Table 1. Selected studies demonstrating... | American Society of Hematology

Table 1.

Selected studies demonstrating a mechanistic link between complement activation and induction of coagulation and/or prothrombotic cell activation in vitro or in animal models

First author/reference	Main finding	Prothrombotic state induced via activation of	Comment
Zimmerman¹³⁰	• Blood coagulation ex vivo in rabbit blood is substantially accelerated by diverse complement activation triggers • Acceleration of coagulation depends on C6	C5-C9	However, such effects were not reproduced in blood form a C6 deficient and a C7 deficient patient.^131,132
Polley¹³³	• Thrombin-mediated platelet activation is substantially increased in presence of purified components C3, C5, C6, C7, C8, and C9; these components adhere to the platelet surface • Adherence of TP components to cell surfaces in absence of convertases happens on activated platelets but not on RBCs	C3 and C5-C9 Also Purified C5-C9 components alone (to a smaller extent)	The activated platelet surface can acquire complement proteins even in absence of convertases leading to increased platelet activation. C3 was probably acquired as C3(H₂O). More recently contact activation of C3^134-136 has been described that could explains this phenomenon.
Polley¹³⁷	• C3a and C3a-desArg activate human platelets	C3	Suggests the presence of C3a receptors on human platelets that upon ligation by C3a/C3a-desArg lead to platelet activation
Wiedmer^138,139	• Assembly of purified sublytic C5b-9 on the platelet membrane increases - platelet prothrombinase activity - rate of plasma clot formation	C5-C9	C5b-9 assembly on platelets accelerate platelet-catalyzed thrombin generation
Sims¹⁴⁰	• C5b-9 causes release of micro-vesicles from platelets that exhibit prothrombinase activity	C5-C9	Properties previously allocated to the activated platelet surface may rather or in addition be caused by platelet microparticles
Hattori¹⁴¹	• C5b-9 induces secretion of large von Willebrand factor (vWF) multimers from endothelial cells	C5-C9	C5b-9 stimulate endothelial cells to secrete prothrombotic, platelet adhesive vWF protein
Foreman¹⁴²	• C5a causes expression of endothelial P-selectin, secretion of von vWF and adhesiveness for neutrophils	C5	By promoting adhesive interactions between neutrophils and endothelial cells C5a induces acute inflammatory responses
Ritis¹⁴³	• C5a induces tissue factor (TF) expression on neutrophils associated with enhanced procoagulant activity	C5	Neutrophils may link complement activation to coagulation pathways; TF is not upregulated on monocytes in response to C5a alone¹⁴⁴
Gushiken¹⁴⁵	• C3 deficient mice: increased tail-bleeding time and decreased platelet aggregation in vivo or ex vivo, respectively.	C3 (and possibly* C5-C9)	C3 deficiency in mice leads to abnormal platelet function
Subramaniam¹⁴⁶ Asfarhar-Kharghan¹⁴⁷	• C3 deficient mice: prolongation of tail-bleeding parameters in vivo; and ex vivo decrease in platelet activation • C5 deficient mice: milder tail-bleeding phenotype (than C3^−/−), but no decrease in platelet activation ex vivo • C5-dependent membrane perturbations specifically lead to prothrombotic TF release	Mainly via C3 regarding platelets Via C5 regarding leukocytes	Suggests a prominent role for C3 and its activation products in platelet activation independent of TP activation. C5 activation acts procoagulantly by inducing TF release
Sauter¹⁴⁸	• Stimulation of the C3a- C3aR axis on platelets leads to prothrombotic activation • In C3aR^−/− (but not C5^−/−) mice time to vessel occlusion was significantly prolonged in a model in vivo	C3	A functional role for C3aR on platelets is proposed

First author/reference	Main finding	Prothrombotic state induced via activation of	Comment
Zimmerman¹³⁰	• Blood coagulation ex vivo in rabbit blood is substantially accelerated by diverse complement activation triggers • Acceleration of coagulation depends on C6	C5-C9	However, such effects were not reproduced in blood form a C6 deficient and a C7 deficient patient.^131,132
Polley¹³³	• Thrombin-mediated platelet activation is substantially increased in presence of purified components C3, C5, C6, C7, C8, and C9; these components adhere to the platelet surface • Adherence of TP components to cell surfaces in absence of convertases happens on activated platelets but not on RBCs	C3 and C5-C9 Also Purified C5-C9 components alone (to a smaller extent)	The activated platelet surface can acquire complement proteins even in absence of convertases leading to increased platelet activation. C3 was probably acquired as C3(H₂O). More recently contact activation of C3^134-136 has been described that could explains this phenomenon.
Polley¹³⁷	• C3a and C3a-desArg activate human platelets	C3	Suggests the presence of C3a receptors on human platelets that upon ligation by C3a/C3a-desArg lead to platelet activation
Wiedmer^138,139	• Assembly of purified sublytic C5b-9 on the platelet membrane increases - platelet prothrombinase activity - rate of plasma clot formation	C5-C9	C5b-9 assembly on platelets accelerate platelet-catalyzed thrombin generation
Sims¹⁴⁰	• C5b-9 causes release of micro-vesicles from platelets that exhibit prothrombinase activity	C5-C9	Properties previously allocated to the activated platelet surface may rather or in addition be caused by platelet microparticles
Hattori¹⁴¹	• C5b-9 induces secretion of large von Willebrand factor (vWF) multimers from endothelial cells	C5-C9	C5b-9 stimulate endothelial cells to secrete prothrombotic, platelet adhesive vWF protein
Foreman¹⁴²	• C5a causes expression of endothelial P-selectin, secretion of von vWF and adhesiveness for neutrophils	C5	By promoting adhesive interactions between neutrophils and endothelial cells C5a induces acute inflammatory responses
Ritis¹⁴³	• C5a induces tissue factor (TF) expression on neutrophils associated with enhanced procoagulant activity	C5	Neutrophils may link complement activation to coagulation pathways; TF is not upregulated on monocytes in response to C5a alone¹⁴⁴
Gushiken¹⁴⁵	• C3 deficient mice: increased tail-bleeding time and decreased platelet aggregation in vivo or ex vivo, respectively.	C3 (and possibly* C5-C9)	C3 deficiency in mice leads to abnormal platelet function
Subramaniam¹⁴⁶ Asfarhar-Kharghan¹⁴⁷	• C3 deficient mice: prolongation of tail-bleeding parameters in vivo; and ex vivo decrease in platelet activation • C5 deficient mice: milder tail-bleeding phenotype (than C3^−/−), but no decrease in platelet activation ex vivo • C5-dependent membrane perturbations specifically lead to prothrombotic TF release	Mainly via C3 regarding platelets Via C5 regarding leukocytes	Suggests a prominent role for C3 and its activation products in platelet activation independent of TP activation. C5 activation acts procoagulantly by inducing TF release
Sauter¹⁴⁸	• Stimulation of the C3a- C3aR axis on platelets leads to prothrombotic activation • In C3aR^−/− (but not C5^−/−) mice time to vessel occlusion was significantly prolonged in a model in vivo	C3	A functional role for C3aR on platelets is proposed

“Possibly” is written when an involvement because of the known complement pathways is logical and likely could have occurred but was not formally tested or controlled for.

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