The Novel Coronavirus and Haemostatic Abnormalities: Pathophysiology, Clinical Manifestations, and Treatment Recommendations.

The COVID-19 pandemic, caused by the SARS-C0V-2 virus, was initially considered and managed in a similar manner to the previous SARS epidemic as they are both caused by coronaviruses. What has now become apparent is that a major cause of morbidity and mortality in COVID-19 is abnormal thrombosis. This thrombosis occurs on a macro- and microvascular level and is unique to this disease. The virus has been demonstrated in the endothelium of the pulmonary alveoli and as such is thought to contribute to the devastating respiratory complications encountered. D-dimer concentrations are frequently raised in COVID to levels not frequently seen previously. The optimal anticoagulation treatment in COVID remains to be determined, and the myriad of pathophysiologic effects caused by this virus in the human host have also yet to be fully elucidated.

Overview of the Haematological Effects of COVID-19 Infection.

From its early origins, COVID-19 has spread extensively and was declared a global pandemic by the World Health Organization in March of 2020. Although initially thought to be predominantly a respiratory infection, more recent evidence points to a multisystem systemic disease which is associated with numerous haematological and immunological disturbances in addition to its other effects. Here we review the current knowledge on the haematological effects of COVID-19.

Early Online.

BACKGROUND: Long-haul flights have been associated with a two- to four-fold increased risk of aviation-related thrombosis (ART). Several studies have investigated the extent to which hypoxic hypobaric exposure, dehydration and prolonged immobilisation during air travel induce changes in haemostasis. OBJECTIVE: To investigate the role of high altitude as a risk factor for ART. METHODS: Healthy volunteers aged ≥18 years (N=40), without risk factors for venous thromboembolism, were exposed to an exacerbated altitude of 18 000 feet (5 486 m) for 1 hour. During the flight, the oxygen (O2) levels of the participants, who received supplemental O2, were measured by pulse oximetry and maintained at >92%. Venous blood and urine samples were collected prior to departure and immediately after flying in an unpressurised twin-engine airplane. D-dimer levels, thromboelastography (TEG) parameters, von Willebrand factor (VWF) activity and urine osmolality were measured. RESULTS: The participants were 19 men and 21 women, with a mean (standard deviation) age of 46 (14) years. A significant difference in D-dimer levels, VWF activity, urine osmolality and TEG parameters (reaction (R) time, kinetic (K) time and maximum amplitude (MA)) before and after the 1-hour flight was observed (p<0.001). Urine osmolality correlated positively with VWF activity levels (r=0.469; p<0.002). CONCLUSION: Air travel at high altitude induced a hypercoagulable state in healthy volunteers. Future research should focus on whether thromboprophylaxis can significantly obviate the activation of coagulation in response to high altitude.

Recommendations for the diagnosis and management of vaccine-induced immune thrombotic thrombocytopenia.

There have recently been safety concerns regarding an increased risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) following administration of SARS-CoV-2 adenoviral vector vaccines. The Southern African Society of Thrombosis and Haemostasis reviewed the emerging literature on this idiosyncratic complication. A draft document was produced and revised by consensus agreement by a panel of professionals from various specialties. The recommendations were adjudicated by independent international experts to avoid local bias. We present concise, practical guidelines for the clinical management of VITT.

Verification of the qLabs international normalized ratio point-of-care device for monitoring of patients attending an anticoagulation clinic.

INTRODUCTION: In the developing world, point-of-care (POC) testing for international normalized ratio (INR) plays an important role in the monitoring of patients on long-term warfarin therapy with limited access to healthcare ensuring safe and effective anticoagulation. A newly developed POC device for INR measurement by healthcare workers is the handheld qLabs POC device® (Micropoint Biotechnologies Incorporated, Guangdong, China). METHODS: The qLabs POC device® was evaluated in 262 patients attending an anticoagulation clinic with regards to accuracy and precision of the INR results. The results were compared to the results obtained on the Stago STA R Max® coagulation analyzer (Stago Diagnostica, Paris, France) on a wide range of normal and abnormal results of clinical relevance. RESULTS: The mean laboratory INR (2.50 ± 1.08) was significantly higher than the qLabs POC device® INR (2.38 ± 1.07) (P < .0001). The correlation coefficient (r) was .88, the slope coefficient was 1.0 (CI, 0.8-1.2), and the intercept was -0.10 (CI, -0.50 to 0.30). The mean of the differences was -0.13% (CI, -0.19 to -0.06). Dosage concordance was 85.46% and clinical agreement was 92.37%. However, clinical agreement was 42.42% in the subgroup above the target range (>3.5). The imprecision was within acceptable limits (<5%) and the error message rate was 4.38%. CONCLUSION: In conclusion, the qLabs POC device® is accurate and precise with high levels of dosage concordance and clinical agreement for INR values within and below the target range.

