Hitting HIT: Heparin therapy

December 20, 2019

Heparin is widely used as an anticoagulant, but evokes in some patients a potentially life-threatening condition called HIT. Clinical scientists at Ludwig-Maximilians-Universitaet (LMU) in Munich have now shown that inhibition of a single enzyme may markedly reduce this risk.

Heparin is frequently employed to mitigate the risk of clot formation in the leg veins following surgery, to treat venous thromboses and to prevent thrombotic occlusions of arteries in patients at risk for heart attacks. However, the agent can also lead to a reduction in the numbers of thrombocytes (otherwise known as platelets) in the bloodstream - an effect known as heparin-induced thrombocytopenia (HIT). Up to 3% of patients who are treated with heparin develop an immunologically triggered subtype of HIT (called type II HIT), which is surprisingly associated with an increase in the incidence of thromboses (clots) in the blood vessels that are potentially life-threatening. The incorporation of platelets into the blood clots explains the occurrence of thrombocytopenia. A new study directed by Wolfgang Siess, Professor of Cardiovascular Pathobiochemistry at LMU's Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases (IPEK), has now demonstrated that this hazardous side-effect can be effectively prevented in vitro by the inhibition of a specific enzyme. The discovery provides a new option for the treatment of type II HIT. The study was carried out in collaboration with research groups led by Professor Michael Spannagl (Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, LMU Medical Center),

Professor Christian Weber and Dr. Philipp von Hundelshausen (both IPEK). The new findings appear in the journal Blood Advances.

Heparin is a large, negatively charged linear polysaccharide made up of a variety of repeat units. Type II HIT is caused by the formation of antibodies that are directed against a specific molecular complex made up of heparin and a protein called PF4, which is secreted by platelets. The so-called Fc domain of the antibodies binds to the corresponding Fc receptor found on the platelet surface, which results in activation of the cells. The activated platelets form aggregates and secrete proteins which mediate the binding of platelets (thrombocytes) to the inner surface of the blood vessels (endothelium) and to certain types of white blood cells (monocytes and neutrophils). This leads to the formation of thrombin and fibrin, and together with platelet activation triggers clot formation. - Hence heparin actually provokes the effect that it is intended to inhibit. "The complex pathogenesis of type II HIT is quite well understood, but the standard therapy of the disorder is suboptimal," says Siess.

A previous study had shown that activation of the Fc receptor on the thrombocyte membrane induces activation of an enzyme known as Bruton's tyrosine kinase (Btk). "We therefore asked whether inhibitors of Btk might be able to reduce the downstream activation of thrombocytes triggered by stimulation of the Fc receptor. We found that each of the six Btk inhibitors we tested was indeed able not only to reduce but to completely block Fc-receptor induced platelet aggregation and secretion in blood. In addition, they all blocked the interaction of thrombocytes with neutrophils - thus preventing the formation of potentially harmful thromboses," Siess explains. "This was a very pleasant surprise for us, as earlier investigations had shown that Btk inhibitors could only partially block platelet activation induced by stimulation of a different receptor."

Inhibitors of Btk therefore offer a new promising therapeutic option for type II HIT, as they target an early and crucial step in the process that gives rise to the disorder. The inhibitors employed in the study have the additional advantage that they have either been approved for the treatment of other diseases, or have been successfully tested in clinical trials.
-end-


Ludwig-Maximilians-Universität München

Related Blood Vessels Articles from Brightsurf:

Biofriendly protocells pump up blood vessels
In a new study published today in Nature Chemistry, Professor Stephen Mann and Dr Mei Li from Bristol's School of Chemistry, together with Associate Professor Jianbo Liu and colleagues at Hunan University and Central South University in China, prepared synthetic protocells coated in red blood cell fragments for use as nitric oxide generating bio-bots within blood vessels.

Specific and rapid expansion of blood vessels
Upon a heart infarct or stroke, rapid restoration of blood flow, and oxygen delivery to the hypo perfused regions is of eminent importance to prevent further damage to heart or brain.

Flexible and biodegradable electronic blood vessels
Researchers in China and Switzerland have developed electronic blood vessels that can be actively tuned to address subtle changes in the body after implantation.

Lumpy proteins stiffen blood vessels of the brain
Deposits of a protein called ''Medin'', which manifest in virtually all older adults, reduce the elasticity of blood vessels during aging and hence may be a risk factor for vascular dementia.

Cancer cells take over blood vessels to spread
In laboratory studies, Johns Hopkins Kimmel Cancer Center and Johns Hopkins University researchers observed a key step in how cancer cells may spread from a primary tumor to a distant site within the body, a process known as metastasis.

Novel function of platelets in tumor blood vessels found
Scientists at Uppsala University have discovered a hitherto unknown function of blood platelets in cancer.

Blood vessels can make you fat, and yet fit
IBS scientists have reported Angiopoietin-2 (Angpt2) as a key driver that inhibits the accumulation of potbellies by enabling the proper transport of fatty acid into general circulation in blood vessels, thus preventing insulin resistance.

Brothers in arms: The brain and its blood vessels
The brain and its surrounding blood vessels exist in a close relationship.

Feeling the pressure: How blood vessels sense their environment
Researchers from the University of Tsukuba discovered that Thbs1 is a key extracellular mediator of mechanotransduction upon mechanical stress.

Human textiles to repair blood vessels
As the leading cause of mortality worldwide, cardiovascular diseases claim over 17 million lives each year, according to World Health Organization estimates.

Read More: Blood Vessels News and Blood Vessels Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.