Day-21 bone marrow findings incorrectly designate residual leukaemia in FLT3-mutated acute myeloid leukaemia treated with intensive induction plus midostaurin: a morphology-focused study.

Early induction response assessment with day-21 bone marrow (D21-BM) is commonly performed in patients with FLT3-mutated acute myeloid leukaemia (AML), where detection of residual leukaemia (RL; blasts ≥5%) typically results in the administration of a second induction course. However, whether D21-BM results predict for RL at the end of first induction has not been systematically assessed. This study evaluates the predictive role of D21-BM morphology in detecting RL following first induction. Between August 2018 and March 2022, all patients with FLT3-AML receiving 7+3 plus midostaurin, with D21-BM performed, were identified. Correlation between D21-BM morphology vs D21-BM ancillary flow/molecular results, as well as vs D28-BM end of first induction response, were retrospectively reviewed. Subsequently, D21-BMs were subjected to anonymised morphological re-assessments by independent haematopathologists (total in triplicate per patient). Of nine patients included in this study, three (33%) were designated to have RL at D21-BM, all of whom entered complete remission at D28-BM. Furthermore, only low-level measurable residual disease was detected in all three cases by flow or molecular methods at D21-BM, hence none proceeded to a second induction. Independent re-evaluations of these cases failed to correctly reassign D21-BM responses, yielding a final false positive rate of 33%. In summary, based on morphology alone, D21-BM assessment following 7+3 intensive induction plus midostaurin for FLT3-AML incorrectly designates RL in some patients; thus correlating with associated flow and molecular results is essential before concluding RL following first induction. Where remission status is unclear, repeat D28-BMs should be performed.

Plasma from patients with vaccine-induced immune thrombotic thrombocytopenia displays increased fibrinolytic potential and enhances tissue-type plasminogen activator but not urokinase-mediated plasminogen activation.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus vector-based COVID-19 vaccines. VITT is associated with markedly raised levels of D-dimer; yet, how VITT modulates the fibrinolytic system is unknown. OBJECTIVES: We aimed to compare changes in fibrinolytic activity in plasma from patients with VITT, patients diagnosed with venous thromboembolism (VTE) after vaccination but without VITT (VTE-no VITT), and healthy vaccinated controls. METHODS: Plasma levels of plasmin-antiplasmin (PAP) complexes, plasminogen, and alpha-2-antiplasmin (α2AP) from 10 patients with VITT, 10 patients with VTE-no VITT, and 14 healthy vaccinated controls were evaluated by enzyme-linked immunosorbent assay and/or Western blotting. Fibrinolytic capacity was evaluated by quantitating PAP levels at baseline and after ex vivo plasma stimulation with 50-nM tissue-type plasminogen activator (tPA) or urokinase for 5 minutes. RESULTS: Baseline PAP complex levels in control and VTE-no VITT individuals were similar but were ∼7-fold higher in plasma from patients with VITT (P < .0001). VITT samples also revealed consumption of α2AP and fibrinogenolysis consistent with a hyperfibrinolytic state. Of interest, VITT plasma produced significantly higher PAP levels after ex vivo treatment with tPA, but not urokinase, compared to the other groups, indicative of increased fibrinolytic potential. This was not due to D-dimer as addition of D-dimer to VTE-no VITT plasma failed to potentiate tPA-induced PAP levels. CONCLUSION: A marked hyperfibrinolytic state occurs in patients with VITT, evidenced by marked elevations in PAP, α2AP consumption, and fibrinogenolysis. An unidentified plasma cofactor that selectively potentiates tPA-mediated plasminogen activation also appears to exist in the plasma of patients with VITT.

Platelet-activating functional assay resolution in vaccine-induced immune thrombotic thrombocytopenia: differential alignment to PF4 ELISA platforms.

