Barry F. Jacobson

The BEST study--a prospective study to compare business class versus economy class air travel as a cause of thrombosis.

BACKGROUND As many as 10% of airline passengers travelling without prophylaxis for long distances may develop a venous thrombosis. There is, however, no evidence that economy class travellers are at increased risk of thrombosis. OBJECTIVES A suitably powered prospective study, based on the incidence of deep-vein thrombosis (DVT) reported in previous studies on long-haul flights, was designed to determine the incidence of positive venous duplex scans and D-dimer elevations in low and intermediate-risk passengers, comparing passengers travelling in business and economy class. PATIENTS/METHODS Eight hundred and ninety-nine passengers were recruited (180 travelling business class and 719 travelling economy). D-dimers were measured before and after the flight. A value greater than 500 ng/ml was accepted as abnormal. A thrombophilia screen was conducted which included the factor V Leiden mutation, the prothombin 20210A mutation, protein C and S levels, antithrombin levels, and anticardiolipin antibodies immunoglobulin G (IgG) and immunoglobulin M (IgM). On arrival, lower limb compression ultrasonography of the deep veins was performed. Logistical regression analysis was used to determine the risk factors related to abnormally high D-dimer levels. RESULTS Only 434 subjects had a full venous duplex scan performed. None had ultrasonic evidence of venous thrombosis. Nine passengers tested at departure had elevated D-dimer levels and these volunteers were excluded from further study. Seventy-four of the 899 passengers had raised D-dimers on arrival. Twenty-two of 180 business class passengers (12%) developed elevated D-dimers compared with 52 of 719 economy class passengers (7%). There was no significant association between elevation of D-dimers and the class flown (odds ratio (OR) 0.61, p = 0.109). The factor V Leiden mutation, factor VIII levels and the use of aspirin were, however, associated with raised D-dimers (OR 3.36, p = 0.024; OR 1.01, p = 0.014; and OR 2.04, p = 0.038, respectively). Five hundred and five passengers were contacted within 6 months and none reported any symptoms of a clinical thrombosis or pulmonary embolus. CONCLUSION The incidence of ultrasonically proven DVT is much lower than previously reported. However, more than 10% of all passengers developed raised D-dimers, which were unrelated to the class flown. A rise in D-dimers is associated with an inherent risk of thrombosis and/or thrombophilia, demonstrates activation of both the coagulation and fibrinolytic systems during long-haul flights, and may indicate the development of small thrombi.

The effect of initiating combined antiretroviral therapy on endothelial cell activation and coagulation markers in South African HIV-infected individuals.

An increased incidence of venous thromboembolism (VTE) is observed in human immunodeficiency virus (HIV)-infected patients. Only a limited number of studies described the effect of combined antiretroviral therapy (cART) on coagulation markers. In a prospective cohort study in cART-naive South African HIV-infected individuals the effect of initiating cART on markers of endothelial cell activation, coagulation and natural anticoagulation was studied. These markers were compared to the reference ranges for an HIV-uninfected control population recruited from hospital staff. A venous ultrasound of both legs was performed to detect asymptomatic deep venous thrombosis (DVT). A total number of 123 HIV-infected participants were included. The patients were predominantly black and severely immuno-compromised. The CD4 cell count increased and the HIV viral load decreased significantly after the initiation of cART (p<0.001). The median follow-up period was 7.2 (± 1.6) months. Laboratory testing before and after initiation of cART was completed by 86 patients. Before initiating cART significantly elevated von Willebrand factor and D-dimer levels, increased activated protein C sensitivity ratio (APCsr) and decreased total and free protein S and protein C levels were observed compared to HIV-negative controls. At follow-up all markers, except APCsr, improved towards the normal range for controls without showing complete normalisation. In a subgroup of 57 patients no asymptomatic DVT was found. Compared to the controls, abnormal levels of coagulation markers were observed in HIV-infected individuals before and after the initiation of cART. Most markers improved after starting cART, but remained significantly different from the controls, indicating a persistent disturbed haemostatic balance.

