Venous thromboembolism risk following temporary immobilisation after injury: evaluation of the Aberdeen VTE risk tool.

BACKGROUND: Temporary lower limb immobilisation following injury is a risk factor for symptomatic venous thromboembolism (VTE). Pharmacological thromboprophylaxis can mitigate this risk but it is unclear which patients benefit from this intervention. The Aberdeen VTE risk tool was developed to tailor thromboprophylaxis decisions in these patients and this evaluation aimed to describe its performance in clinical practice. Secondarily, diagnostic metrics were compared with other risk assessment methods (RAMs). METHODS: A prospective cohort service evaluation was conducted. Adult patients (≥16 years) managed with lower limb immobilisation for injury who were evaluated with the Aberdeen VTE risk tool prior to discharge from the ED were identified contemporaneously between February 2014 and December 2020. Electronic patient records were scrutinised up to 3 months after removal of immobilisation for the development of symptomatic VTE or sudden death due to pulmonary embolism (PE). Other RAMs, including the Thrombosis Risk Prediction for Patients with cast immobilisation (TRiP(cast)) and Plymouth scores, were assimilated retrospectively and diagnostic performance compared. RESULTS: Of 1763 patients (mean age 46 (SD 18) years, 51% women), 15 (0.85%, 95% CI 0.52% to 1.40%) suffered a symptomatic VTE or death due to PE. The Aberdeen VTE tool identified 1053 (59.7%) patients for thromboprophylaxis with a sensitivity of 80.0% (95% CI 54.8% to 93.0%) and specificity of 40.4% (95% CI 38.1% to 42.6%) for the primary outcome. In 1695 patients, fewer were identified as high risk by the TRiP(cast) (33.3%) and Plymouth (24.4%) scores, but with greater specificity, 67.0% and 75.6%, respectively, than dichotomous RAMs, including the Aberdeen VTE tool. CONCLUSION: Routine use of the Aberdeen VTE tool in our population resulted in an incidence of symptomatic VTE of less than 1%. Ordinal RAMs, such as the TRiP(cast) score, may more accurately reflect VTE risk and permit more individually tailored thromboprophylaxis decisions but prospective comparison is needed.

Reducing the use of inappropriate coagulation testing in emergency general surgical patients.

Background and aims Indiscriminate coagulation testing in emergency general surgical patients can lead to inappropriate delay in surgery, cause unnecessary concern and is associated with significant cost. The British Committee for Standards in Haematology recommends against coagulation testing to predict peri-operative bleeding risk in unselected patients. Our aim was to assess the appropriateness of coagulation tests performed in emergency general surgical patients and evaluate the effect of a series of educational interventions on clinical practice. Methods and results Appropriate indications for performing coagulation testing included a positive bleeding history, the presence of liver disease/cholestasis, sepsis or use of anticoagulants. Initial data on 142 patients were collected over 2 weeks of receiving. Following analysis, indications for appropriate coagulation testing were highlighted and data were collected on a further 190 patients. Comparing the audit cycles, we observed a decrease in the proportion of patients who underwent routine testing (49.3% vs 32.6%; p = 0.002) and inappropriate testing (67% of tests vs 34% of tests; p < 0.001). Despite being highlighted, there was no evidence of improved documentation of bleeding histories on admission. Conclusions This observational study suggests that simple educational messages can reduce the inappropriate use of coagulation screening tests in general surgical emergencies. This seems to result from clarification of the appropriate surgical indications for coagulation testing in this group.

Defective α2 antiplasmin cross-linking and thrombus stability in a case of acquired factor XIII deficiency.

