Recombinant factor VIIa enhances deposition of platelets with congenital or acquired αIIbβ3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor–independent thrombin generation

Abstract

A novel approach to treat bleeding episodes in patients with Glanzmann thrombasthenia (GT) and perhaps also in patients receiving ␣ IIb ␤ 3 inhibitors is the administration of recombinant factor VIIa (rFVIIa). The mechanism of action of rFVIIa in these patients is, however, still unclear. We studied the effect of rFVIIamediated thrombin formation on adhesion of ␣ IIb ␤ 3 -deficient platelets under flow conditions. Adhesion of ␣ IIb ␤ 3 -deficient platelets to the extracellular matrix (ECM) of stimulated human umbilical vein endothelial cells or to collagen type III was studied using a model system with washed platelets and red cells. When ␣ IIb ␤ 3 -deficient platelets were perfused over the surface at arterial shear rate for 5 minutes, a low surface coverage was observed (GT platelets, mean ؎ SEM, 37.5% ؎ 5.0%; normal platelets preincubated with an RGD-containing peptide, 7.4% ؎ 2.1%). When rFVIIa, together with factors X and II, was added to the perfusate, platelet deposition significantly increased (GT platelets, mean ؎ SEM, 67.0% ؎ 4.3%; normal platelets preincubated with an RGD-containing peptide, 48.2% ؎ 2.9%). The same effect was observed when normal platelets were pretreated with the commercially available anti-␣ IIb ␤ 3 drugs abciximab, eptifibatide, or tirofiban. It was shown that tissue factor-independent thrombin generation (presumably induced by binding of rFVIIa to adhered platelets) was responsible for the increase in platelet deposition. In conclusion, defective adhesion of ␣ IIb ␤ 3 -deficient platelets to ECM can be restored by tissue factor-independent rFVIIa-mediated thrombin formation. The enhanced generation of platelet procoagulant surface facilitates fibrin formation, so that lack of platelet aggregate formation might be compensated

Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity

“…Red cells were isolated from whole blood from healthy volunteers who had blood group O as described previously. 17 Platelets were isolated from three patients with cirrhosis and three controls according to previously published methods. 17 After the final washing step, platelets from patients or controls were resuspended in pooled normal plasma or in pooled cirrhosis plasma.…”

“…17 Platelets were isolated from three patients with cirrhosis and three controls according to previously published methods. 17 After the final washing step, platelets from patients or controls were resuspended in pooled normal plasma or in pooled cirrhosis plasma. The platelets were mixed with red cells to obtain reconstituted blood with a platelet count of 200,000/ L and a hematocrit of 40%.…”

“…In accordance, mean MELD scores paralleled the Child classification. The MELD score was 10 [6][7][8][9][10][11][12][13][14][15][16][17][18] (median [range]) in the Child A group, 13 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] in the Child B group, 18 in the Child C group, and 28 [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] cirrhosis compared with control, P Ͼ .05 for mild cirrhosis compared with control). In the five patients with acute liver failure, the VWF collagen-binding activity was slightly decreased (90% [86-99]), but this difference did not reach statistical significance.…”

Glanzmann trombastenisi: Cerrahpaşa Tıp Fakültesi deneyimi

“…Development of thrombosis with use of Factor VII in patients with Glanzmann thrombasthenia is present in the literature (12,13). Factor VII acts by increasing subendothelial fibrin production (14). Although Factor VII is an efficient treatment in GT, care should be taken in terms of possible side effect (thrombosis etc.)…”

Activation of platelets in whole blood by recombinant factor VIIa by a thrombin‐dependent mechanism

“…Platelet TF may become 'de-encrypted' following its transfer via microparticles from monocytes (Rauch et al, 2000), but non-activated platelets have inactive TF on their surface which becomes active upon shedding (Siddiqui et al, 2002), and recent data (Muller et al, 2003) suggest that microvesicle-associated TF is functional in the presence of neutrophils. Lisman et al (2003) demonstrated that the adhesion of washed Gp IIb/IIIa-blocked platelets to subendothelial matrices under flow conditions was restored in the presence of 25 nmol/l rFVIIa. Platelets were shown to bind rFVIIa under these conditions.…”