PlatelAct Overview

Wortham Laboratories
Surgical Sealant / Wound Closure Market

The market for surgical closure and securement has entered a phase in which major driving forces are:

♦  The introduction of new procedures and techniques by the surgical profession.

♦  Development by the medical device industry of new wound closure devices and biomaterials.

♦  Growing willingness of surgical specialists to use these procedures and devices in appropriate circumstances.

There is now a continuum between simple closure using sutures and the use of specially designed devices and delivery systems with new bioresorbable securement materials, either as supplements to conventional closure methodology or as stand-alone replacements.

Worldwide expenditure on all medical devices is estimated to have surpassed $331 billion (2012), and in the field of tissue repair and surgical securement the market reached $14 billion.  This $14 billion figure represents a market segment increase of 100% in just over a half decade.  

This dramatic doubling of the market in such a short time has numerous valid reasons:

♦  Our improved understanding of the underlying mechanisms of tissue repair

♦  Patient demographic pressures creating an increased caseload of procedures

♦  Rapidly expanding number of new products available

Strong Market Indicator

The tissue closure and securement market can be regarded as a benchmark indicator for the overall expansion of medical device use.  This is because surgical closure and securement products are growing to be components of all surgical procedures.

These products are used for rapid and efficient closure of surgical wounds, and internal securement of tissues to reduce pain and accelerate rehabilitation.  

Immediate Health and Economic Benefits

Appropriate use of these products is shown to:

♦  Reduce risk of infection

♦  Optimise the repair process to enhance the speed and strength of tissue repair

♦  Reduce complications such as those resulting from post-surgical adhesion  

Responding to a Changing Medical Market

In addition to clinical efficacy and proven patient benefits, advances in tissue closure and securement products meet needs presented by the contemporary medical marketplace.  The shift to outpatient and community-based treatment sites affects the way products are designed, marketed, distributed and incorporated into common medical procedures. In addition to the case for cost-effectiveness, professional preferences are changing - new procedures are being adopted.  The tissue closure and securement market affords the surgical professional the benefit of improved outcomes and a reduction in surgical theatre time and cost.   

Wortham Laboratories

Human platelets are normally in a quiescent state, prevented from premature activation by the presence of the endothelial cell monolayer, by the single-inhibiting effects of prostaglandin I2 (PG I2) and nitric oxide (NO), and by limitations on the local accumulation of platelet agonists.  It has been well established that activation of human platelets occurs when thrombin binds to the protease-activated receptor sites, specifically PAR-1 and PAR-4, on the surface of the platelet. 1-3

Receptor activation begins when thrombin cleaves the N-terminus of PAR-1, between arginine 41 and serine 42, exposing a new N-terminus that serves as a tethered ligand at the extracellular loops of the receptor.4  These receptors activate Gq and G12, leading to the activation of PLCß. 5-7  PI 3-kinase and monomeric G proteins (Rho, Rec, and Rap 1), causes an increase in the cytosolic Ca2+ concentration and inhibiting cAMP formation. 8,9  This process is supported by released ADP and TxA2, which in turn bind to their own GPCRs on the platelet surface. 10  All four of the PAR family members have a structure similar the GPCRs.  Cleavage of human PAR-4 requires a higher concentration of thrombin than does cleavage of PAR-1, but it is more sustained. 11

Proteases other than thrombin can also activate PAR-1.  Studies by Ahmad et al demonstrated Factors IX and Factor IXa share ~300 low-affinity binding sites, with an additional 200-250 sites for Factor IXa. 12-17

PlatelAct offers an alternative way to activate platelets.  Instead of using a foreign thrombin to activate Plasma Rich Platelets (PRP), the serine proteases, Factors II, VII, IX, X in PlatelAct, generates autologous thrombin to activate PRP.  Initiation begins with the addition of calcium from ACD Solution and PlatelAct to the PRP.  The calcium activates Factor X, Factor V, and most notably Factor II, where prothrombin is connected to thrombin.  The Vitamin K factors in PlatelAct support both the extrinsic and intrinsic coagulation cascade system to generate more autologous thrombin.  In turn, both the patients’ own thrombin, Factor IX and Factor IXa bind to the PAR receptor sites, activating the platelets.

During platelet activation, the glycoprotein IIb/IIIa is activated. 18 The binding site for adhesive proteins appears shortly after activation with an agonist.  It provides a site to which fibrinogen and von Willebrand factor will bind.  Activation also causes a change in the membrane surface.  This change enables fibrin forming proteins (coagulation factors) to bind to the membrane.