Validation of the CoaguChek XS international normalised ratio point-of-care analyser in patients at Charlotte Maxeke Johannesburg Academic Hospital, South Africa.

BACKGROUND: Measurement of the international normalised ratio (INR) is essential in the management of patients on long-term warfarin therapy. The CoaguChek XS portable coagulometer is a point-of-care test for INR measurement. It offers the advantage of improved patient accessibility, particularly in peripheral clinics. OBJECTIVES: To evaluate the clinical utility of the CoaguChek XS for monitoring of patients on standard warfarin therapy (INR 2 - 3) as well as those with mechanical heart valve replacements (INR 2.5 - 3.5). METHODS: We compared the performance of the CoaguChek XS device with that of the STAGO laboratory analyser with regard to accuracy and precision in 304 patients referred for routine testing. RESULTS: The mean INR value of the CoaguChek XS of 2.75 (standard deviation (SD) 1.18) was comparable to that of the STAGO (2.65 (SD 1.04)). The Bland-Altman difference plot revealed good agreement. Bias between the two methods was small, and the imprecision was within acceptable limits. Within the target range (2.0 - 3.5), 93.9% of the CoaguChek XS INR readings were within 0.5 units of the standard laboratory method result. There was, however, an increase in the variability of the differences between the two test methods when the INR was >3.6. CONCLUSION: The CoaguChek XS point-of-care device can be used to provide accurate and precise INR measurements over a wide range for monitoring of valvular and non-valvular patients on long-term warfarin therapy.

Correlation between rivaroxaban (Xarelto) plasma activity, patient clinical variables and outcomes in a South African centre.

BACKGROUND: Low-molecular-weight heparin and vitamin K antagonists such as warfarin are the gold standard for prohylaxis and treatment of venous thromboembolic disease (VTED). Direct oral anticoagulants (DOACs) result in predictable anticoagulation with significantly reduced inter- and intra-patient variability. DOAC absorption is rapid, with a short half-life and relatively few drug interactions. DOACs are effective and safe at fixed doses without activity monitoring. However, specific situations may require assessment of accurate drug activity. Rivaroxaban, a DOAC targeting activated coagulation factor X (FXa), is registered for the prevention and treatment of VTED in South Africa. OBJECTIVES: To establish a prophylactic rivaroxaban activity level range and determine any associations with clinical complications, viz. haemorrhage and/or thrombosis. METHODS: Samples from 115 orthopaedic patients were tested 3 hours after a prophylactic oral dose of 10 mg rivaroxaban with STAGO rivaroxaban anti-FXa reagent on an automated coagulation analyser. Patient demographics and clinical outcomes were documented. RESULTS: The mean rivaroxaban anti-FXa level was 105.7 ng/mL. Two patients developed adverse events on therapy. One patient had minor bleeding (menorrhagia) (drug activity level 288.7 ng/mL) and another a deep-vein thrombosis (drug activity level 34.7 ng/mL). Statistical analysis demonstrated an association between drug activity and advancing age (p=0.008), most apparent among those aged ≥65 years. CONCLUSIONS: Measuring rivaroxaban activity levels reduces uncertainty if treatment failure and complications occur. Patients aged ≥65 years should be closely monitored. A local rivaroxaban activity level for patients on rivaroxaban prophylaxis has been established.

Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients.