Background: Anti-platelet factor 4 (PF4) antibodies in vaccine-induced immune thrombotic thrombocytopenia (VITT) appear to be transient, with discrepant persistence depending on the platform used for detection. Objectives: We aimed to report a longitudinal study of antibody persistence using 2 ELISA platforms and 2 platelet-activating functional assays in a clinical cohort of patients with VITT referred for follow-up testing. Methods: In total, 32 Australian patients with VITT or pre-VITT, confirmed by expert adjudication, with samples referred for clinical follow-up were included. Clinical follow-up assays, including Stago and Hyphen ELISAs, procoagulant platelet flow cytometry, and modified PF4-serotonin-release assay, were performed according to the pattern of reactivity for that patient at diagnosis. Results: The median follow-up was 24 weeks after diagnosis. A general decline in anti-PF4 antibody levels and platelet-activating capacity over time was observed with a more rapid median time to resolution of 16 weeks by functional assay vs 24 weeks by Stago ELISA. Decline in platelet-activating antibody levels detected by functional assays mirrored Stago ELISA titer but not Hyphen. However, 87% of patients received a documented second vaccination and 74% received an mRNA booster with no reported adverse events. Conclusion: Anti-PF4 antibodies persist longer than functional platelet-activating antibodies in VITT but do not warrant avoidance of subsequent vaccinations. Persistence detection is assay-dependent. Stago ELISA may be a surrogate where functional assays are unavailable for follow-up testing of confirmed patients with VITT.

Combined immunodeficiency and impaired PI3K signaling in a patient with biallelic LCP2 variants.

BACKGROUND: Inborn errors affecting components of the T-cell receptor signaling cascade cause combined immunodeficiency with various degrees of severity. Recently, homozygous variants in LCP2 were reported to cause pediatric onset of severe combined immunodeficiency with neutrophil, platelet, and T- and B-cell defects. OBJECTIVE: We sought to unravel the genetic cause of combined immunodeficiency and early-onset immune dysregulation in a 26-year-old man who presented with specific antibody deficiency, autoimmunity, and inflammatory bowel disease since early childhood. METHODS: The patient was subjected to whole-exome sequencing of genomic DNA and examination of blood neutrophils, platelets, and T and B cells. Expression levels of the Src homology domain 2-containing leukocyte protein of 76 kDa (SLP76) and tonic and ligand-induced PI3K signaling were evaluated by flow-cytometric detection of phosphorylated ribosomal protein S6 in B and T cells. RESULTS: Compound heterozygous missense variants were identified in LCP2, affecting the proline-rich repeat domain of SLP76 (p.P190R and p.R204W). The patient's total B- and T-cell numbers were within the normal range, as was platelet function. However, neutrophil function, numbers of unswitched and class-switched memory B cells, and serum IgA were decreased. Moreover, intracellular SLP76 protein levels were reduced in the patient's B cells, CD4+ and CD8+ T cells, and natural killer cells. Tonic and ligand-induced levels of phosphorylated ribosomal protein S6 and ligand-induced phosphorylated PLCγ1 were decreased in the patient's B cells and CD4+ and CD8+ T cells. CONCLUSIONS: Biallelic variants in LCP2 impair neutrophil function and T-cell and B-cell antigen-receptor signaling and can cause combined immunodeficiency with early-onset immune dysregulation, even in the absence of platelet defects.

Vaccine-induced immune thrombotic thrombocytopenia post dose 2 ChAdOx1 nCoV19 vaccination: Less severe but remains a problem.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but established complication of 1st dose ChAdOx1 nCoV19 vaccination (AZD1222), however this complication after dose 2 remains controversial. OBJECTIVES: To describe the clinicopathological features of confirmed cases of VITT post dose 2 AZD1222 vaccination in Australia, and to compare this cohort to confirmed cases of VITT post 1st dose. METHODS: Sequential cases of clinically suspected VITT (thrombocytopenia, D-Dimer > 5x upper limit normal and thrombosis) within 4-42 days of dose 2 AZD1222 referred to Australia's centralised testing centre underwent platelet activation confirmatory testing in keeping with the national diagnostic algorithm. Final classification was assigned after adjudication by an expert advisory committee. Descriptive statistics were performed on this cohort and comparative analyses carried out on confirmed cases of VITT after 1st and 2nd dose AZD1222. RESULTS: Of 62 patients referred, 15 demonstrated presence of antibody mediated platelet activation consistent with VITT after dose 2 AZD1222. Four were immunoassay positive. Median time to presentation was 13 days (range 1-53) platelet count 116x10^9/L (range 63-139) and D-dimer elevation 14.5xULN (IQR 11, 26). Two fatalities occurred. In each, the dosing interval was less than 30 days. In comparison to 1st dose, dose 2 cases were more likely to be male (OR 4.6, 95% CI 1.3-15.8, p = 0.03), present with higher platelet counts (p = 0.05), lower D-Dimer (p = 01) and less likely to have unusual site thromboses (OR 0.14, 95% CI 0.04-0.28, p = 0.02). CONCLUSIONS: VITT is a complication of dose 2 AZD1222 vaccination. Whilst clinicopathological features are less severe, fatalities occurred in patients with concomitant factors.