Comparative blood coagulation studies in the ostrich.

Blood coagulation of the ostrich was compared to that of mammalian (man and sheep), avian (chicken) and reptilian (puff adder) systems. The international normalised ratio (INR), partial thromboplastin time (PTT), thrombin time and fibrin degradation were determined, as well as the various coagulation factors in venous ostrich plasma, using human physiological substrates. Thromboplastin was isolated from fresh brain tissue with the exception of the reptile for which lung tissue was used. The levels of markers of the coagulation [antithrombin III (AT), factor X (FX) and prothrombin], the fibrinolytic (alpha2-antiplasmin) and the kallikrein system were determined using chromogenic substrates. Elevated values for INR, PTT and thrombin time were obtained as compared to known human standards. It was found that factors VII, IX, X, XI and XII were absent from ostrich plasma. A study of the homologous and heterologous thromboplastin activities indicated that ostrich plasma exhibited a lower thromboplastic activity when compared to human standards, but was comparable to avian and reptilian values. Ostrich plasma revealed 42.2% FX, 72.9% AT, 35.3% prothrombin, 115.6% alpha2-antiplasmin and 19.8% plasma kallikrein, relative to human plasma. All the results suggest that the ostrich coagulatory system has not evolved to include all the complex myriad of reactions found in the human system.

Quality of Vitamin K Antagonist Control and 1-Year Outcomes in Patients with Atrial Fibrillation: A Global Perspective from the GARFIELD-AF Registry

Aims Vitamin K antagonists (VKAs) need to be individually dosed. International guidelines recommend a target range of international normalised ratio (INR) of 2.0–3.0 for stroke prevention in atrial fibrillation (AF). We analysed the time in this therapeutic range (TTR) of VKA-treated patients with newly diagnosed AF in the ongoing, global, observational registry GARFIELD-AF. Taking TTR as a measure of the quality of patient management, we analysed its relationship with 1-year outcomes, including stroke/systemic embolism (SE), major bleeding, and all-cause mortality. Methods and Results TTR was calculated for 9934 patients using 136,082 INR measurements during 1-year follow-up. The mean TTR was 55.0%; values were similar for different VKAs. 5851 (58.9%) patients had TTR<65%; 4083 (41.1%) TTR≥65%. The proportion of patients with TTR≥65% varied from 16.7% in Asia to 49.4% in Europe. There was a 2.6-fold increase in the risk of stroke/SE, 1.5-fold increase in the risk of major bleeding, and 2.4-fold increase in the risk of all-cause mortality with TTR<65% versus ≥65% after adjusting for potential confounders. The population attributable fraction, i.e. the proportion of events attributable to suboptimal anticoagulation among VKA users, was 47.7% for stroke/SE, 16.7% for major bleeding, and 45.4% for all-cause mortality. In patients with TTR<65%, the risk of first stroke/SE was highest in the first 4 months and decreased thereafter (test for trend, p = 0.021). In these patients, the risk of first major bleed declined during follow-up (p = 0.005), whereas in patients with TTR≥65%, the risk increased over time (p = 0.027). Conclusion A large proportion of patients with AF had poor VKA control and these patients had higher risks of stroke/SE, major bleeding, and all-cause mortality. Our data suggest that there is room for improvement of VKA control in routine clinical practice and that this could substantially reduce adverse outcomes. Trial Registration ClinicalTrials.gov NCT01090362

The impact of risk assessment on the implementation of venous thromboembolism prophylaxis in foot and ankle surgery

