A Longitudinal Study of Thrombosis and Bleeding Outcomes With Thromboprophylaxis in Pregnant Women at Intermediate and High Risk of VTE.

BACKGROUND: The efficacy and safety of thromboprophylaxis in pregnancy at intermediate to high risk of venous thrombo-embolism (VTE) is an area of ongoing research. AIM: This study aimed to assess thrombosis and bleeding outcomes associated with thromboprophylaxis in women at risk of VTE. METHODS: A cohort of 129 pregnancies, who received thromboprophylaxis for the prevention of VTE, were identified from a specialist obstetric clinic in Johannesburg, South Africa. Intermediate-risk pregnancies, with medical comorbidities or multiple low risks, were managed with fixed low-dose enoxaparin antepartum and for a median (interquartile range) of 4 (4) weeks postpartum. High-risk pregnancies, with a history of previous VTE, were managed with anti-Xa adjusted enoxaparin antepartum and for a median of 6 (0) weeks postpartum. Pregnancy-related VTE was objectively confirmed. Major bleeding, clinically relevant nonmajor bleeding (CRNMB) and minor bleeding were defined according to the International Society on Thrombosis and Hemostasis Scientific Subcommittee. RESULTS: Venous thrombo-embolism occurred antepartum in 1.4% (95% CI: 0.04-7.7) of intermediate and 3.4% (95% CI: 0.4-11.7) of high-risk pregnancies. Bleeding events occurred in 7.1% (95% CI: 2.4-15.9) of intermediate and 8.5% (95% CI: 2.8-18.7) of high-risk pregnancies. Of these bleeding events, 3.1% (95% CI: 1.0-8.0) were classified as major bleeding. On univariate analysis, no independent predictors of bleeding were identified. CONCLUSION: The rates of thrombosis and bleeding in this predominantly African population were consistent with similar studies and can be used to inform pregnant women of the benefits of anticoagulation and the risks of potential bleeding.

Baseline characteristics of 32 patients with Gaucher disease who were treated with imiglucerase: South African data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry.

BACKGROUND: Gaucher disease (GD) is a rare inherited autosomal recessive metabolic disorder with a prevalence in the general population of ~1 per 100 000. To optimise the recognition, diagnosis and management of patients with GD in South Africa (SA), it is important to have an understanding of local patterns of presentation of the disease. OBJECTIVES: To describe the baseline pretreatment characteristics of the SA cohort of patients enrolled into the International Collaborative Gaucher Group (ICGG) Gaucher Registry whowere treated with imiglucerase (Cerezyme; Sanofi Genzyme). METHODS: The ICGG Gaucher Registry is an observational, longitudinal, international database that tracks the clinical, demographic, genetic, biochemical and therapeutic characteristics of patients with GD globally, irrespective of disease severity, treatment status or treatment choice. The study population included all SA patients reported in the ICGG Gaucher Registry as of 1 May 2020. RESULTS: The registry included 49 SA GD patients, of whom 32 received imiglucerase as first primary GD therapy. All the patients had GD type 1, 59.4% were female, and mean and median ages at diagnosis were 14.7 and 9.8 years, respectively. The most common genotype was N370S/N370S (37.5%). At treatment initiation, 30.0% of patients had been splenectomised. Among patients for whom data were available, anaemia was present in one-third of non-splenectomised patients and 12.5% of those with splenectomy, and moderate or severe thrombocytopenia was reported in two-thirds of non-splenectomised patients. Bone pain was present in 30.8% and 57.1% of non- splenectomised and splenectomised patients, respectively. No bone crises were reported, and data relating to other bone complications were available for only ≤3 patients. CONCLUSIONS: Haematological findings and bone pain in this group are similar to those in the global ICGG Gaucher Registry cohort. Lack of baseline data for other bone complications limits interpretation in that regard. Clinicians who treat patients with GD are encouraged to submit accurate, complete and up-to-date information so that comprehensive data for the subset of SA GD patients can be maintained to improve recognition and diagnosis, and guide appropriate and effective use of treatment for SA patients.

Heparin-induced thrombocytopenia: An update for the COVID-19 era.

The increased use of heparin during the current COVID-19 pandemic has highlighted the risk of a rare but potentially serious complication of heparin therapy, viz. heparin-induced thrombocytopenia (HIT). This is a short review on the pharmacology of heparin and its derivatives, and the pathophysiology of HIT. Guidance on laboratory testing for and clinical management of HIT is presented in accordance with international guidelines. There are important similarities and differences between HIT and the new entity of vaccine-induced immune thrombotic thrombocytopenia, also known as thrombosis with thrombocytopenia syndrome, which clinicians need to be aware of.