Central venous access device practice across haematology and oncology centres in Australia and New Zealand: a cross-sectional survey.

Central venous access devices (CVADs) are commonly used in malignancies. We conducted an online, anonymous cross-sectional survey of practice regarding CVAD management in haematology centres among clinicians in Australia and New Zealand. We identified variation in clinical practice regarding CVAD selection, insertion, management and removal. These findings highlight research gaps in CVAD care.

Anticoagulation Strategies in Non-Critically Ill Patients with Covid-19.

BACKGROUND: Optimal thromboprophylaxis for hospitalized patients with coronavirus disease 2019 (Covid-19) is uncertain. METHODS: In an open-label, adaptive platform trial, we randomly assigned hospitalized adults with Covid-19 to low-dose low-molecular-weight heparin thromboprophylaxis or intermediate-dose or low-dose plus aspirin. In response to external evidence, the aspirin intervention was discontinued and a therapeutic-dose arm added. The primary end point was death or the requirement for new organ support by day 28, analyzed with a Bayesian logistic model. Enrolment was closed as a result of operational constraints. RESULTS: Between February 2021 and March 2022, 1574 patients were randomly assigned. Among 1526 participants included in the analysis (India, n=1273; Australia and New Zealand, n=138; and Nepal, n=115), the primary outcome occurred in 35 (5.9%) of 596 in low-dose, 25 (4.2%) of 601 in intermediate-dose, 20 (7.2%) of 279 in low-dose plus aspirin, and 7 (14%) of 50 in therapeutic-dose anticoagulation. Compared with low-dose thromboprophylaxis, the median adjusted odds ratio for the primary outcome for intermediate-dose was 0.74 (95% credible interval [CrI], 0.43 to 1.27; posterior probability of effectiveness [adjusted odds ratio<1; Pr], 86%), for low-dose plus aspirin 0.88 (95% CrI, 0.47 to 1.64; Pr, 65%), and for therapeutic-dose anticoagulation 2.22 (95% CrI, 0.77 to 6.20; Pr, 7%). Overall thrombotic and bleeding rates were 0.8% and 0.4%, respectively. There were 10 serious adverse reactions related to anticoagulation strategy, of which nine were grade 1 or 2 across study interventions and one grade 4 episode of retroperitoneal hematoma in a patient receiving intermediate-dose anticoagulation. CONCLUSIONS: In hospitalized non­critically ill adults with Covid-19, compared with low-dose, there was an 86% posterior probability that intermediate-dose, 65% posterior probability that low-dose plus aspirin, and a 7% posterior probability that therapeutic-dose anticoagulation reduced the odds of death or requirement for organ support. No treatment strategy met prespecified stopping criteria before trial closure, precluding definitive conclusions. (Funded by Australian National Health and Medical Research Council or Medical Research Future Fund Investigator and Practitioner Grants and others; ClinicalTrials.gov number, NCT04483960.)

Cannula provoked upper extremity superficial vein thrombophlebitis: are we overtreating?

Cannula provoked upper extremity superficial vein thrombophlebitis (UESVT) is common. Retrospective audit of 93 consecutive patients, 51% male, median age 57 years (range 20-91), with symptomatic UESVT revealed varied management including symptomatic management (37%), prophylactic (37%) and higher dose anticoagulation (27%). There was 2% (95% confidence interval (CI) 0-7.6) thrombus extension and 1% (95% CI 0-5.9) major bleeding, both limited to cancer. We argue anticoagulation is unnecessary in most UESVT patients.

