Isothiocyanates as anti-thrombotics and thrombolytics

Thromboembolic conditions, such as stroke, myocardial infarction or pulmonary embolism occur with high incidence world-wide, due to the increasing age of populations and due to an increasingly unhealthy life-style. Especially high risk patients thus often receive preventive anti-thrombotic medication to prevent the occurrence of acute, potentially lethal events. Our researchers have identified new small molecule compounds that could be developed into new anti-thrombotic or thrombolytic drugs. Currently, several anti-thrombotic drugs are available to reduce risk of thrombosis, and thrombolytics are used to lyse existing thrombi, e.g. in the first few hours after a stroke. However, the aforementioned drugs increase the patient's bleeding risk, and some are expensive to produce, or not ideal for self-administration or for storage under non- ambient conditions. Since the global incidence of thromboembolic conditions is very high, new preventive and therapeutic drugs have a high market potential.

Using aggregometry and FACS, our researchers showed that the ITCs can prevent PLT activation, degranulation and aggregation, and were efficient in reversing PLT aggregation. The effect was dose-dependent. Signaling pathways associated with PLT activation and aggregation, as well as mitochondrial respiratory function, were altered upon ITC treatment. The data also show that the ITCs can prevent and reduce thrombus formation as well as tissue damage in a murine carrageenan-induced thrombosis model (the effect at least equalling that of heparin), suggesting ITCs as potential novel therapeutics.

Platelet (PLT) activation, degranulation and aggregation is a central aspect of hemostasis. Our team of researchers found that specific isothiocyanates (ITCs) are effective anti-thrombotics, and they set out to elucidate the mechanism of how ITCs can influence blood coagulation: so far, kinase signalling pathways associated with PLT activation and degranulation as well as PLT mitochondrial respirative function seem to be altered:

• The isothiocyanates AITC, BITC and PEITC prevent platelet activation
• AITC, BITC and PEITC prevent and reverse platelet aggregation
• Potential as therapeutic and preventive drugs for thromboembolic conditions
• ITCs are small molecules and can be produced cost-effectively and are highly stable

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