Table 2.

Approaches to vascular targeting of ATAs

Target category	Targets	Goal/advantages	Challenges
Clot components	Fibrin coagulation factors; activated platelets	Concentrate ATA in occlusive or growing clots; inhibit prothrombotic functions of targets	Targets rapidly disappear or become inaccessible in clots; clot permeation; short PK restricts prophylactic utility
Blood cells	Resting platelets	Use natural tropism for the above goal; inhibit prothrombotic functions of platelets	Limited animal data on PK, targeting and effects; restricted access to and effect on preformed occluding clots
	RBCs	Significantly prolonged PK and restricted side effects of RBC-bound ATAs enable safe TTT in animal models	Restricted access to and effect on preformed occlusive clots; animal studies are limited to mouse models
Endothelium	PECAM	Prophylactic anchoring of ATAs on EC preconditions to subsequent thrombosis	No/poor access for EC-targeted ATAs to EC in sites of preformed/ongoing thrombosis
	ICAM	As above; enriched anchoring of ATAs in inflamed EC; inhibition of WBC trafficking	As above
	Selectins and VCAM	As above; high selectivity to inflamed EC	As above; transient target exposure and fast internalization limit amplitude and duration of action
	ACE	Enriched anchoring in the pulmonary vasculature	As in PECAM; fast internalization

The outline provides an historical perspective: from the oldest and most intensively studied approaches to target clot components to less well established but promising techniques to deliver ATAs to cellular targets in the vasculature. ACE, angiotensin converting enzyme; VCAM, vascular cell adhesion molecule.