indicating extreme plasmin generation, and clot formation was not measurable, probably because of the extremely fast fibrinolysis. Fibrinolysis returned to normal after treatment in both patients. In conclusion, patients with lymphoma showed signs of impaired fibrinolysis and increased clot strength, whereas hyperfibrinolysis was seen in patients with acute promyelocytic leukemia and light-chain amyloidosis. Thus, investigating fibrinolysis in patients with hematological cancer could have diagnostic value.

Prophylaxis with low dose tranexamic acid in acute myeloid leukemia patients undergoing intensive chemotherapy.

Patients suffering from acute myeloid leukemia (AML) carry a high risk of serious bleeding complications due to severe thrombocytopenia for long periods of time during treatment. Prior to prophylactic platelet transfusion becoming the standard of care, intracranial bleeding was a major contributor to death in AML patients. However, despite prophylactic platelet transfusions, up to 79% of patients with AML experience clinically significant bleeding during treatment. Antifibrinolytics are effective and well tolerated hemostatic agents widely used in many patient groups, and in this study, we investigated the effect of low dose tranexamic acid (TXA) in patients with AML and thrombocytopenia. We compared bleeding and thrombosis between 113 thrombocytopenic AML patients receiving TXA 500 mg three times daily (n = 36) versus no-TXA (n = 77). Clinical information was obtained systematically from electronic medical records, and laboratory data were collected from the laboratory information system. No difference was demonstrated in number of patients with at least one bleeding episode (TXA: 89% vs. no-TXA: 93%, p = 0.60), median number of bleeding days (TXA: 2.5 days vs. no-TXA 2.0 days, p = 0.30), bleeding location or transfusion needs between the two groups. However, platelet count was found to be a significant risk factor for bleeding, with a probability of bleeding of 35% with a platelet count below 5 × 109/L (logistic regression, p < 0.01). We found no difference in thromboembolic events between the two groups (TXA: 8% vs. no-TXA 10%, p = 0.99). In conclusion, treatment with low dose TXA is safe, but we found no evidence to suggest that it reduces bleeding in AML patients with thrombocytopenia.

The real-world use and efficacy of pomalidomide for relapsed and refractory multiple myeloma in the era of CD38 antibodies.

Pomalidomide-dexamethasone (Pd) has been a standard care treatment for relapsed and refractory multiple myeloma since 2013. However, the outcomes of Pd after exposure to CD38 antibodies are not known. Here we describe the real-world use and efficacy of pomalidomide in a Danish, nationwide cohort of daratumumab-exposed patients. We identified 328 patients that were treated with pomalidomide. Of these, 137 received Pd, 65 daratumumab-pomalidomide-dexamethasone (DPd), 43 pomalidomide-cyclophosphamide-dexamethasone (PCd), 19 carfilzomib-pomalidomide-dexamethasone (KPD), 11 pomalidomide-bortezomib-dexamethasone (PVd), and 52 pomalidomide in other combinations. Patients treated with Pd in this cohort had a partial response or better (≥ PR) rate of 35.8% and median time to next treatment (mTNT) of 4.9 months, almost identical to the results of previous prospective clinical trials. Although treatment with the various pomalidomide-containing triplet regimens resulted in higher ≥ PR rates (PCd: 46.5%, PVd: 63.6%, DPd: 55.4%, KPd: 63.2%), the mTNT achieved was not significantly better than with Pd in most cases (PCD: 5.4, PVD: 5.3, DPD: 4.7 months). The exception to this was KPd (mTNT 7.4 months), but this regimen was mainly used earlier in the course of the disease (median time from diagnosis 2.3 years vs. 3.7-4.3 years). The most important predictor of outcomes was not the choice of index regimen (p = 0.72), but prior exposure (p = 0.0116). Compared to CD38 antibody-naïve patients, triple-class-exposed patients achieved reduced ≥ PR rate (38.0% vs. 47.3%), shorter mTNT (4.0 vs. 5.9 months), and shorter median overall survival (12.4 vs. 24.2 months) with pomalidomide treatment.

Catheter-directed thrombolysis for massive deep vein thrombosis in an adolescent with severe antithrombin deficiency.

In this case report we describe a case of massive deep vein thrombosis in an adolescent. The case was complicated by severe antithrombin deficiency caused by a previously unreported mutation. We discuss the use of catheter directed thrombolysis and (F)Xa inhibitors in children and adolescents.

The real-world outcomes of multiple myeloma patients treated with daratumumab.

Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. METHODS: Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). RESULTS: Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). CONCLUSION: The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients.

Platelet characteristics in patients with essential thrombocytosis.

BACKGROUND: Essential thrombocytosis (ET) is a myeloproliferative disorder characterized by an increased platelet count. ET is associated with an increased risk of thrombosis, and procoagulant features of the disease may include an increased number of reactive reticulated platelets and an increased aggregation potential. We aimed to explore the association between platelet count, platelet turnover, and platelet aggregation in patients with ET. METHODS: We included 24 ET patients who discontinued antiplatelet therapy prior to blood sampling. Reticulated platelets were assessed as immature platelet count (IPC) and immature platelet fraction by automated flow cytometry (Sysmex XE-5000). Platelet aggregation was investigated by impedance aggregometry (Multiplate® Analyzer) and aggregation potential by flow cytometry (NAVIOS). RESULTS: Our results showed that ET patients had increased IPC compared to healthy individuals (median 12.3 vs. median 6.9, P < 0.0001). Furthermore, a positive correlation between platelet count and impedance aggregation was demonstrated using arachidonic acid (r = 0.48, P = 0.02), thrombin-receptor-activating-peptide (r = 0.46, P = 0.03) and adenosine diphosphate (r = 0.56, P = 0.007) as agonists. Finally, an increased aggregation potential was demonstrated in ET patients compared to healthy individuals. CONCLUSIONS: The study showed that ET patients compared to healthy individuals have an increased amount of reticulated platelets and increased aggregation potential. These findings might in part explain the increased thromboembolic risk in patients with ET. © 2018 International Clinical Cytometry Society.

Bronchoscopy in patients with haemoptysis and normal computed tomography of the chest is unlikely to result in significant findings.

INTRODUCTION: The standard evaluation of haemoptysis in a department of respiratory medicine would currently consist of chest radiography, contrast-enhanced computed tomography (CT) and fibre-optic bronchoscopy (FOB), regardless of the result of the CT. Our aim was to evaluate whether patients presenting with haemoptysis but no positive finding on a contrast-enhanced CT of the chest are at risk for having serious disease, first of all lung cancer, and thus whether FOB is mandatory for such patients. METHODS: We searched the literature and retrospectively reviewed all records of patients referred with haemoptysis between 2000 and 2010 at the Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Denmark. RESULTS: A total of 379 patient records were reviewed for inclusion in the clinical part of the study. Of these, 269 had the information required for the study and had been examined with CT. In all, 16 of the 269 patients were diagnosed with lung cancer. In all of these, a tumour or other findings indicating a possible tumour were seen on the chest CT. No additional cases of lung cancer were discovered during FOB, and no cases had been missed by the CT. CONCLUSION: CT should be used as first-line examination in patients with a history of haemoptysis. Furthermore, in patients above 40 years of age with positive findings of any kind on the CT, further examination with FOB is indicated. However, if the chest CT is without pathological findings, it is most unlikely that FOB will reveal anything of significance. FUNDING: none. TRIAL REGISTRATION: not relevant.