The Anticoagulant and Nonanticoagulant Properties of Heparin

Abstract

Heparins represent one of the most frequently used pharmacotherapeutics. Discovered around 1926, routine clinical anticoagulant use of heparin was initiated only after the publication of several seminal papers in the early 1970s by the group of Kakkar. It was shown that heparin prevents venous thromboembolism and mortality from pulmonary embolism in patients after surgery. With the subsequent development of low-molecular-weight heparins and synthetic heparin derivatives, a family of related drugs was created that continues to prove its clinical value in thromboprophylaxis and in prevention of clotting in extracorporeal devices. Fundamental and applied research has revealed a complex pharmacodynamic profile of heparins that goes beyond its anticoagulant use. Recognition of the complex multifaceted beneficial effects of heparin underscores its therapeutic potential in various clinical situations. In this review we focus on the anticoagulant and nonanticoagulant activities of heparin and, where possible, discuss the underlying molecular mechanisms that explain the diversity of heparin's biological actions.

Circulating Histones in Sepsis: Potential Outcome Predictors and Therapeutic Targets

“…Beyond anticoagulation, heparin inhibits the function of several adhesion molecules, the synthesis of inflammatory cytokines including TNF-α, IFN-γ, IL-6, and IL-8 via inhibition of NF-κB signaling, and the cleavage of complement proteins ( 96 ). Usually, the mechanisms by which heparin is able to express its anti-inflammatory properties can be divided into two models of action: 1) binding to soluble plasma ligands such as complement proteins, pro-inflammatory chemokines and cytokines, which significantly interferes the classical and alternative complement pathways as well as terminal cell lysis and dissociates cytokines and other proteins from their stationary binding; 2) binding to cell-surface-bound receptors or macromolecules including P-selectin, L-selectin, and intercellular adhesion molecule-1, which inhibits interactions between endothelial cells and blood cells (e.g., leukocytes, platelets) ( 97 ). Of note, these functions are mostly affected by structural parameters, such as chain length, degree of sulfation, carbohydrate backbone and sulfation pattern ( 95 ).…”

Similarities and perspectives on the two C’s—Cancer and COVID‐19

“…It may also be said that these two pathophysiological processes are not mitigated by intensified anticoagulation either despite heparins possibly exhibiting anti-inflammatory properties and at least theoretically anti-cancer properties. 53,54 Thus, in severe cases of the two C's-COVID-19 patients who require critical care support and the patients with aggressive or metastatic cancer disease, higher doses of heparin may not be the answer while combination therapies may be, subject to randomized trials. These adjuvant therapies could include anti-inflammatory agents; antineoplastic drugs; anti-complement drugs; and in cases of low bleeding risk, antiplatelet agents (see Figure 2).…”

“…If the principal trigger for thrombosis in COVID‐19 is the uncontrolled inflammation driving immuno‐thrombosis and in malignancies, the cancer procoagulant particles, they are unlikely to be “cleared” by the anticoagulant drugs. It may also be said that these two pathophysiological processes are not mitigated by intensified anticoagulation either despite heparins possibly exhibiting anti‐inflammatory properties and at least theoretically anti‐cancer properties 53,54 . Thus, in severe cases of the two C’s—COVID‐19 patients who require critical care support and the patients with aggressive or metastatic cancer disease, higher doses of heparin may not be the answer while combination therapies may be, subject to randomized trials.…”

The Multiple Faces of Heparin: Opportunities in COVID-19 Infection and Beyond

“…In this issue, Beurskens et al from the cardiovascular institute in Maastricht published a review on the pleiotropic anticoagulant and nonanticoagulant effects of heparin. 3 They describe in detail the structure of heparin as a glycosaminoglycan. The chemical structure of heparin is commonly known by its anticoagulant activity toward factor Xa and thrombin, which is mostly related to its high affinity binding to antithrombin (AT).…”

“…Beurskens et al 3 have precisely described the many antithrombotic and anticoagulant actions of heparin. Antithrombotic actions include release of tissue factor pathway inhibitor, modulation of fibrinolytic activity, binding of chemokines and cytokines, and activation of growth factors.…”