Assessment of immunological anti-platelet factor 4 antibodies for vaccine-induced thrombotic thrombocytopenia (VITT) in a large Australian cohort: A multicenter study comprising 1284 patients.

BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus-based vaccines aimed to prevent and minimize COVID-19 and related pathophysiology. OBJECTIVES: To describe patterns of testing for anti-platelet factor 4 (PF4) antibodies using various ELISA assays in a large Australian cohort and comparative functional platelet activation assays in a subset. PATIENTS/METHODS: Asserachrom HPIA IgG ELISA was performed in 1284 patients over a period of 12 months, supplemented in select cohorts by comparative ELISA using three other methods (n = 78-179), three different functional assays (flow cytometry, serotonin release assay, and/or Multiplate; n = 476), and rapid immunological chemiluminescence anti-PF4 assay (n = 460), in a multicenter study. RESULTS: For first episode presentations, 190/1284 (14.8%) ELISA tests were positive. Conversely, most (445/460; 96.7%) chemiluminescence anti-PF4 test results were negative. All functional assays showed associations of higher median ELISA optical density with functional positivity and with high rates of ELISA positivity (64.0% to 85.2%). Data also identified functional positivity in 14.8%-36.0% of ELISA negative samples, suggesting false negative VITT by HPIA IgG ELISA in upward of one third of assessable cases. CONCLUSION: To our knowledge, this is the largest multicenter evaluation of anti-PF4 testing for investigation of VITT. Discrepancies in test results (ELISA vs. ELISA or ELISA vs. functional assay) in some patients highlighted limitations in relying on single methods (ELISA and functional) for PF4 antibody detection in VITT, and also highlights the variability in phenotypic test presentation and pathomechanism of VITT.

Idiopathic upper extremity deep vein thrombosis: A systematic review.

BACKGROUND: Idiopathic upper extremity deep vein thrombosis (UEDVT) management is controversial and ranges from anticoagulation alone to the addition of further interventions such as thrombolysis and decompressive surgery. OBJECTIVES: The objective of this systematic review was to assess the effects of anticoagulation alone compared to anticoagulation with additional interventions such as thrombolysis or decompressive surgery on the incidence of recurrent UEDVT and post-thrombotic syndrome (PTS) in patients with idiopathic UEDVT (including those associated with the oral contraceptive pill). PATIENTS/METHODS: A systematic search was conducted for studies which focused on acute UEDVT treatment defined as therapies starting within 4 weeks of symptom onset. We limited studies to those that recruited 10 or more subjects and involved at least 6 weeks to 12 months anticoagulation alone or together with additional interventions with at least 6-month follow-up. Primary outcomes were symptomatic recurrent radiologically confirmed UEDVT and PTS. Secondary outcomes were symptomatic venous thromboembolism, bleeding and mortality. RESULTS: We found seven studies which reported recurrent UEDVT rates and five that reported PTS rates. All studies were retrospective or cross-sectional. None compared anticoagulation alone to anticoagulation with additional intervention. Study heterogeneity precluded meta-analysis and risk of bias was moderate to serious. Recurrent UEDVT occurred in 0% to 12% post-anticoagulation alone and 0% to 23% post-additional interventions. PTS rates varied from 4% to 32% without severe PTS. Only limited studies reported on our secondary outcomes. CONCLUSION: There is limited evidence behind idiopathic UEDVT management. Prospective comparative studies in this area are essential.

Understanding vaccine-induced thrombotic thrombocytopenia (VITT).