Acquired factor XIII (FXIII) deficiency is a rare and life-threatening condition that is often misdiagnosed or missed completely. A 72-year-old woman presented with symptoms of major unprovoked bleeding but routine coagulation screening tests and platelet count were normal. Low activated FXIII (FXIIIa) activity levels and abnormal urea clot stability led to diagnosis of acquired FXIII deficiency. A modified Bethesda inhibitor titre of 1.6 Bethesda units/ml indicated the presence of a FXIII inhibitor. Bleeding responded to a single dose of FXIII concentrate and immunosuppression with prednisolone induced remission. A subsequent relapse was treated with combined prednisolone and Rituximab resulting in a prolonged, ongoing remission. Here we analyse the mechanisms underlying this idiopathic case of acquired FXIII deficiency. Prospective analysis of patient plasma revealed minimal FXIIIa activity and antigen in presentation and relapse samples. Thrombi formed from these samples lysed rapidly and showed an absence of cross-linked α2 AP. Western blotting revealed the presence of FXIII-B, indicating only FXIII-A and FXIII-A2 B2 were affected. FXIII activity and antigen levels normalised on remission. Our data suggest the presence of inhibitor-induced clearance of FXIII from plasma. As a consequence, reduced thrombus stability was evident due to defective α2 AP cross-linking, thereby explaining symptoms of excessive bleeding.

Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9.

The congenital sideroblastic anemias (CSAs) are relatively uncommon diseases characterized by defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Here we demonstrate that mutations in HSPA9, a mitochondrial HSP70 homolog located in the chromosome 5q deletion syndrome 5q33 critical deletion interval and involved in mitochondrial Fe-S biogenesis, result in CSA inherited as an autosomal recessive trait. In a fraction of patients with just 1 severe loss-of-function allele, expression of the clinical phenotype is associated with a common coding single nucleotide polymorphism in trans that correlates with reduced messenger RNA expression and results in a pseudodominant pattern of inheritance.

Guideline on aspects of cancer-related venous thrombosis.

The guideline was drafted by a writing group identified by the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). All the authors are consultants in haematology in the UK. A search was performed of PubMed and Embase using the term 'cancer' combined with 'thrombosis', 'treatment', 'prophylaxis' and 'clinical presentation'. The search covered articles published up until December 2014. Only human studies were included and articles not written in English were excluded. References in recent reviews were also examined. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH and the BCSH executive. The guideline was then reviewed by the sounding board of the British Society for Haematology (BSH). This comprises 50 or more members of the BSH who have reviewed the guidance and commented on the content and application to the UK setting. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found at: http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the prevention and management of venous thromboembolism (VTE) in patients with cancer and to advise on an approach to screening for cancer in patients with unprovoked VTE in whom cancer was not initially suspected based on clinical grounds.

Destination healthcare facility of shocked trauma patients in Scotland: analysis of transfusion and surgical capability of receiving hospitals.

AIMS: Haemorrhage is a leading cause of death from trauma. Management requires a combination of haemorrhage control and resuscitation which may incur significant surgical and transfusion utilisation. The aim of this study is to evaluate the resource provision of the destination hospital of Scottish trauma patients exhibiting evidence of pre-hospital shock. METHODS: Patients who sustained a traumatic injury between November 2008 and October 2010 were retrospectively identified from the Scottish Ambulance Service electronic patients record system. Patients with a systolic blood pressure less than 110 mmHg or if missing, a heart rate greater than 120 bpm, were considered in shock. The level of the destination healthcare facility was classified in terms of surgical and transfusion capability. Patients with and without shock were compared. RESULTS: There were 135,004 patients identified, 133,651 (99.0%) of whom had sustained blunt trauma, 68,411 (50.7%) were male and the median (IQR) age was 59 (46). There were 6721 (5.0%) patients with shock, with a similar age and gender distribution to non-shocked patients. Only 1332 (19.8%) of shocked patients were taken to facilities with full surgical capability, 5137 (76.4%) to hospitals with limited (general and orthopaedic surgery only) and 252 (3.7%) to hospitals with no surgical services. In terms of transfusion capability, 5556 (82.7%) shocked patients were admitted to facilities with full capability and 1165 (17.3%) to a hospital with minimal or no capability. CONCLUSIONS: The majority of Scottish trauma patients are transported to a hospital with full transfusion capability, although the majority lack surgical sub-specialty representation.

Fibrinogenolysis and fibrinolysis in vaccine-induced immune thrombocytopenia and thrombosis.

BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia. OBJECTIVES: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT. METHODS: Plasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen. RESULTS: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1ß, IL-6, IL-8, TNFα, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors. CONCLUSION: VITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

Skin cancer in essential thrombocythaemia and polycythaemia vera patients treated with hydroxycarbamide.

