Proposed “COVID-19 Thrombinopathy” cascade and the role of heparins (Preprint)

2021 ◽  
Author(s):  
Nadarajah Varatharajah
Keyword(s):  
Molecular Weight ◽  
Thrombin Generation ◽  
Anticoagulation Therapy ◽  
Medical Community ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins ◽  
Clinical Challenge ◽  
Anti Platelet Agent ◽  
Life Threatening

UNSTRUCTURED Management of life threatening coagulopathy in COVID-19 still remains a clinical challenge. There is still uncertainty regarding the choice and the dose of anticoagulation in Covid-19 coagulopathy especially in critically ill patients. In this article, a new term “COVID-19 thrombinopathy” and a proposed cascade are introduced in order to highlight the non-traditional pathways of thrombin generation which are likely active in COVID-19 (or sepsis), so that the medical community can focus on targeting “thrombin” and “non-traditional thrombin generation” rather than considering general “anticoagulation” based on traditional coagulation pathways. The medical community generalizes unfractionated heparin (UFH) and low molecular weight heparins (LMWH) as “heparins” and also interchanging those in clinical practice. UFH and LMWHs are “heparins” but the targets, therapeutic actions and side effects differ. In addition, during anticoagulation therapy, UFH dosing is based on blood level (therapeutic effect) but LMWH is weight based irrespective of the requirement/underlying clinical condition. Compared to UFH, interestingly and importantly, LMWH has shown to stabilize the clot and make the clot more resistant to breakdown. Preventing platelet activation and its role in traditional and non-traditional thrombogenesis is also essential since it appears to play a major role in COVID-19 thrombinopathy. Further clinical trials are needed to evaluate the benefits of UFH in “COVID-19 thrombinopathy” preferably along with a globally available ADP/P2Y12 blocking anti-platelet agent like Clopidogrel.

Role of low-molecular-weight heparins in the treatment of sudden hearing loss

2003 ◽  
Vol 24 (5) ◽  
pp. 328-333 ◽  
Author(s):  
Wen L. Yue ◽  
Pei Li ◽  
Pei Y. Qi ◽  
Hui J. Li ◽  
Hong Zhou
Keyword(s):  
Molecular Weight ◽  
Hearing Loss ◽  
Sudden Hearing Loss ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins

Defibrotide Augments the Anticoagulant Actions of Heparin and Low Molecular Weight Heparins

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4086-4086
Author(s):  
Jawed Fareed ◽  
Omer Iqbal ◽  
Debra Hoppensteadt ◽  
Cafer Adiguzel ◽  
Massimo Iacobelli ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Whole Blood ◽  
Thrombin Generation ◽  
Synergistic Effects ◽  
Low Molecular Weight ◽  
Inhibitory Effects ◽  
Clotting Time ◽  
Low Molecular Weight Heparins ◽  
Significant Prolongation ◽  
Antithrombotic Effects

Abstract Defibrotide represents a polydeoxyribonucleotide derived antithrombotic and antiischemic drug, which has been used in the management of vascular disorders and is currently being developed in other clinical indications. Defibrotide is a polyelectrolyte-based agent with target effects on endothelium, platelets, and blood cells. In addition, the aptameric consensus sequences in the nucleotides exhibit inhibitory effects towards thrombin and related proteases. In the anticoagulant assays defibrotide exhibits relatively weak effects (<5 USP U/mg). These studies were undertaken to study whether there is an interaction between defibrotide and unfractionated heparin (UFH) in various systems of anticoagulation. The interaction of defibrotide with commercially available low molecular weight heparins (LMWHs), enoxaparin and dalteparin, was also studied. For the first investigation, to evaluate the effect of defibrotide on the anticoagulant effects of UFH, native whole blood freshly drawn from human volunteers (n = 20) was supplemented with UFH at a fixed concentration of 5 μg/mL (0.8 U/mL), and graded amounts of defibrotide were added in a concentration range of 12.5 – 100 μg/mL. The whole blood celite Activated Clotting Time test (ACT) and the thrombin generation markers fibrinopeptide A (FPA), thrombin-antithrombin complex (TAT), and prothrombin fragment 1.2 (F1.2) were measured. Parallel controls with saline were included. While defibrotide did not produce a significant prolongation of the ACT compared to saline (128 ± 9 s vs 132 ± 7 s), it produced a concentration-dependent increase in the heparinized whole blood leading to an almost doubling of the anticoagulant action of UFH (248 ± 19 s vs 418 ± 21 s). Additional studies carried out by varying the concentrations of the two agents also revealed supraadditive to synergistic effects. Defibrotide also augmented the inhibitory effects of UFH on thrombin generation markers in a concentration-dependent fashion. Similar studies carried out with the two LMWHs did not reveal a similar interaction in the anticoagulant assays such as the ACT; however, significant interactions between defibrotide and the LMWHs were observed in the thrombin generation studies. For the second investigation, studies were carried out using plasma samples collected from heparinized patients (aPTT of 50 – 100 s). These studies also revealed that supplementation of defibrotide augmented the anticoagulant effects of UFH in a concentration-dependent fashion. While defibrotide at 12.5 μg/mL did not significantly increase the aPTT of normal plasma, when supplemented to heparinized plasmas (n = 50 with aPTT of 64.6 ± 14.0 s) it produced a strong prolongation of the clotting time (96.1 ± 20.6 s). In the third investigation, animal models of thrombosis including the rat jugular vein clamping model, demonstrated an augmentation of the antithrombotic effects of intravenously administered UFH by defibrotide. However, no augmentation of the hemorrhagic effect was observed in the rat tail bleeding model. These studies demonstrate that defibrotide exhibits a strong anticoagulant interaction with UFH and to a lesser degree LMWH. While the combination of defibrotide and UFH exhibits enhanced anticoagulant/antithrombotic activities, it does not exhibit any alteration of the hemorrhagic profile. These studies clearly suggest that defibrotide can be combined with UFH to achieve a superior anticoagulant approach with better safety/efficacy profile.

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