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.

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.

The benefit of pharmacological venous thromboprophylaxis in foot and ankle surgery.

BACKGROUND: Ten percent of patients with a deep-vein thrombosis (DVT) will develop a fatal pulmonary embolism (PE), often initially asymptomatic. The risks and benefits of pharmacological thromboprophylaxis are well documented in respect of total joint arthroplasty and hip fractures, but little is understood about the incidence of venous thromboembolism (VTE) or the potential risks and benefits of chemoprophylaxis in foot and ankle surgery. OBJECTIVE: To determine whether prophylactic chemoprophylaxis had any impact on the prevention of VTE in a cohort of foot and ankle surgical patients requiring the combination of below-knee cast immobilisation and non-weightbearing for ≥4 weeks. METHODS: Between March 2014 and April 2015, a prospective cohort study of 142 patients was performed. All completed a thrombosis risk assessment form prior to surgery and were commenced on rivaroxaban (Xarelto) 10 mg/d postoperatively. The primary outcome measure was clinical VTE confirmed by compression ultrasonography (DVT) or a ventilation/perfusion scan (PE). RESULTS: Three patients (2.1%) developed a clinical DVT. Two did so well beyond the immobilisation and anticoagulation period, and one was non-compliant with therapy. The average risk factor score in this subgroup was 7. No patient had a DVT while on the prescribed regimen of anticoagulant therapy. Five patients (3.5%) developed wound breakdown, two requiring surgical debridement with local skin flap closure. One case of menorrhagia that may have been linked to the anticoagulant therapy was reported. When compared with a previous study, pharmacological thromboprophylaxis significantly reduced VTE risk (p=0.02). CONCLUSIONS: Oral pharmacological thromboprophylaxis significantly reduces the risk of VTE in patients requiring cast immobilisation and non-weightbearing following foot and ankle surgery. The risk/benefit ratio favours this treatment as opposed to the treatment of major morbidity following non-fatal VTE.

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.

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.

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.

Aspirin resistance in South African Caucasian patients with thrombotic cerebrovascular events.

OBJECTIVE: Stroke is the second commonest cause of death in both high and low- and middle-income countries [Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. The Lancet 2006; 367:1747-57]. In South Africa, a population undergoing demographic and epidemiological transition, stroke is the third commonest cause of death [Norman R, Bradshaw D, Schneider M, Pieterse D, Groenewald P. Revised burden of disease estimates for the comparative risk factor assessment, South Africa, 2000. Cape Town: Medical Research Council. 2006]. Although aspirin remains an essential part of stroke prevention, platelet response to therapeutic doses is not uniform. Some patients exhibit aspirin resistance and develop secondary thrombotic events. We decided to determine the prevalence of aspirin resistance and/or platelet hypersensitivity, as determined by platelet aggregometry, in sixty Caucasian patients who have suffered one or more Strokes and/or Transient Ischaemic Attacks (TIAs) as compared with sixty control subjects. METHODS: Aspirin resistance was determined by platelet aggregation (>20%) to one or more of the four agonists, namely arachidonic acid (1.5 mM), adrenaline (0.05 microg/ml), collagen (0.2 microg/ml) or ADP (0.1x10(-5) M). RESULTS: Two patients demonstrated "complete aspirin resistance" (non-responder to aspirin) with resistance to arachidonic acid (high concentration) noted. Three patients demonstrated "partial aspirin resistance" (semi-responder to aspirin). One contol subject showed "complete aspirin resistance". There is a 1.67% chance of a control subject being resistant to aspirin in a general South African Caucasian population. A history of prior stroke or transient ischaemic attack was associated with a statistically significant increase in risk of aspirin resistance with an odds ratio of 5.36. CONCLUSION: These results essentially concur with those of the studied literature in showing an 8% prevalence (statistically significant) of aspirin resistance (complete and partial) in South African Caucasian patients with previous atherothrombotic cerebrovascular events i.e. CVAs and/or TIAs. The current study shows an increased prevalence of aspirin resistance in people who have had prior strokes/TIAs and raises the question whether people who have had these events are somehow predisposed to vascular events or indeed recurrent vascular events. "Aspirin resistant" patients or "poor responders" to aspirin must be considered at heightened risk of atherothrombotic events and laboratory monitoring of antiplatelet therapy may become clinically useful.