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare, but serious, syndrome characterised by thrombocytopenia, thrombosis, a markedly raised D-dimer and the presence of anti-platelet factor-4 (PF4) antibodies following COVID-19 adenovirus vector vaccination. VITT occurs at a rate of approximately 2 per 100 000 first-dose vaccinations and appears exceedingly rare following second doses. Our current understanding of VITT pathogenesis is based on the observations that patients with VITT have antibodies that bind to PF4 and have the ability to form immune complexes that induce potent platelet activation. However, the precise mechanisms that lead to pathogenic VITT antibody development remain a source of active investigation. Thrombosis in VITT can manifest in any vascular bed and affect multiple sites simultaneously. While there is a predilection for splanchnic and cerebral venous sinus thrombosis, VITT also commonly presents with deep vein thrombosis and pulmonary embolism. Pillars of management include anticoagulation with a non-heparin anticoagulant, intravenous immunoglobulin and 'rescue' therapies, such as plasma exchange for severe cases. VITT can be associated with a high mortality rate and significant morbidity, but awareness and optimal therapy have significantly improved outcomes in Australia. A number of questions remain unanswered, including why VITT is so rare, reasons for the predilection for thrombosis in unusual sites, how long pathological antibodies persist, and the optimal duration of anticoagulation. This review will provide an overview of the presentation, diagnostic workup and management strategies for patients with VITT.

Isolated distal DVT in trauma: A study of the management of isolated distal deep vein thrombosis acquired as an inpatient in trauma patients.

BACKGROUND: Isolated distal deep vein thromboses (IDDVT) are common complications of trauma inpatient admission, however their management is controversial. We aimed to analyse outcomes in patients admitted to a level three tertiary referral centre who received therapeutic anticoagulation compared to those that did not. We hypothesised that therapeutic anticoagulation would be safe and effective in trauma inpatients who develop IDDVT. METHODS: We performed a review of the electronic case notes of all patients with venous thromboembolism listed as a complication whilst admitted as an inpatient under the trauma unit at a tertiary institution over a 4-year period, from October 2014 to October 2018. Demographic data was collected, as well as data regarding management, major bleeding and progression of thrombosis to proximal DVT or PE. RESULTS: 91 IDDVT in trauma inpatients were identified. 33 patients received therapeutic anticoagulation within seven days of their diagnosis. No major bleeding was observed in this group, while one episode of thrombus progression was observed. 58 patients were not given therapeutic anticoagulation within seven days of IDDVT diagnosis. There were seven episodes of thrombus progression in this group on median day 5 post diagnosis, while no major bleeding was observed. CONCLUSION: Only approximately 1/3rd of patients with IDDVT after trauma received therapeutic anticoagulation, and in these selected cases it appears safe. Those who did not receive therapeutic anticoagulation had a significant rate of thrombosis extension into the proximal system and pulmonary embolus. Further studies on correctly identifying who can be safely anticoagulated are required and for those who cannot be, these data show more aggressive surveillance and prophylaxis needs to be considered.

Development of a risk score to predict peripherally inserted central catheter thrombosis in active cancer.

BACKGROUND: Peripherally inserted central catheter (PICC) thrombosis is common. AIMS: To explore the prevalence of symptomatic PICC thrombosis and pulmonary embolism (PE)/deep vein thrombosis (DVT) in cancer and non-cancer cohorts. In active cancer, we assessed the Khorana risk score (KRS) and Michigan risk score (MRS) for predicting PICC thrombosis and modifications to improve discriminative accuracy. METHODS: We reviewed consecutive cancer patients receiving chemotherapy through a PICC inserted April 2017 to July 2018. For each case, we identified a contemporaneous non-cancer control. RESULTS: Among 147 cancer patients, median age 64 years, PICC duration 70 days (range, 2-452), 7% developed PICC thrombosis (95% confidence interval (CI) 3.6-12.2) and 4% (95% CI 2-9) PE/DVT. Among 147 controls, median age 68 years, PICC duration 18.3 days (range, 0.5-210), 0.7% (95% CI 0-4) developed PICC thrombosis and 2% (95% CI 0.4-6) PE/DVT. In our cancer cohort, no KRS < 1 patients developed PICC thrombosis (95% CI 0-11) compared with 9% (95% CI 5-16) in KRS ≥ 1 (P = 0.12). PICC thrombosis occurred in 4.7% (95% CI 1.5-11.7) MRS ≤ 3 compared with 10.9% (95% CI 4.1-22.2) MRS > 3 (P = 0.32). The addition of thrombocytosis, a variable from KRS, to MRS (modified MRS (mMRS)) improved discriminative value for PICC thrombosis (c-statistic MRS 0.63 (95% CI 0.44-0.82), mMRS 0.72 (95% CI 0.58-0.85)). PICC thrombosis occurred in 1.4% (95% CI 0-8.3) mMRS ≤ 3 and 11.8% (95% CI 6.1-21.2) mMRS > 3 (P = 0.02). More patients were categorised as low risk using mMRS ≤ 3 (47%) than KRS < 1 (22%). CONCLUSION: Cancer patients had longer PICC durations and higher PICC thrombosis rates than those without (7% vs 0.7%). mMRS more accurately classified low PICC thrombosis risk than KRS <1(47% vs 22%). Prospective validation of mMRS is warranted.

