R. Maclean

Guidelines for supportive care in multiple myeloma 2011

Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate‐induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011.

Management dilemmas in acute pulmonary embolism

Background Physicians treating acute pulmonary embolism (PE) are faced with difficult management decisions while specific guidance from recent guidelines may be absent. Methods Fourteen clinical dilemmas were identified by physicians and haematologists with specific interests in acute and chronic PE. Current evidence was reviewed and a practical approach suggested. Results Management dilemmas discussed include: sub-massive PE, PE following recent stroke or surgery, thrombolysis dosing and use in cardiac arrest, surgical or catheter-based therapy, failure to respond to initial thrombolysis, PE in pregnancy, right atrial thrombus, role of caval filter insertion, incidental and sub-segmental PE, differentiating acute from chronic PE, early discharge and novel oral anticoagulants. Conclusion The suggested approaches are based on a review of the available evidence and guidelines and on our clinical experience. Management in an individual patient requires clinical assessment of risks and benefits and also depends on local availability of therapeutic interventions.

Characterization of Nitric Oxide Consumption Pathways by Normal, Chronic Granulomatous Disease and Myeloperoxidase-Deficient Human Neutrophils

The detailed mechanisms by which acutely activated leukocytes metabolize NO and regulate its bioactivity are unknown. Therefore, healthy, chronic granulomatous disease (CGD) or myeloperoxidase (MPO)-deficient human neutrophils were examined for their ability to consume NO and attenuate its signaling. fMLP or PMA activation of healthy neutrophils caused NO consumption that was fully blocked by NADPH oxidase inhibition, and was absent in CGD neutrophils. Studies using MPO-deficient neutrophils, enzyme inhibitors, and reconstituted NADPH oxidase ruled out additional potential NO-consuming pathways, including Fenton chemistry, PGH synthase, lipoxygenase, or MPO. In particular, the inability of MPO to consume NO resulted from lack of H2O2 substrate since all superoxide (O2minusdu;) reacted to form peroxynitrite. For healthy or MPO-deficient cells, NO consumption rates were 2- to 4-fold greater than O2minusdu; generation, significantly faster than expected from 1:1 termination of NO with O2minusdu; Finally, fMLP or PMA-stimulated NO consumption fully blocked NO-dependent neutrophil cGMP synthesis. These data reveal NADPH oxidase as the central regulator of NO signaling in human leukocytes. In addition, they demonstrate an important functional difference between CGD and either normal or MPO-deficient human neutrophils, namely their inability to metabolize NO which will alter their ability to adhere and migrate in vivo.

Real world usage of PCC to “rapidly” correct warfarin induced coagulopathy

BACKGROUND Life threatening bleeding and emergency procedures in patients on vitamin K antagonists are indications for urgent reversal with prothrombin complex concentrate and vitamin K. Rapid reversal in these situations is emphasized in the literature and guidelines, but only very limited information is available on its real life use, especially on the timing of treatment in relation to presentation. MATERIALS AND METHODS We retrospectively audited emergency warfarin reversal in 131 consecutive patients. We studied the indication, use of vitamin K, time between presentation and administration of vitamin K and PCC, effectiveness in INR reduction and clinical outcome. RESULTS The median PCC dose was 26.8 IU/kg. The median INR was reduced from 3.1 to 1.2. Vitamin K (5 mg) was given in 91.6% of evaluable patients. We found significant delays in administration of PCC and vitamin K. The median time between presentation and administration of vitamin K/PCC was 3.6 and 5.2 hours respectively. The times in intracranial haemorrhage were 2.7 and 3.0 hours and in emergency procedures 17.4 and 15.9 hours respectively. Mortality related to bleeding was 7.6% overall but in patients with intracranial haemorrhage 22.8%. The thrombotic rate within 7 days of reversal was 1.5%. DISCUSSION The local protocol for reversal with PCC and vitamin K was adhered to well but the delay in pre-procedural patients, suggests that intravenous vitamin K alone may be sufficient in many cases and PCC administration can be avoided by better planning. Intracranial haemorrhage in warfarinised patients carries a high mortality. Treatment delays should be avoided by making PCC stocks available within emergency departments, simple dosing structures independent of INR and administering PCC without waiting for INR and CT scan results in those with strong suspicion of intracranial haemorrhage and clear trauma. Future reports and studies should always include the time from presentation to PCC treatment.

The use of ecarin chromogenic assay and prothrombinase induced clotting time in the monitoring of lepirudin for the treatment of heparin-induced thrombocytopenia.

Lepirudin (r‐hirudin) is one of the two alternative anticoagulants licensed to treat patients with heparin‐induced thrombocytopenia (HIT). Manufacturer’s guidelines state that lepirudin should be monitored using the activated partial thromboplastin time (APTT) ratio. However, several studies have demonstrated a plateau effect of higher concentrations of lepirudin on APTT ratios and variable results when comparing different APTT reagents. This study compares APTT ratios (using two different APTT reagents) with two other commercially available methods for directly quantifying plasma lepirudin levels: ecarin chromogenic assay and prothrombinase‐induced clotting time in 95 samples from five patients receiving lepirudin anticoagulation for HIT.

Factor V Leiden and the common haemochromatosis mutation HFE C282Y: is there an association in familial venous thromboembolic disease?

