A proposal for staging COVID-19 coagulopathy.

Coronavirus disease 2019 (COVID-19) is associated with significant hypercoagulability. However, despite prophylactic anticoagulation, critically ill patients with this condition develop thromboses. This forum discusses the lungs as the epicenter for the hemostatic issues, puts forward a proposal for staging COVID-19 coagulopathy based on available diagnostic markers, and suggest considering current and future treatment options based on these different stages.

Heparin – Messias or Verschlimmbesserung?

A heightened risk of thrombosis noted early on with the severe acute respiratory syndrome coronavirus 2 infection led to the widespread use of heparin anticoagulation in the coronavirus disease 2019 (COVID‐19) pandemic. However, reports soon started appearing in the literature where an apparent failure of heparin to prevent thrombotic events was observed in hospitalized patients with this viral infection. In this review, we explore the likely mechanisms for heparin failure with particular relevance to COVID‐19. We also explore the role of anti‐Xa assays and global hemostatic tests in this context. The current controversy of dosing heparin in this disease is detailed with some possible mechanistic reasons for anticoagulant failure. We hope that lessons learnt from the use of heparin in COVID‐19 could assist us in the appropriate use of this anticoagulant in the future.

ISTH guidelines for antithrombotic treatment in COVID-19.

Antithrombotic agents reduce risk of thromboembolism in severely ill patients. Patients with coronavirus disease 2019 (COVID-19) may realize additional benefits from heparins. Optimal dosing and timing of these treatments and benefits of other antithrombotic agents remain unclear. In October 2021, ISTH assembled an international panel of content experts, patient representatives, and a methodologist to develop recommendations on anticoagulants and antiplatelet agents for patients with COVID-19 in different clinical settings. We used the American College of Cardiology Foundation/American Heart Association methodology to assess level of evidence (LOE) and class of recommendation (COR). Only recommendations with LOE A or B were included. Panelists agreed on 12 recommendations: three for non-hospitalized, five for non-critically ill hospitalized, three for critically ill hospitalized, and one for post-discharge patients. Two recommendations were based on high-quality evidence, the remainder on moderate-quality evidence. Among non-critically ill patients hospitalized for COVID-19, the panel gave a strong recommendation (a) for use of prophylactic dose of low molecular weight heparin or unfractionated heparin (LMWH/UFH) (COR 1); (b) for select patients in this group, use of therapeutic dose LMWH/UFH in preference to prophylactic dose (COR 1); but (c) against the addition of an antiplatelet agent (COR 3). Weak recommendations favored (a) sulodexide in non-hospitalized patients, (b) adding an antiplatelet agent to prophylactic LMWH/UFH in select critically ill, and (c) prophylactic rivaroxaban for select patients after discharge (all COR 2b). Recommendations in this guideline are based on high-/moderate-quality evidence available through March 2022. Focused updates will incorporate future evidence supporting changes to these recommendations.

Disseminated Intravascular Coagulation: The Past, Present, and Future Considerations.

Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no "one-size-fits-all criteria." Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.

The problem with coagulopathy .

Coagulopathy is inextricably linked to the field of hemostasis and thrombosis. In the same manner hemostasis and thrombosis may deal with bleeding and clot formation, coagulopathy also may be connected to bleeding or thrombosis, depending on the circumstances. However, when the same designation, "coagulopathy," may represent two clinically distinct presentations, it can create confusion. It is our obligation as hemostasis and thrombosis specialists to scotch this dubiety and direct the correct usage of coagulopathy.

Rotational thromboelastometry in critically ill COVID-19 patients does not predict thrombosis.