BACKGROUND The purpose of this prospective study was to determine whether the more frequently quoted procedure and patient specific risk factors have any impact in the implementation of venous thromboembolism (VTE) prophylaxis following foot and ankle surgery. METHODS Two hundred and sixteen patients were included in the study. A variety of operative procedures was carried out with the common denominator being a below knee cast for at least 4 weeks and nonweightbearing for an average of 6 weeks in 130 patients. The remainder of the patients (88) had hallux surgery not requiring a cast and were allowed to weightbear. No patient received any form of thromboprophylaxis postoperatively. All patients were subjected to compression ultrasonography for deep vein thrombosis (DVT) between 2 and 6 weeks postoperatively. RESULTS There was a 5.09% incidence of VTE (0.9% pulmonary embolism) overall. As no VTE (neither DVT nor pulmonary embolus) developed in the hallux subgroup, i.e. patients not requiring immobilization and were allowed to weightbear, the incidence of VTE in the cast/nonweightbearing group was 8.46%. The results are descriptive and only statistically analyzed where possible, as the sample size of the VTE group was small. There was no significant difference in number of risk factors and no association between gender in the VTE and non VTE groups. 90.9% of patients in the VTE group had a total risk factor score of 5 or more and 73.7% of patients in the non VTE group had a total risk factor score of 5 or more. The average timing to the diagnosis of VTE in this current study was 33.1 days. CONCLUSIONS In view of the unacceptable incidence of VTE and the average total risk factor score of 5 or more (for which thromboprophylaxis is recommended) in the majority of the patients, the authors feel that the routine use of thromboprophylaxis in foot and ankle surgery requiring nonweightbearing in combination with short leg cast immobilization, is warranted. This prophylaxis should continue until the patient regains adequate mobility either by weightbearing (in or out of the cast) or removal of cast immobilization (weightbearing or nonweightbearing), usually between 28 and 42 days.

Delayed hypersensitivity to low molecular weight heparin (LMWH) in pregnancy

Heparin is currently the anticoagulant of choice for the prevention and treatment of thrombo-embolic disease in pregnancy because it does not cross the placenta [1]. The use of low molecular weight heparin (LMWH) is preferred to unfractionated heparin (UFH) as it is associated with a lower risk of bleeding, osteoporosis, heparin induced thrombocytopenia (HIT) and hypersensitivity reactions [2, 3, 4, 5]. Fondaparinux can be considered as a valuable alternative to LMWH during pregnancy in those patients with heparin induced skin reactions and/or HIT.

In vitro effects of thawing fresh-frozen plasma at various temperatures.

Thawing fresh-frozen plasma (FFP) in South Africa is uncontrolled because the plasma is issued frozen from the blood bank and thawing techniques and temperatures are at the discretion of the clinician. Following anecdotal reports of disseminated intravascular coagulation (DIC) developing in patients who received FFP thawed in an uncontrolled manner, the effects of various thawing temperatures on coagulation parameters were studied. Fifteen adult units of FFP were each divided into 4 satellite units by the South African Blood Transfusion Service before freezing at -25°C. These bags were then defrosted in a waterbath at 22°C, 37°C, 45°C and 60°C, respectively, and removed as soon as they had thawed. Samples were collected for measurement of International Normalized Ratio (INR), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimers. These tests were done according to standard operating procedures. FFP samples were also used in place of agonist in platelet aggregation studies to assess whether the FFP could induce platelet aggregation. Results were analyzed with the percentage similarity model. Using this method the percentage similarity (%sim) of each bag thawed at each temperature with the same donor’s bag thawed at 37°C was calculated. The mean, standard deviation, and percentage coefficient of variation of the percentage similarities were then derived. Data sets were also compared using the Wilcoxon test. The fibrinogen values remained stable at 22-45°C (%sim = 97-99%) while there was a significant decrease in fibrinogen levels at 60°C compared with 37°C (p<0.001,%sim = 75%). INR and PTT values were highest in the bags thawed at 60°C (%sim = 114% and 110%, respectively) with the difference between the INR levels at 60°C compared with 37°C showing statistical significance (p<0.05). D-dimers were high at all temperatures tested with widely ranging results at each temperature. The FFP did not induce platelet aggregation at any of the thawing temperatures. In summary, INR and PTT values increase at a thawing temperature of 60°C compared with 37°C. D-dimers are elevated in thawed FFP. Fibrinogen levels are markedly decreased in FFP thawed at 60°C compared with that thawed at 37°C. FFP should be thawed at 37°C in a strictly controlled environment.

