Hemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel. Fig.1 and its legend briefly describes this complex process.
Figure 1: The cell-based model of hemostasis shows the different components of the hemostatic system that are affected by snake venom proteins
(Reprinted from Toxicon, Sajevic et al., 2011, © 2011, with permission from Elsevier.)
Platelet aggregation: Following vessel wall injury, platelets bind to exposed sub-endothelium. Through receptors on their plasma membrane - glycoprotein complex GPIb-V-IX and GPVI and integrin α2β1 - platelets interact with vWF bound on the exposed collagen or directly to the collagen. Platelets are activated on binding. They change their shape from flat to spherical and numerous pseudopodia bursts. They release different mediators, e.g. ADP and thromboxane A2, and start to synthesise prostaglandins. Released molecules bind to receptors on neighbouring platelets and activate them. Activation of fibrinogen receptor GPIIb/IIIa on subsequent fibrinogen binding cross-links platelets and forms the plug.
Coagulation cascade: Following damage to the blood vessel wall, the cells bearing tissue factor (TF) (smooth muscle cells, macrophages and fibroblasts) come into the contact with coagulation factors in the blood. TF in complex with FVIIa activates minute amounts of FIX and FX. FXa activates prothrombin into thrombin which activates platelets, FV, FVIII and FXI. Additional FIXa is formed by FXIa, bound to platelets. On the surface of platelets, FIXa forms a complex with FVIIIa, which activates FX. FXa complexed with FVa then produces large amounts of thrombin. Thrombin converts fibrinogen to monomeric fibrin that polymerizes to fibrin fibres. These are cross-linked by thrombin activated FXIII.
Fibrinolysis: Tissue plasminogen activator (t-PA) and urokinase (u-PA) activate plasminogen to plasmin, which then degrades the fibrin clot. Regulation of coagulation. The coagulation is regulated by inhibitors of coagulation factors, such as anti-thrombin (AT), anti-plasmin (AP) and α2-macroglobulin (α2-MG). The most important inhibitory mechanism is the protein C (PROC) anticoagulant pathway that is activated at the same time as the activation of coagulation factors. On the surface of non-activated endothelial cells, thrombin binds to thrombomodulin and activates PROC (APROC) which then, in the complex protein S (PS), cleaves FVa and FVIIIa.
Snake venom contains numerous proteins that disturb hemostasis. They belong to a large variety of protein families and act at different levels of hemostasis. They cause hemorrhage (see hemorrhagic toxin) by damaging endothelial cells or disturbing their interactions with the basement membrane, disturb platelet aggregation (see platelet aggreg. activating toxin and Platelet aggreg. inhibiting toxin) which is crucial for forming blood clots, impair the blood coagulation cascade (blood coagulation cascade activating toxin and blood coagulation cascade inhibiting toxin), degrade fibrinogen (see fibrinogenolytic toxin) and even lyse already formed blood clot (fibrinolytic toxin). All these effects explain why disturbance of hemostasis is among the most severe effects following a snake bite.
In other venomous species, only a few toxins have been described to impair hemostasis.
See also UniProtKB-keyword.
Hemostasis impairing toxin
Venom protein entries in UniProtKB/Swiss-Prot
(all links/actions below point to uniprot.org website)915 entries grouped by family
1 entry
5'-nucleotidase family
1 entry
AB hydrolase superfamily, Lipase family
1 entry
Arthropod phospholipase D family, Class II subfamily, Class IIa sub-subfamily
1 entry
Arthropod phospholipase D family, Class II subfamily, Class IIb sub-subfamily
19 entries
Disintegrin family, Dimeric disintegrin subfamily
1 entry
Disintegrin family, Short disintegrin subfamily
5 entries
Ficolin lectin family, Veficolin subfamily
52 entries
Flavin monoamine oxidase family, FIG1 subfamily
3 entries
Multicopper oxidase family
1 entry
Natriuretic peptide family
4 entries
Not in a family
5 entries
Nucleotide pyrophosphatase/phosphodiesterase family
1 entry
Peptidase S1 family, CLIP subfamily
206 entries
Peptidase S1 family, Snake venom subfamily
1 entry
Phospholipase A2 family
7 entries
Phospholipase A2 family, Group I subfamily
44 entries
Phospholipase A2 family, Group I subfamily, D49 sub-subfamily
9 entries
Phospholipase A2 family, Group II subfamily
82 entries
Phospholipase A2 family, Group II subfamily, D49 sub-subfamily
10 entries
Phospholipase A2 family, Group II subfamily, K49 sub-subfamily
2 entries
Phospholipase A2 family, Group II subfamily, N49 sub-subfamily
1 entry
Phospholipase A2 family, Group II subfamily, Q49 sub-subfamily
1 entry
Phospholipase A2 family, Group III subfamily
2 entries
Scoloptoxin-11 family
173 entries
Snaclec family
1 entry
Snake three-finger toxin family, Ancestral subfamily, Orphan group II sub-subfamily
3 entries
Snake three-finger toxin family, Ancestral subfamily, Orphan group V sub-subfamily
3 entries
Snake three-finger toxin family, Short-chain subfamily, Antiplatelet toxin sub-subfamily
1 entry
Snake three-finger toxin family, Short-chain subfamily, Orphan group I sub-subfamily
1 entry
Snake three-finger toxin family, Short-chain subfamily, Orphan group XX sub-subfamily
2 entries
Snake three-finger toxin family, Short-chain subfamily, Type IB cytotoxin sub-subfamily
2 entries
SNTX/VTX toxin family
1 entry
True venom lectin family
10 entries
Venom Kunitz-type family
6 entries
Venom metalloproteinase (M12B) family
45 entries
Venom metalloproteinase (M12B) family, P-I subfamily
3 entries
Venom metalloproteinase (M12B) family, P-II subfamily
78 entries
Venom metalloproteinase (M12B) family, P-II subfamily, P-IIa sub-subfamily
8 entries
Venom metalloproteinase (M12B) family, P-II subfamily, P-IIb sub-subfamily
2 entries
Venom metalloproteinase (M12B) family, P-II subfamily, P-IIc sub-subfamily
7 entries
Venom metalloproteinase (M12B) family, P-II subfamily, P-IId sub-subfamily
9 entries
Venom metalloproteinase (M12B) family, P-II subfamily, P-IIe sub-subfamily
15 entries
Venom metalloproteinase (M12B) family, P-III subfamily
49 entries
Venom metalloproteinase (M12B) family, P-III subfamily, P-IIIa sub-subfamily
13 entries
Venom metalloproteinase (M12B) family, P-III subfamily, P-IIIb sub-subfamily
16 entries
Venom metalloproteinase (M12B) family, P-III subfamily, P-IIIc sub-subfamily
6 entries
Venom metalloproteinase (M12B) family, P-III subfamily, P-IIId sub-subfamily
1 entry