The involvement in venous thrombosis of the two most common mutations of the hereditary haemochromatosis gene (HFE C282Y and HFE H63D) was investigated in 239 patients with objectively proven venous thrombosis. Neither mutation showed an increased prevalence in the cohort (HFE C282Y: 13.0% (95% CI 9.3–17.8) patients, 16.2% (95% CI 14.3–18.2) controls; HFE H63D: 28.3% (95% CI 22.9–34.3) patients, 28.1% (95% CI 25.8–30.6) controls. Neither mutation was increased in patients with factor V Leiden (FVL) compared to those without. However, HFE C282Y was increased among patients who had both FVL and a family history of thrombosis (7/20), compared with those with FVL and no family history (1/22) (relative risk 7.97, 95% CI 1.5–43.1, P = 0.016).

Effect of extremes of body weight on drug level in patient treated with standard dose of rivaroxaban for venous thromboembolism; real life experience

Venous thromboembolism (VTE) is a leading cause ofmorbidity and mortalityworldwide. Appropriate anticoagulation is crucial in the treatment and prevention of recurrent VTE. Overdosing of an anticoagulant could result in life-threatening bleeding while under-dosing could result in lack of efficacy leading to recurrence of thrombosis. It is possible that “extremes in body weight” [EBW] (b50 kg or N120 kg) may alter the exposure profile of an anticoagulant and its benefit: risk ratio. Monitoring of anticoagulant intensity of direct acting oral anticoagulants (DOACs) is not routinely required due to their predictable anticoagulant effects but assessment of drug levels may be useful in some situations including EBW as recommended by both International Society for Thrombosis and Haemostasis (ISTH) [1] and the British Committee for Standards in Haematology (BCSH) guidelines [2]. Patients with EBW, both very low and very high, are underrepresented in clinical trials and in preclinical dose-finding studies. The mean weight was around 84 kg; with the majority of participants in phase III clinical studies weighing between 60 and 100 kg [3]. Sub-analysis of EINSTEIN DVT and PE studies in which weight was categorised into three groups as 50 kg, 50–100 kg and N100 kg, foundno association between body weight and the risk of recurrent VTE and similar rates of recurrent VTE by treatment group (2.3% on rivaroxaban vs 2.0% on VKA in patients N100 kg) [4]. However, none of the phase III trials with DOACs reported the patients with body mass index (BMI) N40 kg/m or their clinical outcome. The guidance from the SSC of the ISTH on use of DOACs in obese patients 2016 [3], recommended against the use of DOACs in patients with BMI N40 kg/m2 or the weight N 120 kg due to limited clinical data in this group of patients. We assessed the effect of EBWon rivaroxaban levels and clinical outcome with standard dose of rivaroxaban (15 mg BD for three weeks followed by 20 mg once daily) in the treatment of venous thromboembolism (VTE) in a routine clinical practice. The study was untaken as a part service evaluation project in a tertiary haemostasis and thrombosis centre in UK and approved by the trust clinical effectiveness unit. An unselected group of 219 patients with VTE (53% deep vein thrombosis [DVT], 41% pulmonary embolism [PE] and 6% PE and DVT: 51% male, 49% female, mean age 59 years) were studied. Rivaroxaban levels were measured in blood samples taken 2–4 h from the last dose of rivaroxaban in patients on rivaroxaban 20 mg daily after an initial

Limitation of the activated partial thromboplastin time as a monitoring method of the direct thrombin inhibitor argatroban

Argatroban is licensed for patients with heparin‐induced thrombocytopenia and monitoring is conventionally by activated partial thromboplastin time (APTT) ratio with a target of 1.5–3.0 and not exceeding 100 s. The APTT may be influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. Variable but not clinically significant sensitivity of APTT reagents to argatroban has been highlighted in other studies.

The investigation of a prolonged APTT with specific clotting factor assays is unnecessary if an APTT with Actin FS is normal

Introduction:  An isolated prolongation to the activated partial thromboplastin time (APTT) can be caused by the presence of the lupus anticoagulant or an intrinsic or contact factor deficiency, of which only deficiencies of factors VIII, IX or XI are associated with bleeding. Our local protocol states that further investigation of a prolonged APTT by specific assays of FVIII, FIX and FXI should only be undertaken where the APTT with one reagent (Synthasil) is more than 3 s prolonged, and further investigation by an APTT with a second reagent (Actin FS) is also prolonged, unless there is a history of bleeding in the patient, in which case assays are indicated irrespective of the APTT.

Major surgery in severe haemophilia A with inhibitors using a recombinant factor VIIa and activated prothrombin complex concentrate hybrid regimen

Major surgery in persons with haemophilia A and inhibitors is increasingly being performed. Both recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (APCC) are used to cover surgery but it remains unclear what the optimal dosing schedules are. We describe the use of a hybrid regimen in four inhibitor patients undergoing eight major surgical procedures using rFVIIa in the initial 2–6 postoperative days followed by FEIBA® for the remaining period. All patients were also treated with tranexamic acid while receiving rFVIIa. We performed six major orthopaedic procedures, one emergency orchidectomy and one open appendectomy. The dosing schedules were at the higher end of those described in the literature but within the recommendations of the summary of product characteristics. Despite this, we encountered non‐surgical bleeding in four of eight episodes. Three of these occurred in one individual suggesting a patient factor. The overall outcome was good for all episodes. The hybrid regimen combines flexibility of dose and dosing frequency of rFVIIa in the immediate postoperative setting with the advantage of a reduced dosing frequency with FEIBA® in the subsequent days. This study also emphasizes that surgical procedures in this patient group remain a challenge.