BACKGROUND AND PURPOSE: Patients with suspected stroke first assessed by ambulance paramedics require early recognition to facilitate appropriate triage and early treatment. We determined paramedic's accuracy in detecting acute stroke signs by comparing agreement between neurological signs recorded in the Face Arm Speech Test (FAST), a stroke recognition instrument, by paramedics on the scene and by stroke physicians after admission. METHODS: Suspected stroke patients admitted by ambulance paramedics directly to an acute stroke unit through a rapid ambulance protocol were examined by a trainee stroke neurologist or admitting stroke physician over a 1-year period. Recorded neurological signs (facial weakness, arm weakness, speech disturbance) in confirmed acute stroke/transient ischemic attack (TIA) cases were compared between paramedics and the stroke neurologist/physician. RESULTS: Ambulance crews referred 278 suspected stroke patients of whom 217 (78%) had confirmed stroke (n=189) or TIA (n=28); 95% were examined by the stroke neurologist (median 18 hours after paramedic assessment). Recorded signs and agreement between paramedics and stroke physicians in confirmed stroke group were: facial weakness, 68% versus 70% (kappa=0.49; 95% CI: 0.36 to 0.62); arm weakness, 96% versus 95% (kappa=0.77; 95% CI: 0.55 to 0.99); and speech disturbance, 79% versus 77% (kappa=0.69; 95% CI: 0.56 to 0.82). Interrater agreement was complete for arm weakness in 98% cases. CONCLUSIONS: Recognition of neurological deficits by ambulance paramedics using FAST shows good agreement with physician assessment, even allowing for temporal evolution of deficits. The high prevalence and good agreement for arm weakness suggest that this sign may have the greatest usefulness for prehospital ambulance triage and paramedic-based neuroprotective trials.

Respiratory health of brickworkers in Cape Town, South Africa. Radiographic abnormalities.

A cross-sectional study utilizing internal controls based on dust exposure determinations was performed on 268 brickworkers. Smoking, age, and other information from a detailed respiratory questionnaire and results from a physical examination and pulmonary function tests were investigated in relation to radiographic abnormality. The prevalence of pneumoconiosis was near 4%. The roles of smoking, workplace dust exposure, and age as factors predicting radiographic abnormality are discussed.

Identification of Fungi and Fungal Pathogens Associated with Hypolixus haerens and Decayed and Cankered Stems of Amaranthus hybridus.

Discoloration, cankers, and decay in branches, stems, and root collars of Amaranthus hybridus were observed in Bloemfontein, South Africa. Examination of symptomatic stems revealed larval galleries of the pigweed weevil (Hypolixus haerens). The objectives of this study were to: identify the most common fungal species associated with this damage, determine if the adult pigweed weevil might be a vector for the fungi, and test if the associated fungi can cause the stem canker disease observed in the field. The most common fungal species isolated were Fusarium subglutinans from discolored tissues adjacent to insect galleries (42%), F. subglutinans from weevil larvae (29%), the Alternaria tenuissima group from adult weevils (31%), and the A. tenuissima group from cankered stems (40%). Three of the seven most common fungal species produced cankers following wounding and inoculation, with F. sambucinum and F. oxysporum being the most aggressive. Although fungal species compositions differed (P < 0.01) among the four tissue/insect stage combinations tested, all four had the same major fungal species, suggesting the pigweed weevil as a vector for the Fusarium pathogens. There is significant potential for yield loss affiliated with this insect-fungal association. The identification of this insect-fungal relationship and the pathogens involved in disease set the stage for further research on the etiology and disease management of this important insect-fungal relationship.

First Report of Fusarium sambucinum, F. oxysporum, and F. subglutinans Associated with Stem Decay of Amaranthus hybridus in South Africa.

