Table 1.

Effects of RBCs related to thrombosis and hemostasis and underlying mechanisms

Effects	Mechanisms	Pro- or antithrombotic	References ##
Hemorheological effects	RBCs increase blood viscosity because of a rise in hematocrit, an increase in RBC aggregation, or a decrease in RBC deformability (increasing flow resistance)	Pro	2, 3, 4, 5
	Conversely, anemia is associated with low blood viscosity and bleeding tendency due to reduced platelet margination toward endothelium and enhanced NO availability	Anti	2, 3, 4, 5
	RBCs undergo shear-dependent reversible aggregation mediated by plasma proteins (mainly fibrinogen, immunoglobulins) and/or local osmotic gradient	Pro	14, 15, 16, 70, 71, 72, 73, 74
	RBCs with increased rigidity occlude small vessels	Pro	11, 12
	Deformability of RBCs reduces frictional resistance to flow	Anti	8, 11, 12, 13
	RBC maintain biconcave shape and a high surface-to-volume ratio due to cytoskeleton and water/ions balance	Pro or Anti	5
	RBCs migrate to the center of blood flow and push platelets toward the endothelium (margination) in a hematocrit- and shear-dependent manner	Pro	59, 60, 61
Effects on platelet reactivity	RBCs increase platelet adhesion and aggregation by release of ADP and thromboxane A2	Pro	66, 67
	RBC form aggregates with platelets via adhesive molecules (ICAM-4 and fibrinogen with αIIbβ3)	Pro	62, 63, 64
	Free hemoglobin released during hemolysis scavenges nitric oxide, a platelet inhibitor and vasodilator	Pro	50, 51, 68, 69
	Free hemoglobin suppresses platelet activation by release of S-nitrosothiols, functional equivalents of NO	Anti	48, 53
Interactions with vessel wall	RBCs bind directly to endothelium via adhesive molecules (Lutheran blood group/basal cell adhesion molecule/band 3, integrin α4Bβ1, CD36, ICAM-4, phosphatidylserine, etc.)	Pro	10, 54, 55
	In FeCl3-induced thrombosis RBCs bind to endothelium via unknown mechanisms	Pro	57
	RBCs modulate endotheliocyte activation through release of NO, NO equivalents, and ATP	Anti	49, 52
Thrombin generation	Phosphatidylserine is exposed on RBCs by Ca2+-dependent scramblase in response to high-shear stress, complement attack, oxidative stress, apoptosis, etc.	Pro	18, 19, 20, 21, 22, 23, 24, 25
	RBCs release membrane-derived procoagulant microvesicles bearing phosphatidylserine during in vivo aging and in vitro storage	Pro	28, 29, 30, 31, 33, 34
	Meizothrombin, a protein C activator with low fibrinogen-cleaving activity, is formed on RBCs and released into the blood	Anti	20
	Factor IX is activated directly by an elastase-like enzyme on the RBC membrane	Pro
Structure and properties of clot and thrombi	RBCs make the fibrin network more porous	Anti	65, 79, 80
	Variable deformability of RBCs affect blood clot mechanics	Pro or Anti
	Factor XIIIa-mediated RBC retention increases thrombus size	Pro	81, 82, 83
Effects on fibrinolysis and thrombolysis	RBCs reduce clot permeability	Pro	84, 86, 87
	RBCs suppress tPA-induced plasminogen activation	Pro
	RBCs decrease fibrin fiber dimeter and change the network structure, thus reducing susceptibility to fibrinolysis	Pro
	RBCs are potential transportation cargo for targeted delivery of thrombolytic drugs	Anti	45
Effects on clot contraction	Compacted RBCs form impermeable seal	Pro or Anti	88, 89
	RBCs undergo compressive deformation from biconcave to polyhedral and intermediate forms	Pro or Anti	91, 92, 93
	RBCs are redistributed in contracted clots toward the middle	Pro or Anti	89
Hemostatic effects of RBC transfusions	RBC transfusion stops bleeding associated with anemia and thrombocytopenia	Pro	39, 47
	RBC transfusion improves platelet responsiveness to stimulation	Pro
Complications of RBC transfusions	“Storage lesion” of RBCs includes: - oxidative stress and membrane damage - phosphatidylserine exposure - release of microvesicles - hemolysis - increased membrane rigidity - release of free hemoglobin - activation of complement - depletion of NO and its functional equivalents - apoptosis (eryptosis)	Pro	31, 32, 34, 36, 37, 40, 41, 42, 43, 44, 45, 47, 48, 49