In addition to the complexity due to the large variety of molecules with different properties, the phospholipids in red cells are organized in a specific and asymmetric fashion across the phospholipid bilayer. Such asymmetric distribution is found in all plasmamembranes and the loss of this organization with the exposure of phosphatidylserine (PS) has major physiologic consequences.

PS exposure requires inhibition of the flipase as well as activation of the scrambling process, possibly by elevation of intracellular calcium, and the involvement of signal transduction molecules such as protein kinase C (PKC). While PS exposure has been recognized as an early step in apoptosis, the mechanisms that lead to this exposure have not been elucidated. We feel that a better understanding of the exposure of PS in RBC will also render information of PS exposure in the plasma membrane of other cells and as such shed light on an important step in programmed cell death.

In steady state, the choline containing phospholipids, sphingomyelin (SM) and phosphatidylcholine (PC) are mainly found on the outside of the bilayer while the aminophospholipds are mainly (phosphatidylethanol-amine, PE), or exclusively (phospha-tidylserine, PS), found in the inner monolayer. This organization is maintained by an active set of transport sytems that "flip" and "flop" phospholipids across the membrane. The flipase actively transports aminophospholipids from outer to inner monolayer, while the scramblase, when activated, moves all phospholipids in both direction, thereby scrambling the distribution. PS exposed on the surface forms a docking site for hemostatic factors such as the prothrombinase complex, factor Xa, Va, and II. In addtion, PS is recognized by macrophages and interacts with proteins such as annexin (AV).