Amaranthus hybridus (common name: amaranth) is a fast-growing crop with nutritious leaves and seeds that is cultivated in semi-arid regions throughout the world. In South Africa, cultivation of this crop as a leafy vegetable is increasing. In autumn 1997, extensive tissue discoloration and decay were observed in branches, stems, and root collars of mature A. hybridus in Bloemfontein, Free State Province. Symptoms included discolored phloem, xylem, and pith, black cankers, and weakened stems prone to wind breakage. Examination of these tissues revealed larval galleries of the pigweed weevil (Hypolixus haerens), the main insect pest of A. hybridus in South Africa (1). Six-month-old A. hybridus stems were split and small samples of discolored tissue adjacent to the larval galleries of each stem and the associated larvae were placed aseptically on corn-meal agar containing streptomycin and incubated for 4 to 7 days. The seven fungi most frequently isolated from discolored stem tissues (n = 166) were Fusarium subglutinans (46%), a Phomopsis sp. (11%), Alternaria alternata (10%), F. oxysporum (9%), F. solani (5%), a Phoma sp. (5%), and F. sambucinum (4%). The nine fungi most frequently isolated from larvae (n = 90) were F. subglutinans (46%), F. solani (8%), F. equiseti (8%), F. oxysporum (7%), A. alternata (6%), a Phomopsis sp. (4%), F. proliferatum (3%), F. sambucinum (2%), and a Phoma sp. (2%). Stems of greenhouse-grown A. hybridus were inoculated with the seven most common species isolated from the discolored stem tissues. One isolate of each species was used. Inoculations involved wounding stems by removing approximately 36 mm2 of the epidermis 5 cm above the soil, placing a colonized water agar plug on the wound, and wrapping Parafilm around the stems at the wound site. Wounded and nonwounded (untreated) controls were also included. A noncolonized water agar plug was applied to wounded controls but not to nonwounded controls. Ten plants per isolate and 10 wounded and nonwounded control plants were used in each of two separate trials (180 total plants). Treatments were assigned randomly. Four weeks after inoculation, canker lengths were measured and stem sections were surface disinfected and transferred to water agar plates. The presence of the fungi was confirmed after 20 days. Only F. sambucinum, F. oxysporum, and F. subglutinans caused cankers with frequencies of 100, 100, and 65% (n = 20), and mean lesion lengths of 30, 26, and 10 mm, respectively. Lesions were never observed on either of the controls. Discoloration and cankers were similar to that observed in the field. F. sambucinum, F. oxysporum, and F. subglutinans were recovered from 65, 50, and 60% of the tissues, respectively, and none of the Fusarium spp. were recovered from the control treatments (n = 20 for all). In artificial inoculations, these species can act as pathogens independent of the pigweed weevil and are likely the cause of the discoloration, decay, and cankers observed in branches, stems, and root collars of mature A. hybridus. However, there are no prior reports of a Fusarium sp. causing disease on A. hybridus, and H. haerens larvae were observed in all symptomatic stems in the field. Further studies are needed to determine the potential for significant disease loss associated with this insect-fungal association and the potential role of these fungi in further weakening Amaranthus stems that are colonized by H. haerens. Reference: (1) S. vdM. Louw et al. Afr. Crop Sci. J. 3:93, 1995.

Venous thromboembolism: prophylactic and therapeutic practice guideline.

BACKGROUND: Pharmacological prophylactic anticoagulation in many countries, including South Africa, is under-prescribed. This has resulted in unacceptable rates of morbidity and mortality. METHOD: The Southern African Society of Thrombosis and Haemostasis held a meeting to update the previous guideline and review new literature including guidelines from other societies. The following specialties were represented on the committees: anaesthetics, cardiology, clinical haematology, critical care, obstetrics and gynaecology, haematopathology, internal medicine, neurology, orthopaedic surgery and pulmonology. A draft document was presented at the meeting, which was then revised by consensus agreement. To avoid local bias, the guideline was adjudicated by recognised international external experts. RESULTS AND CONCLUSION: A concise, practical updated guideline for thromboprophylaxis and treatment in medical and surgical patients has been produced for South African conditions. It is hoped that this guideline will continue to improve anticoagulation practice in this country, which we believe will directly benefit patient outcomes.

Venous thromboembolism--prophylactic and therapeutic practice guideline.

BACKGROUND: Pharmacological prophylactic anticoagulation in many countries, including South Africa, is under-prescribed, which unfortunately results in unacceptable morbidity and mortality in a substantial number of patients. METHOD: The Southern African Society of Thrombosis and Haemostasis reviewed the available literature as well as guidelines from other societies. Specialties represented on the committees included anaesthetics, cardiology, clinical haematology, critical care, gynaecology, haematopathology, internal medicine, neurology, orthopaedic surgery, pulmonology and vascular surgery. A draft document was produced, which was revised by consensus agreement. To avoid local bias, the guidelines were adjudicated by recognised independent international external experts. RESULTS AND CONCLUSION. A concise, practical guideline for thrombo-prophylaxis and treatment in medical and surgical patients has been produced for South African conditions. These guidelines will hopefully lead to improved anticoagulation practice in this country, which we believe will directly benefit patient outcomes.

The utility of thrombo-elastography in the monitoring of aspirin therapy.

To assess the utility of the thrombo-elastogram in monitoring of aspirin therapy 25 healthy volunteers were selected and given low-dose aspirin therapy. Thrombo-elastography and platelet aggregometry were conducted at baseline and 1 week later. After 1 week of aspirin therapy, thrombo-elastogram data failed to demonstrate a significant change in the clotting profile. Platelet aggregometry identified significant changes in the clotting profile in response to stimulation with arachidonic acid, adrenaline and ADP. We conclude that thrombo-elastography may not have utility in monitoring of response to aspirin.