Background: Critically ill COVID-19 patients are in a hypercoagulable state with increased risk of thrombotic complications. Rotational thromboelastometry (ROTEM) is a viscoelastic test with the potential to reflect COVID-19-associated hypercoagulability and may therefore be useful to predict thrombotic complications. Objective: To investigate the potential of ROTEM profiles to predict thrombotic complications in critically ill COVID-19 patients. Patients/Methods: Retrospective multicenter cohort study in 113 adult patients with confirmed COVID-19 infection admitted to the intensive care unit (ICU) of two large teaching hospitals in the United States and in the Netherlands. ROTEM profiles of the EXTEM, INTEM, and FIBTEM tracings were measured within 72 h of ICU admission. Thrombotic complications encompass both arterial and venous thromboembolic complications, diagnosed with electrocardiogram, ultrasound, or computed tomography. ROTEM profiles were compared between patients with and without thrombosis. Univariable logistic regression followed by receiver operating characteristic (ROC) curves analysis was performed to identify ROTEM parameters associated with thrombosis. Results and Conclusions: Of 113 patients, 27 (23.9%) developed a thrombotic event. In the univariable analysis, EXTEM clot amplitude at 10 min (CA10) and EXTEM maximum clot formation (MCF) were associated with thrombosis with a p < 0.2 (p = 0.07 and p = 0.05, respectively). In ROC curve analysis, EXTEM CA10 had an area under the curve (AUC) of 0.58 (95% CI 0.47-0.70) and EXTEM MCF had an AUC of 0.60 (95% CI 0.49-0.71). Thereby, ROTEM profiles at ICU admission did not have the potential to differentiate between patients with a high and low risk for thrombotic complications.

D-dimers-"Normal" Levels versus Elevated Levels Due to a Range of Conditions, Including "D-dimeritis," Inflammation, Thromboembolism, Disseminated Intravascular Coagulation, and COVID-19.

D-dimers reflect a breakdown product of fibrin. The current narrative review outlines how D-dimers can arise in normal individuals, as well as in patients suffering from a wide range of disease states. D-dimers in normal individuals without evident thrombosis can arise from background fibrinolytic activity in various tissues, including kidney, mammary and salivary glands, which ensures smooth flow of arising fluids where any blood contamination could be immediately lysed. In addition, healthy individuals can also regularly sustain minor injuries, often unbeknown to them, and wound healing follows clot formation in these situations. D-dimers can also arise in anxiety and following exercise, and are also markers of inflammation. Lung inflammation (triggered by microbes or foreign particles) is perhaps also particularly relevant, since the hemostasis system and fibrinolysis help to trap and remove such debris. Lung inflammation in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may contribute to D-dimer levels additive to thrombosis in patients with COVID-19 (coronavirus disease 2019). Indeed, severe COVID-19 can lead to multiple activation events, including inflammation, primary and secondary hemostasis, and fibrinolysis, all of which may contribute to cumulative D-dimer development. Finally, D-dimer testing has also found a role in the diagnosis and triaging of the so-called (COVID-19) vaccine-induced thrombotic thrombocytopenia.

SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP.

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.

D-dimers: a most misunderstood test.

The role of D-dimers in the management of venous thromboembolism is well established and testing for D-dimers has become common in most acute settings. Although it has been validated for the purpose of excluding venous thromboembolism, the test is increasingly ordered to 'diagnose' venous thromboembolism. Furthermore, in the COVID-19 pandemic, heavy reliance has been put on this test with the inclusion of D-dimers to guide treatment pathways. This review summarises the appropriateness of D-dimer tests in these different clinical settings.

Thromboprophylaxis in COVID-19 - Rationale and considerations.

The Corona Virus Disease-2019 (COVID-19) pandemic is associated with a very high incidence of thrombotic complications. The exact mechanisms for this excess risk for clots have not been elucidated although one of the often-quoted pathophysiological entity is immunothrombosis. Recognition of thrombotic complications early on in this pandemic led to an over-explosion of studies which looked at the benefits of anticoagulation to mitigate this risk. In this review, we examine the rationale for thromboprophylaxis in COVID-19 with particular reference to dosing and discuss what may guide the decision-making process to consider anticoagulation. In addition, we explore the rationale for thrombosis prevention measures in special populations including outpatient setting, pregnant females, children, those with high body mass index and those on extracorporeal membrane oxygenation.

Heparin - Messias or Verschlimmbesserung?

A heightened risk of thrombosis noted early on with the severe acute respiratory syndrome coronavirus 2 infection led to the widespread use of heparin anticoagulation in the coronavirus disease 2019 (COVID-19) pandemic. However, reports soon started appearing in the literature where an apparent failure of heparin to prevent thrombotic events was observed in hospitalized patients with this viral infection. In this review, we explore the likely mechanisms for heparin failure with particular relevance to COVID-19. We also explore the role of anti-Xa assays and global hemostatic tests in this context. The current controversy of dosing heparin in this disease is detailed with some possible mechanistic reasons for anticoagulant failure. We hope that lessons learnt from the use of heparin in COVID-19 could assist us in the appropriate use of this anticoagulant in the future.