Erythrocyte sedimentation rate as a marker of inflammation and ongoing coagulation in stroke and transient ischaemic attack

OBJECTIVE Systemic infection and inflammation have been implicated in the aetiology of thrombotic cerebral events, particularly in younger patients. We decided to determine whether those patients with raised D-dimer levels, indicating continuing thrombosis and fibrinolysis, had evidence of concurrent infection or inflammation as manifested by a raised erythrocyte sedimentation rate (ESR) measured after an ischaemic stroke/transient ischaemic attack (TIA). METHODS One hundred and forty-eight patients who had suffered either single or recurrent cerebrovascular episodes were analysed. The patients were referred to the thrombosis and haemostasis unit at Johannesburg Hospital for evaluation of their thrombotic profiles, including D-dimer levels. Concurrent infection was assessed by measurement of white cell count (WCC) and ESR. The variable time interval between the date of the most recent cerebrovascular event and the date of venesection was determined. A history was taken, a physical and neurological examination was performed, and a cardiology assessment and neuroimaging studies were done. RESULTS Raised D-dimer levels correlated significantly with ESR levels (p = 0.0094) in all patients. This was particularly evident when comparing the 70 younger patients (aged less than 45 years) with the 78 older patients (> 45 years) with raised D-dimers (p = 0.0070). When analysing other markers of inflammation/infection in association with raised D-dimer levels and ESR, mean fibrinogen levels were significantly raised at 6.56 g/l (p = 0.0122). An elevated WCC, as a categorical variable, was significantly associated with an elevated ESR (p = 0.0092). CONCLUSION There is a significant correlation between elevated D-dimer levels (indicating abnormalities of coagulation and fibrinolysis) and markers of inflammatory and/or infective processes. This is particularly evident in black patients below the age of 45 years. These patients are believed to be at decreased risk for generalised atheromatous disease compared with older white patients. The ramifications of these findings are potentially important with regard to thrombotic cerebrovascular disease aetiology, investigation, management and prevention.

Human immunodeficiency virus infection and acute deep vein thromboses.

Abnormalities that predispose to a hypercoagulable state with an increased incidence of venous thrombosis have been described in human immunodeficiency virus (HIV) infections and are associated with an increased mortality. A recent systematic review by Klein et al concluded that further studies are essential to elucidate the link between HIV infection and deep vein thrombosis (DVT). We prospectively evaluated 24 consecutive, active people presenting with an acute DVT; 13 consented to HIV testing, revealing an HIV prevalence of 84% (95% confidence interval [CI], 0.65-1.04). In a matched healthy control group, the HIV prevalence was 4% (95% CI, 0.039-0.041). The high HIV prevalence in the DVT group that consented to testing was also significantly higher compared to that in the South African population, estimated to be 10% in 2005. Although the study numbers were low, a statistically significant increased prevalence of HIV infection was found in patients with acute DVTs.

Selective serotonin reuptake inhibitor-induced disturbances of haemostasis - Mechanisms and therapeutic implications

Serotonin (5-hydroxytryptamine; 5-HT) has important peripheral functions that include roles in platelet function, primarily in aggregation and modulation of vascular tone. Platelet serotonin is derived predominantly via uptake from the enterochromaffin system. Selective serotonin reuptake inhibitors (SSRIs) substantially reduce platelet serotonin stores via uptake inhibition. SSRIs are associated with infrequent clinical reports of haemostatic dysfunction, primarily easy bruising.These clinical reports have not, however, been paralleled by prospective studies, which have not found any disturbances in haemostatic function secondary to SSRI therapy. SSRI-associated haemostatic dysfunction appears to be a rare adverse event, and has not been reported to be associated with mortality or substantial morbidity. Nevertheless, a high index of suspicion is warranted in any patient on SSRI therapy who develops unexplained changes in haemostatic function.