Hydroxycarbamide (HC) is used as a cytoreductive treatment in myeloproliferative neoplasms (MPN). Observational studies have raised the possibility that HC contributes to the development of secondary malignancies, including skin tumours in MPN patients. In this retrospective observational study, we report a single-centre experience of 324 HC-treated MPN patients with long-term follow-up, compared to 47 MPN patients not on HC. Thirty-three patients (10.2%) (HC) versus one patient (2.1%) (no HC) developed skin tumours during follow-up (Hazard ratios [HR] 5.70, 95% confidence intervals 0.66-48.09, p = 0.112). However, male gender, age at MPN diagnosis, type of MPN (polycythaemia rubra vera) and previous history of skin cancer were prognostic variables associated with development of skin cancer.

Guidelines on travel-related venous thrombosis.

Long duration travel is a weak risk factor for the development of venous thromboembolism (VTE). The incidence of VTE after flights of >4 h is 1 in 4656 and for flights of more than 8 h in low and intermediate risk flyers is around 0.5%. Severe symptomatic pulmonary embolism in the period immediately after travel is extremely rare after flights of <8 h. In flights over 12 h the rate is 5 per million. VTE may be attributable to travel if it occurs up to 8 weeks following the journey. The risk of travel-related thrombosis is higher in individuals with pre-existing risk factors for the development of VTE. There is no evidence for an association between dehydration and travel-associated VTE and so whilst maintaining good hydration is unlikely to be harmful it cannot be strongly recommended for prevention of thrombosis (recommendation grade 2, level of evidence, B). There is indirect evidence that maintaining mobility may prevent VTE and, in view of the likely pathogenesis of travel-related VTE, maintaining mobility is a reasonable precaution for all travellers on journeys over 3 h (2B). Global use of compression stockings and anticoagulants for long distance travel is not indicated (1C). Assessment of risk should be made on an individual basis but it is likely that recent major surgery (within 1 month), active malignancy, previous unprovoked VTE, previous travel-related VTE with no associated temporary risk factor or presence of more than one risk factor identifies those travellers at highest thrombosis risk (1C). Travellers at the highest risk of travel-related thrombosis undertaking journeys of >3 h should wear well fitted below knee compression hosiery (2B). Where pharmacological prophylaxis is considered appropriate, anticoagulants as opposed to anti-platelet drugs are recommended based on the observation that, in other clinical scenarios, they provide more effective thromboprophylaxis. Usual contraindications to any form of thromboprophylaxis need to be borne in mind (2C).

Aspirin and other antiplatelet drugs in the prevention of venous thromboembolism.

While there is good evidence for a protective effect of aspirin against occlusive vascular events in individuals with arterial disease, its role in preventing venous thromboembolism (VTE) is unclear. In this article we review the role of aspirin and other antiplatelet drugs in prevention of venous thromboembolism in surgical patients, high risk medical patients requiring aspirin for other reasons, patients with myeloproliferative disorders, long distance travellers and patients receiving treatment with the IMiD class of drugs. Overall, data from the PEP study and Anti-Platelet Trialists' systematic review show that aspirin reduces the risk of VTE by around 25% in high risk surgical patients. Data from retrospective and before/after studies also suggest efficacy in reducing VTE in myeloma patients on IMiD drugs in combination with dexamethasone or chemotherapy. However, there has been no direct comparison with coumarins or heparin to indicate that aspirin is the optimal form of thromboprophylaxis. In patients who require aspirin because of high risk of arterial vascular occlusion (including patients with polycythaemia vera and essential thrombocythaemia), the additional small reduction in VTE risk is an added benefit with no additional risk associated. There is no evidence for a role of aspirin in prevention of travel-related thrombosis. At present there is no clear evidence that aspirin is the drug of choice for the prevention of VTE in any patient group.

Sex hormones and thrombosis.

There is compelling evidence that use of oral formulations of female hormone replacement and of the combined oral contraceptive induces a prothrombotic state. This translates to an increased thrombotic risk. Within the individual, the absolute risk is determined by the interaction between that induced by hormone use and heritable and acquired risk factors for thrombosis. Knowledge of the accumulating epidemiologic and clinical trial-derived data on this topic is essential for the delivery of evidence-based counseling in the clinical environment and is the subject of this review.