Immune thrombocytopenia following immunisation with Vaxzevria ChadOx1-S (AstraZeneca) vaccine, Victoria, Australia.

Emerging evidence suggest a possible association between immune thrombocytopenia (ITP) and some formulations of COVID-19 vaccine. We conducted a retrospective case series of ITP following vaccination with Vaxzevria ChadOx1-S (AstraZeneca) and mRNA Comirnaty BNT162b2 COVID-19 (Pfizer-BioNTech) vaccines and compare the incidence to expected background rates for Victoria during the first six months of the Australian COVID-19 vaccination roll-out in 2021. Cases were identified by reports to the Victorian state vaccine safety service, SAEFVIC, of individuals aged 18 years or older presenting with thrombocytopenia following COVID-19 vaccination without evidence of thrombosis. Twenty-one confirmed or probable cases of ITP were identified following receipt of AstraZeneca (n = 17) or Pfizer-BioNTech (n = 4) vaccines. This translates to an observed incidence of 8 per million doses for AstraZeneca vaccine, twice the expected background rate of 4.1 per million. The observed rate for Pfizer-BioNTech was consistent with the expected background rate. The median time to onset for the cases post AstraZeneca vaccination was 10 days (range 1-78) and median platelet nadir 5 × 109/L (range 0-67 × 109/L). Hospital presentations or admissions for management of symptoms such as bleeding occurred in 18 (86%) of the cases. The majority of cases (n = 11) required intervention with at least 2 therapy modalities. In conclusion, we observed a substantially higher than expected rate of ITP following AstraZeneca vaccination. ITP is the second haematological adverse event, distinct from that of thrombosis with thrombocytopenia syndrome (TTS), observed following AstraZeneca vaccination.

Two Weeks of Low Molecular Weight Heparin for Isolated Symptomatic Distal Vein Thrombosis (TWISTER study).

BACKGROUND: Treatment of low-risk patients with isolated symptomatic distal deep vein thrombi (IDDVT) is uncertain. OBJECTIVE: assess whether two weeks of therapeutic anticoagulation is efficacious/safe for IDDVT. PRIMARY OUTCOME: symptomatic three-month venous thromboembolism (VTE) incidence in the two-week anticoagulation group. Secondary outcomes included post-thrombotic syndrome (PTS) and bleeding. METHODS: Prospective multicentre cohort study. Consecutive low-risk IDDVT patients enrolled within 72 h of diagnosis and treated with therapeutic dose enoxaparin or rivaroxaban. At two weeks, patients had repeat complete whole leg compression ultrasound (CUS)/clinical review. If resolution of leg symptoms AND no radiological evidence of thrombus extension, anticoagulation was stopped. If ongoing symptoms and/or radiographic extension within distal veins, anticoagulation was continued for four more weeks. Patients with extension into the popliteal vein on two-week ultrasound were treated off-study. Patients were reviewed at three and six months. FINDINGS/INTERPRETATION: 241 eligible patients received ≥2 weeks anticoagulation. 167/241 (69%) were assigned to the 2-week anticoagulation group; 71/241 (30%) to the six-week anticoagulation group; 3/241 patients (1%) had extension into the popliteal vein on two-week CUS. Two patients in the two-week anticoagulation group had symptomatic IDDVT recurrence in ≤3 months; VTE recurrence 2/156; 1.3%(95% CI 0.05-4.85%). 69% of patients had complete resolution of symptoms within two weeks. Six-month PTS rates were 8/184, 4.4%(95% CI 2.1-8.5%). No major bleeding was reported. Our findings suggest it's safe/efficacious to stop therapeutic anticoagulation at two weeks in low-risk IDDVT patients with resolution of symptoms/no extension on ultrasound. This could replace 6-12 weeks of anticoagulation for ambulatory, low-risk IDDVT patients. TRIAL REGISTRATION: ClinicalTrials.govNCT01252420.