Thrombo-embolic and bleeding complications in patients with mechanical valve replacements--a prospective observational study.

BACKGROUND AND OBJECTIVES: Long-term anticoagulation therapy is essential to prevent thrombo-embolic events in patients with mechanical valve replacements. In order to offer indigent patients mechanical heart valve replacement surgery, dedicated anticoagulation clinics are necessary for follow-up. This study assessed the safety and efficacy of lifelong oral anticoagulation therapy in Johannesburg General Hospital mechanical heart valve replacement recipients. The incidence of bleeding and thrombo-embolic complications was documented in three groups of patients with mechanical valve replacements. The groups included patients with aortic valve replacements (AVRs), mitral valve replacements (MVRs) and double (aortic and mitral) valve replacements (DVRs). MATERIALS AND METHODS: A prospective observational study was conducted over a 4-month period. Data on 306 patients attending the Johannesburg General Hospital anticoagulation clinic between 2000 and 2005 were analysed. Of the total patients selected, 205 were assigned to the mechanical valve replacement group (which included 63 patients with AVRs, 93 with MVRs and 49 with DVRs); a control group of 101 nonmechanical valve replacement patients were also included. At each visit the level of anticoagulation was assessed from the international normalised ratio (INR) values, and the presence of bleeding and/or thrombo-embolic complications was documented. RESULTS: There were a total of 51 bleeding and thrombo-embolic complications in the study population. Patients with DVRs had a higher proportion of combined complications (30.61%) than patients with single valve replacements (14.29% in the AVR group and 18.05% in the MVR group) and patients in the control group (12.87%). There were 38 bleeding complications, 30 minor and 8 major. Twelve thrombo-embolic events were documented. Individually, there was no significant difference in thrombo-embolic and bleeding complications between the subgroups. Eighty-two per cent of patients in the mechanical valve replacement group were within the therapeutic range for anticoagulant control (INR 2.5-3.5) v. 54% in the control group (INR 2.0-3.0). Anticoagulant control was of a high quality and was not a contributing factor to the incidence of bleeding and/ or thrombo-embolic complications. CONCLUSION: The finding of a low incidence of bleeding and thrombo-embolic complications in patients with mechanical valve replacements supports the continued placement of mechanical valves in our setting and use of oral anticoagulation therapy at an INR of 2.5-3.5. However the increased risk of both bleeding and thrombo-embolic complications in the DVR group is cause for great concern and warrants further investigation.

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.

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 degrees C. These bags were then defrosted in a waterbath at 22 degrees C, 37 degrees C, 45 degrees C and 60 degrees 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 degrees 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 degrees C (%sim = 97-99%) while there was a significant decrease in fibrinogen levels at 60 degrees C compared with 37 degrees C (p<0.001, %sim = 75%). INR and PTT values were highest in the bags thawed at 60 degrees C (%sim = 114% and 110%, respectively) with the difference between the INR levels at 60 degrees C compared with 37 degrees 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 degrees C compared with 37 degrees C. D-dimers are elevated in thawed FFP. Fibrinogen levels are markedly decreased in FFP thawed at 60 degrees C compared with that thawed at 37 degrees C. FFP should be thawed at 37 degrees C in a strictly controlled environment.

Fluoxetine and hemostatic function: a pilot study.

BACKGROUND: Isolated case reports have appeared implicating fluoxetine as a cause of impaired hemostatic function. The authors attempted to investigate this phenomenon. METHOD: The hemostatic function of 10 patients with DSM-III-R major depression was investigated before and after a trial of treatment with fluoxetine. The tests included international normalized ratio, partial thromboplastin time, factors II, V, VII, VIII:C, IX, X, XI, XII, fibrinogen, thrombin time, bleeding time, euglobulin lysis time, protein kinase C, antithrombin, platelet counts, D dimer, lupus inhibitor, and platelet sensitivity studies to the following agonists: adenosine diphosphate, epinephrine, collagen, and arachidonic acid. Hemostatic data on a patient with a drug-related bleeding episode are not available. RESULTS: No significant difference was found in any of the parameters tested. CONCLUSION: This study failed to demonstrate any compromised hemostatic function associated with fluoxetine therapy. However, the possibility of a type II statistical error exists. It is possible that bleeding events may occur as an idiosyncratic reaction to fluoxetine treatment.