Chronic anticoagulation is not associated with a reduced risk of acute kidney injury in hospitalised Covid-19 patients.

BACKGROUND: Coronavirus-19 (COVID-19) has been declared a global pandemic by the World Health Organisation. Severe disease typically presents with respiratory failure but Acute Kidney Injury (AKI) and a hypercoagulable state can also occur. Early reports suggest that thrombosis may be linked with AKI. We studied the development of AKI and outcomes of patients with COVID-19 taking chronic anticoagulation therapy. METHODS: Electronic records were reviewed for all adult patients admitted to Manchester University Foundation Trust Hospitals between March 10 and April 302,020 with a diagnosis of COVID-19. Patients with end-stage kidney disease were excluded. AKI was classified as per KDIGO criteria. RESULTS: Of the 1032 patients with COVID-19 studied,164 (15.9%) were taking anticoagulant therapy prior to admission. There were similar rates of AKI between those on anticoagulants and those not anticoagulated (23.8% versus 19.7%) with no difference in the severity of AKI or requirement of renal replacement therapy between groups (1.2% versus 3.5%). Risk factors for AKI included hypertension, pre-existing renal disease and male sex. There was a higher mortality in those taking anticoagulant therapy (40.2% versus 30%). Patients taking anticoagulants were less likely to be admitted to the Intensive Care Unit (8.5% versus 17.4%) and to receive mechanical ventilation (42.9% versus 78.1%). CONCLUSION: Patients on chronic anticoagulant therapy did not have a reduced incidence or severity of AKI suggesting that AKI is unlikely to be thrombotic in nature. Therapeutic anticoagulation is currently still under investigation in randomised controlled studies to determine whether it has a potential role in COVID-19 treatment.

Lessons learnt from COVID-19 coagulopathy.

The coronavirus disease 2019 (COVID-19) pandemic has already left an indelible mark in human lives. Despite the havoc it created, this pandemic also saw significant advances in the management of an infectious disease wherein worldwide collaborative efforts from health care professionals have been unprecedented. One of the commonest complications recognised early in the pandemic is the development of coagulopathy. In this review, the lessons learnt from COVID-19 coagulopathy are summarised with some perspectives on future clinical and research strategies. These include how local versus systemic coagulopathy can matter, how we can put D-dimers to effective use, exhort more input into identifying a simple platelet activation marker, rethink the role of fibrinogen, look differently at lupus anticoagulant and heparin-induced thrombocytopenia, bring back disseminated intravascular coagulation into our differential diagnosis slate and most importantly channel more funding into haemostasis and thrombosis research.

COVID-19 (SARS-CoV-2) in Non-Airborne body fluids: A systematic review & Meta-analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been predominantly respiratory. This study aimed to evaluate the presence of virus in non-airborne body fluids as transmission vehicles. Medline, EMBASE, and Cochrane Library databases were searched from December 01, 2019, to July 01, 2020, using terms relating to SARS-CoV-2 and non-airborne clinical sample sources (feces, urine, blood, serum, serum, and peritoneum). Studies in humans, of any design, were included. Risk of bias assessment was performed using the Quality Assessment of Diagnostic Accuracy 2 tool. Preferred Reporting Items for Systematic Reviews & Meta-Analyses) guidelines were used for abstracting data. If ≥5 studies reported proportions for the same non-respiratory site, a meta-analysis was conducted using either a fixed or random-effects model, depending on the presence of heterogeneity. A total of 22 studies with 648 patients were included. Most were cross-sectional and cohort studies. The SARS-CoV-2 RNA was most frequently detected in feces. Detectable RNA was reported in 17% of the blood samples, 8% of the serum, 16% in the semen, but rarely in urine. Prevalence of SARS-CoV-2 in non-airborne sites varies widely with a third of non-airborne fluids. Patients with bowel and non-specific symptoms have persistence of virus in feces for upto 2 weeks after symptom resolution. Although there was a very low detection rate in urine, given the more frequent prevalence in blood samples, the presence of SARS-CoV-2 in patients with disrupted urothelium or undergoing urinary tract procedures, is likely to be higher. Healthcare providers need to consider non-airborne transmission and persistence of SARS-CoV-2 in body fluids to enable appropriate precautions to protect healthcare workers and carers.