PlatelAct also contains a linear complex sugar, agar, made from beta-galactopyranose linked to 3,6-anhydro-L-galactopyranose.  This sugar will cross-link with the ions of platelet phospholipids and cations from amine groups in fibrinogen/fibrin monomers and tissue proteins, forming an -1, 6-linked galactophospho and -1, 6-galactoamine bond, enhancing the adhesive properties of the platelets.


1.  Anderson, H., Greenburg, D.L., Fujikawa, K., et al; Protease-activated Receptor 1 as the Primary Mediator of Thrombin-Stimulated Platelet Procoagulant Activity; The National Academy of Sciences, 1999, 7-11.

2.  Riewald, M., Ruf, W., Mechanistic Coupling of Protease Signaling and Initiation of Coagulation by Tissue Factor; PNAS, Vol 98, No. 14: July 2001, 7742-7747.

3.  Perini, R., Wallace, J.L., Proteinase-Activated Receptors (PARs), Platelets and Angiogenesis; Drug Development Research, Vol 59, Issue 4; Sept 2003, 395-399.

4.  Brass, L.F., Thrombin and Platelet Activation; Chest, Vol 124, No. 3: Sept 2003 Supplement, 185-255.

5. Offermanns, S., Toombs, C.F., Hu, Y.H., et al; Defective Platelet Activation in G Alpha (q)-Deficient Mice. Nature, Vol 389, 1997, 183-186.

6.  Jantzen, H.M., Milstone, D.S., Gousset, L., et al; Impaired Activation of Murine Platelets Lacking G Alpha (i2). J Clin Invest; Vol 108, 2001, 477-483.

7.  Jin, J., Kunapsuli, S.P., Coactivation of Two Different G Proteincoupled Receptors is Essential for ADP-Induced Platelet Aggregation; Proc Natl Acad Sci USA, Vol 95: 1998, 8070-8074.

8.  Klages, B., Brandt, V., Simon, M.I., et al; Activation of G12/G13 Results in Shape Change and Rho/Rho-Kinase-Mediated Myosin Light Chain Phosphorylation in Mouse Platelets; J Cell Biol, Vol 144: 1999, 745-754.

9.  Woulfe, D., Jiang, H., Mortensen, R., et al; Activation of Rap1B G(i) Family Members in Platelets; J Biol Chem, Vol 277:2002, 23382-23390.

10.  Murray, R., Fitzgerald, G.A., Regulation of Thromboxane Receptor Activation in Human Platelets; Proc Natl Acad Sci USA, Vol 86: Jan 1989, 124-128.

11.  Andrade-Gordon, P., Derian, C.K., Maryanoff, B.E., et al; Administration of a Potent Antagonist of Protease-Activated Receptor-1 (PAR-1) Attenuates Vascular Restenosis Following Balloon Angioplasty in Rats; J Pharmaco and Exp Therap; Vol 298, No. 1:2001, 34-42.

12.  Ahmad, S.S., Rawala-Sheikh, R., Walsh, P.N., Comparative Interactions of Factor IX and Factor IXa with Human Platelets; J Biol Chem, Vol 264, No. 6: Feb 1989, 3244-3251.
13.  London, F.S., Marcinkiewicz, M., Walsh, P.N., PAR-1 Stimulated Factor IXa Binding to a Small Platelet Subpopulation Requires a Pronounced and Sustained Cytoplasmic Calcium; Biochemistry, Vol 45, No. 23: June 2006, 7289-7298.

14.  London, F.S., Marcinkiewicz, M., Walsh, P.N., A Subpopulation of Platelets Respond to Thrombin or SFLLRN Stimulation with Binding Sites for Factor IXa; J Biol Chem, Vol 279, No. 19: May 2004, 19854-19859.

15.  Gailani, D., Ho, D., Sun, M.F., et al; Model for a Factor IX Activation Complex on Blood Platelets: Dimeric Conformation of Factor XIa in Essential; Blood, Vol 97, No. 10: May 2001, 3117-3122.

16.  Stern, D.A., Drillings, M., Kisiel, W., et al; Activation of Factor IX Bound to Cultured Bovine Aortic Endothelial Cells; Proc Natl Acad Sci USA; Vol 81: Feb 1984, 913-917.

17.  Soons, H., Janssen-Claessen, T., Hember, H.C., et al; The Effect of Platelets in the Activation of Human Blood Coagulation Factor IX by Factor XIa; Blood, Vol 68, No. 1: Jul 1986, 140-148.

18.  Phillips, D.R., Nannizzi-Alaino, L., Prosod, K.S., Beta 3 Tyrosine Phosphorylation in Alpha IIb Beta 3 (Platelet Membrane GP IIb-IIa) Outside in Integrim Signaling; Thromb Haemost, Vol 86:2001, 246-258.