Figure 1.
Panel A shows a schematic drawing of an adult worm pair. The large adult male embraces the smaller female worm and both worms have two suckers by which they attach to the blood vessel wall. Panel B shows a scanning electron microscope image of a single S. mansoni adult male, which is about 1 cm long with a diameter of 1 mm. Panel C shows a cross-section of an adult S. mansoni worm pair (m, male; f, female; arrows mark the vessel wall) in a mesenteric venule of a mouse. This cross-section illustrates how close the worm pair is to the vessel wall and suggests the extent to which the worms must disturb blood flow (Panel C is adapted from D. G. Colley and W. E. Secor, PLoS Neglected Tropical Diseases 2007 [10]).
Figure 2.
Proposed modulation of primary haemostasis by schistosomes.
Primary haemostasis consists of the activation of blood platelets and the formation of a platelet plug. Exposure of subendothelial collagen, due to endothelial damage or the presence of soluble activators or surfaces of pathogens, can facilitate binding of VWF. Platelets adhere to VWF through GPIb present on their surface, followed by their activation and degranulation. Platelets release molecules, such as ADP, thromboxane A2, serotonin, and platelet factor 3, which stimulate further platelet aggregation and activation, stimulate vasoconstriction, and activate secondary haemostasis. Primary haemostasis is inhibited by PGI2 from endothelial cells, which inhibits degranulation of platelets, and by the degradation of extracellular ADP to AMP and subsequently to the inhibitor adenosine by endothelial ATPDases, such as CD39. Schistosomes interfere with the primary haemostasis through the proposed degradation of extracellular ADP by SmAP, SmATPDase1, and/or SmPDE, and potentially stimulate the release of PGI2 through up-regulation of the production of bradykinin by sK1 or SmSP1. Stimulation is indicated by green arrows. Red lines indicate inhibition. Schistosome proteins are indicated in the shaded boxes. Abbreviations: glycoprotein Ib (GPIb), High-molecular-weight kininogen (HMWK), prostacyclin (PGI2), Schistosoma mansoni alkaline phosphatase (SmAP), Schistosoma mansoni ATP-diphosphohydrolase-1 (SmATPDase1), Schistosoma mansoni phosphodiesterase (SmPDE), von Willebrand Factor (VWF).
Figure 3.
Proposed modulation of secondary haemostasis and vascular tone by schistosomes.
Secondary haemostasis can be activated through two different pathways: either by the presence of TF or by contact of coagulation factors with collagen, pathogens, or other negatively charged surfaces. This triggers a cascade of cleavage reactions, ultimately leading to the cleavage of fibrinogen to fibrin and the formation of a stable fibrin clot. This process is regulated by antithrombin, TFPI, and protein C. Schistosomes potentially interfere with secondary haemostasis at several steps in the cascade. Schistosome whole worm homogenate blocks the conversion of XII to XIIa and inhibits the actions of XIIa. The proteolytic activity of thrombin is inhibited by the schistosome antigen Sm22.6. Furthermore, schistosome heparin-like glycosaminoglycans may enhance the activity of antithrombin and, possibly, TFPI, and the schistosome serpin SHW 4-2 might mimic human antithrombin. The vascular tone can be influenced by schistosomes through the production of both vasodilating and vasoconstricting eicosanoids and the presence of sK1 and SmSP1 that could potentially convert HMWK into the vasodilator bradykinin. The green arrows indicate stimulation. Inhibition is indicated by the red lines. The shaded boxes indicate schistosome proteins. Abbreviations: activated coagulation factor XII (XIIa), coagulation factor XII (XII), High-molecular-weight kininogen (HMWK), tissue factor (TF), tissue factor pathway inhibitor (TFPI).
Figure 4.
Proposed modulation of the fibrinolytic system by schistosomes.
The fibrinolytic system inhibits blood coagulation through degradation of the formed fibrin clot by plasmin. Plasminogen is cleaved to plasmin by plasma kallikrein, but mainly by t-PA and urokinase, which are inhibited by PAI-1 and PAI-2. Furthermore, plasmin activity is inhibited by TAFI. Schistosomes may stimulate fibrinolysis by the presence of enolase, GAPDH, and annexin, which bind plasminogen and facilitate its conversion to plasmin by t-PA. Green arrows indicate stimulation. Inhibition is indicated by the red lines. Schistosome proteins are denoted in the shaded box. Abbreviations: tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2), thrombin-activatable fibrinolysis inhibitor (TAFI), glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
Table 1.
Proposed interference with the haemostatic system and vascular tone by schistosome molecules.