Role of Red Blood Cells in Coagulation MDR

Where are red clots primarily found and what are they made of?

Classically found in the venous system

Primarily composed of RBCs and fibrin

How does an increase in hematocrit change where RBC and platelets are located in the blood?

With an increase in hematocrit, platelets are translocated from an even dispersion to the periphery, as the RBC preferentially move to the center of the vessels

• Increased contact of the platelets with the endothelium and with each other may predispose to activation and clot formation

What mediates RBC roleaux formation?

Interactions between the RBC membrane and plasma proteins such as fibrinogen, immunoglobins, and lbumin

Roleau form more rapidly in the presence of inflammation, resulting in a more rapid sedimentation rate

Formation of RBC rouleaux is a direct result of high concentrations of circulating fibrinogen or other acute phase proteins

What is the major pro-aggregatory substance for platelets secreted by RBCs?

ADP

• Has specific platelet receptors (P2Yq, P2Y12)

What is the trigger for ADP and ATP to be released from RBCs?

Mechanical deformation

What coagulation factor can the RBC membrane activate?

Factor IX

What role does phosphatidyl serine (PS) on the RBC membrane play in coagulation?

Normal RBCs have active scramblase enzymes, which play a role in reorganization of the phospholipid bilayer and can support propagation of coagulation through exposure of PS

PS exposure on the membrane stabilizes the tenase complex and allows thrombin generation

Why do red clots have less dense fibrin mesh than other clots?

RBCs have a band 3 receptor than when activated may allow RBC to adhere ot the vascular endothelium where it may trigger clot formation

RBCs can express intra-cellular adhesion molecule (ICAM)-4, which can act as a ligand for platelet integrin a2b BIII and also for leukocyte beta 1 and 2 integrins

In addition to platelets, this receptor may be able to directly bind fibrinogen, alone or in a complex, with the CD47 receptor

This interaction may help to stabilize red colts which are formed of a meshwork of platelets, RBCs, and fibrin

Due to the additional stabilization from RBCs, red clots tend to have less dense fibrin mess than other clots, and thus are relatively resistant to fibrinolysis, since plasminogen activation occurs in a fibrin-dependent manner

Shape of RBCs in a Red Clot

RBCs within the fibrin strands are compressed and have a shape change, characterized as a ‘polyhedrocyte’

Fibrin[ogen] can bind to RBCs through a motif on the fibrinogen Aa-chain

How does the body deal with free hemoglobin?

It is scavenged by haptoglobin which is produced in the liver and circulates in plasma

Once the Hb-haptoglboin complex is created, it is endocytosed by monocytes through interactions at the hemoglobin scavenger receptor (CD163) and subsequently degraded

Following endocytosis, hemoglobin is broken down by hemeoxygenase-1 into Fe2+, CO, and biliverdin in the lysosome

The endocytosis of the hemoglobin-haptoglobin complex is not associated with activation of the monocyte/macrophage and may in fact induce anti-inflammatory pathways

Consequence of Free Hemoglobin - NO

Free hemoglobin has nitric oxide (NO) scavenging properties, resulting in vasoconstriction

• NO reacts with OxyHb and irreversibly reduces it to metHb

Arginase released from lysed RBCs breaks down arginine, which is a NO precursor

NO is also an inhibitor of platelet aggregation and a protective mechanism from the endothelium to prevent thrombosis

NO decreases platelet adhesion to vascular endothelial surfaces by decreasing adhesion molecule expression

NO may also decrease coagulation factor XIII activity, resulting in enhanced clot stability and fibrin cross-linking

Inflammatory Properties of Free Heme

Associated with oxidant injury and promotion of inflammation

Can generate ROS

Inflammatory cytokine production by monocytes and macrophages can be induced by heme through direct interaction with TLR, activating nuclear factor KB