Upper Extremity Deep Vein Thrombosis: Current Knowledge and Future Directions.

Upper extremity deep vein thrombosis (UEDVT) has been increasing in incidence due to the escalating use of central venous catheters such as peripherally inserted central catheters. UEDVT can be primary idiopathic or secondary to pacemaker leads, intravascular catheters or cancer. In comparison to conventional venous thromboembolism such as lower limb deep vein thrombosis or pulmonary embolism the risk factors, investigations, and management are not well defined. We review current evidence in primary and secondary UEDVT, highlighting areas in need of further research. We also explore the entity of venous thoracic outlet syndrome, which is said to be a risk factor for recurrent primary UEDVT and is the rationale behind surgical interventions.

Safety of rapid injection of undiluted ferric carboxymaltose to patients with iron-deficiency anaemia: a Phase II single-arm study.

BACKGROUND: Ferric carboxymaltose is increasingly utilised to treat iron deficiency and is usually diluted in saline and administered as an intravenous infusion over 15 min. Although this is highly convenient compared with older formulations, we hypothesised the drug could be administered, safely given as a rapid bolus injection. AIMS: To define the risk of serious adverse events following administration of an undiluted, rapid, high-dose ferric carboxymaltose injection. Secondary aims included all other adverse events, as well as longitudinal effects on haemoglobin, iron stores, phosphate and hepcidin. METHODS: In a single-arm, Phase II study in 121 patients with iron-deficiency anaemia, we administered up to 1000 mg of ferric carboxymaltose as a rapid undiluted bolus injection, and recorded adverse events and collected blood samples over the first hour, and again at 2 and 4 weeks post-treatment. RESULTS: No patient experienced a serious adverse event. Flushing during the injection was common, as was a transient headache in the subsequent weeks. One patient experienced Grade 3 chest tightness, necessitating emergency department assessment but not admission or treatment. Treatment produced an average 12.3 g/L improvement in haemoglobin within 2 weeks, but commonly caused reductions in serum phosphate (although none of these was clinically symptomatic). Parenteral iron caused elevations in hepcidin sustained to 4 weeks post-injection. Patients stated they would be prepared to receive the treatment again. CONCLUSION: Rapid injection of undiluted ferric carboxymaltose is well tolerated and could provide an approach to treat patients in the ambulatory setting.

Venous thromboembolism in primary central nervous system lymphoma during frontline chemoimmunotherapy.

BACKGROUND: In primary central nervous system lymphoma (PCNSL), venous thromboembolism (VTE) can cause significant morbidity and hinder chemotherapy delivery. OBJECTIVES: To assess VTE incidence, timing and adequacy of inpatient and outpatient VTE prophylaxis in patients with PCNSL receiving chemoimmunotherapy with curative intent. PATIENTS/METHODS: We reviewed patients diagnosed with PCNSL between 1997 and 2018 who received methotrexate, procarbazine, and vincristine ± Rituximab. Patient demographics, VTE prophylaxis and incidence, adverse events of anticoagulation, and survival outcomes were collected. RESULTS: Fifty-one PCNSL patients were included (median 67 years [range, 32-87], 30 males [59%]). Thirteen patients (25%, 95% confidence interval [CI], 14-40) developed VTE at a median of 1.6 months from diagnosis (range, 0-4). Patients with Khorana Risk Score ≥2 were more likely to have VTE than those with a KRS < 2 (60% vs 15%; P = .01). Eighty-five percent had deviations from inpatient VTE prophylaxis guidelines, and outpatient prophylaxis was not routinely administered. Three patients required inferior vena cava filters. Hemorrhagic complications of anticoagulation included an intracranial hemorrhage from therapeutic anticoagulation and three cases of major bleeding from prophylactic anticoagulation. No patients died from VTE or its treatment. CONCLUSIONS: Patients with newly diagnosed PCNSL are at high risk of VTE. Further research is required into optimal VTE prophylaxis in PCNSL.