Multiple sclerosis in Coloured South Africans.

Detailed case histories of seven Coloured South Africans with multiple sclerosis are presented; the summary of one South African-born Indian is included. Apart from an isolated case report in 1947, this is the first time that multiple sclerosis has been reported in detail in this South African racial group. All the Coloured patients presented for the first time during the last 12 years.

IgM rheumatoid factor removal and performance of the FTA-ABS (IgM) test in congenital syphilis.

OBJECTIVE: To determine the performance of the FTA-ABS (IgM) test in congenital syphilis after eliminating interference by IgM rheumatoid factor (RF) and preventing competitive inhibition by IgG. DESIGN: The FTA-ABS (IgM) test was carried out before and after RF removal (achieved by immunoprecipitation of the IgG) in infants with congenital syphilis and controls. SETTING: Newborns delivered in the Peninsula Maternal and Neonatal Services in Cape Town and infants presenting at Red Cross War Memorial Children's Hospital. SUBJECTS: Infants with congenital syphilis aged 0-4 months were divided into those with clinical signs at presentation and those who were asymptomatic at delivery. In addition, patients without congenital syphilis but with similar clinical signs at presentation were investigated as were control infants. OUTCOME MEASURE: The diagnosis of congenital syphilis was based on the criteria suggested by Kaufman et al (1977). RESULTS: Amongst symptomatic infants with congenital syphilis the FTA-ABS (IgM) test was positive in 34 (92%) of 37 cases prior to abolishing the RF effect and in 29 (78.4%) of 37 cases afterwards (p = 0.19). In 12 cases of congenital syphilis who were asymptomatic at birth, 10 had positive FTA-ABS (IgM) tests before RF removal and only three had positive tests afterwards (p = 0.006). False positive tests were not found amongst 15 symptomatic infants whose clinical features mimicked those of the infants with congenital syphilis. Among 51 healthy infants the test had a false-positive rate of 2% in newborns and 13% in older infants. The false positive reactions were eradicated by IgG precipitation. CONCLUSIONS: Following IgG and RF removal there was an improvement in the specificity of the FTA-ABS (IgM) test but this was at the expense of a loss of sensitivity, particularly in asymptomatic newborns. For newborns, if the FTA-ABS (IgM) test was positive, the patient was likely to require treatment for congenital syphilis, regardless of whether the result was due to the presence of RF or specific IgM.

Active haptic detection and discrimination of shape.

In previous research, we have shown that detection thresholds for Gaussian shapes increase with a power of 1.3 of spatial width. In the present three experiments, we generalized this finding to more complex shapes and to discrimination tasks. In Experiment 1, we found that the slope of the psychometric function for detection (i.e., distinguishing curved from flat surfaces) was independent of surface shape. In Experiment 3, we found the same result for discrimination of two different curved shapes. In Experiment 2, we found that detection and discrimination functions had the same dependence on spatial width, except that discrimination thresholds were two to four times larger. Possible neural mechanisms underlying these results are discussed.

Relative efficacy of nebulised ipratropium bromide and fenoterol in acute severe asthma.

In a double-blind, randomised, controlled clinical trial of 145 patients with acute asthma, the efficacy of nebulised 4-hourly ipratropium bromide plus 4-hourly fenoterol (group I, 50 patients), 2-hourly fenoterol (group II, 50 patients) and 4-hourly fenoterol (group III, 45 patients) was assessed. All patients received an optimal infusion of aminophylline and 81 patients (27 in each group) received hydrocortisone for clinical indications. It was found that cholinergic side-effects in group I were not more common than in group II. Tremor was more common in group II. Assessment of bronchodilator efficacy was confined to the 81 patients whose therapy included hydrocortisone. Peak expiratory flow rate, forced expiratory volume in 1 second, and forced vital capacity were expressed as a percentage of predicted for each individual and the mean values for each group plotted. It was found that the response rate, as assessed by the area under the curve, was significantly more rapid in group I compared with both group II (P less than 0.001) and group III (P less than 0.005). These findings were consistent for all three lung function measurements. However, there was no significant difference in the responses between group II and group III. It is concluded that adding ipratropium bromide to conventional regimens is likely to benefit patients with acute asthma.