Heparin – not only thinning the blood

In this issue of Blood, An et al¹  report that thrombotic disorders such as factor V Leiden are often treated with drugs like low molecular weight heparin (LMWH) to prevent placental failure and recurrent pregnancy loss. To date, the involvement of thrombotic mechanisms in this process is highly debated. An et al¹  have identified a new mechanism by which LMWH improves pregnancy outcome in a murine model of factor V Leiden that is unrelated to its anticoagulation capabilities.

The story of heparin has continued for nearly 100 years since its discovery by William Henry Howell and his colleague, Jay McLean, at John Hopkins Medical School (Baltimore, MD) in 1914, and it was published a few years later.²  Heparin was recognized for its anticoagulant properties, and its initial isolation from canine liver cells (hepar) proved challenging, with very low yields and toxic side effects. By 1937 these issues were overcome by Charles Best, better known for his discovery of insulin, who focused on the mass production of heparin from different tissues and on eliminating the safety concerns associated with the compound. With the work of the Swedish scientist Erik Jorpes,³  Best’s improvements in the safety, purity, and quality of isolated heparin successfully brought the compound to clinical trials in the late 1930s. Since then, heparin has been safely used to prevent blood clotting during surgery or in patients suffering from strokes and heart disease. Heparin is also administered during dialysis and in other diseases where its anticoagulation properties are not required yet have been shown to have additional beneficial effects. For example, heparin demonstrated anti-angiogenic effects in cancer patients via substrate inhibition of the cleaving enzyme heparanase.⁴ 

Although it is widely used, current knowledge of the noncoagulant actions of heparin is surprisingly very limited. Researchers may be discouraged by the contrasting results of different studies investigating the intriguing “side effects” of heparin; however, this is likely due to the varying types and dosages of heparin used within each study. The work by An et al¹  presented in this issue aids in deciphering the molecular coagulation-independent actions of this drug. Heparin, a highly sulfated proteoglycan with an antithrombin (AT) binding site, possesses a similar molecular structure to other proteoglycans found on every cell surface. As part of the extracellular matrix, proteoglycans play important roles in cell signaling pathways by acting as molecular sponges, attracting molecules due to their charge and affinity to proteins. Heparin shows comparable affinity to many of these molecules, and thus it comes as no surprise that its presence might change the physiology of a single cell or even a whole organ. The most commonly known use of heparin in cell biology is its application in stem cell cultures. Tanaka et al⁵  showed that supplementation of heparin and fibroblast growth factor in stem cell cultures is crucial to maintaining proliferation and blocking terminal differentiation.

Slowly, heparin has made its way into different research areas, including reproduction and development. Currently, heparin is used to prevent recurrent pregnancy loss, as it was shown by Girardi et al⁶  that heparin inhibits the activation of the complement cascade, a feature of antiphospholipid syndrome.⁶  While initially applied to improve blood flow to the implantation site, heparin additionally hinders recurrence of preeclampsia, a potentially life-threatening hypertensive disorder of pregnancy (reviewed in detail in Kingdom and Drewlo⁷ ). Interestingly, a Canadian study by Rey et al⁸  showed that women without thrombophilia who were treated with heparin showed an improvement in pregnancy outcome unrelated to the anticoagulant actions of the drug. These findings reintroduced interest about the coagulation-independent actions of heparin in pregnancy. The work by An et al¹  presented in this issue provides new insights into the potentially beneficial noncoagulant roles of heparin in pregnancy by using low molecular weight heparin (LMWH) in different mouse models. The study compares the effects of LMWH treatment with other anticoagulant compounds in order to demonstrate the potential benefit of the nonanticoagulant properties of LMWH in a pregnancy model of factor V Leiden placental failure, an inherited prothrombotic disorder. Using mouse strains in which different pathways and individual components related to thrombus formation are compromised, An et al¹  concluded that the prevention by heparin on pregnancy loss was not based on its antithrombin activity. Furthermore, An et al¹  showed elegantly that thrombin-mediated maternal platelet activation is central in the mechanism of placental failure. Although these data are very intriguing, ideally, glycol-split heparin (chemically modified heparin without the AT site) should be included in future studies to show whether the beneficial pregnancy-related effects of heparin are solely based on the heparan sulfate proteoglycan backbone and are independent of the AT site. Chemical alterations to the backbone size might provide additional information about the molecular actions of heparin.

As outlined, heparins are widely used in pregnancy; yet, beyond the classic effects on coagulation, there is still a vast lack of knowledge on how heparin contributes to improved pregnancy outcomes. Work by An et al¹  demonstrates new concepts supporting the clinical importance of this drug and its noncoagulation-dependent aspects, opening the way to a renaissance of heparin and its use in clinical practice.