Dear Sebastian

I hope I have understood your question properly. Are you asking whether you have drawn the platelet plug correctly? I understand what you are trying to describe but there is a small mistake in the depiction. You have drawn it as though the platelet plug is within the subendothelial matrix. It usually happens along the damaged endothelial cells within the vascular lumen rather than deep in the subendothelial matrix. Would you agree with that?

I do.

This leaves me with a specific question for the situation with the red circle around it.

If you would be so kind, are you able to indicate whether the following statements are correct or incorrect when applied to the aforementioned state with red circle: 

• This is an unstable platelet plug. 
• No fibrin nor Factor VIII was involved in its creation.
• Fibrinogen is not the same molecule as fibrin.

It would be greatly appreciated.

The three statements are correct but the third one doesn't relate to the middle picture (because fibrinogen is not involved there). The third statement is relevant to the third picture though. You can even extend it 'Fibrinogen is not the same molecule as fibrin. Fibrinogen is the precursor molecule of fibrin'

I hope that is of help. Good luck.

Thank you so much dr. Sivakumaran. Your help is much appreciated. For validating purposes the following questions are to be answered preferentially by someone with a high degree of expertise.

The first question is a truism but needed to convince an ignorant haematologist: Is there an additional expert who is able to confirm that the pre-cursor fibrinogen is not the same molecule as fibrin?

Secondly, is there an expert able to confirm that a young, unstable platelet plug does not contain fibrin but fibrinogen? I.e. able to confirm that up until this point fibrin did not play a role in the formation of this young, unstable platelet plug?

Dear Sebastian

Fibrinogen is a very large protein. It is cleaved by thrombin to generate fibrin. (basically a chopped up fibrinogen molecule). Fibrin when it is formed is a monomer. It polymerises to form the strong fibrin clot. I have attached some pictures that will help you to understand

Your second question is interesting. I would suggest you put this as a new question. If you don't get any answer, I will direct you to right people.

Good luck

Dear Dr van Jole:

1-Primary Haemostasis

It is the set of events that leads to platelet plug formation, first step in stopping the bleeding, preventing release of cellular components of blood. During this phase involves two mechanisms: a vascular and other platelet.

• a) vascular spasm. Immediately to the production vessel rupture way, a powerful contraction of muscle fibers of the same occurs. The result is a decreasing vasoconstriction vessel diameter, and even if it is small can reach close, reducing blood loss.

• b) Formation of platelet plug. In the formation of the platelet plug can distinguish the following steps:

1. Accession or platelet adhesion.

2. secretion and platelet aggregation.

1-Accession or platelet adhesion

After the rupture of the vascular endothelium platelets adhere to subendothelial structures, mainly collagen fibers that arise by broken surface will contact and platelets. In this process platelets lose their discoid shape, becoming spherical and emitting spikes through which adhere to surrounding tissue. In the process of joining various platelet membrane glycoproteins are required, the plasma von Willebrand factor and subendothelial collagen and basement membrane. This process lasts very little, about 2-3 seconds.

Normally, the endothelium functions as an inert surface for hemostatic factors that circulate within the vessel. Any change in the endothelial wall, can lead to activation of coagulation and their regulatory systems. Vascular injury can occur directly or indirectly. Initially, when the vascular endothelium is damaged, it responds with a local vasoconstriction induced by platelet released serotonin. The exposure of the underlying collagen fibers subendotelio attract the circulating platelets adhere to collagen trying to close the endothelial defect and experiencing significant metabolic changes that promote continuity of hemostasis.

2-secretion and platelet aggregation

It is called the aggregation process by which platelets are fixed to each other. This process requires Ca ++ and ADP to be released from platelet granules by a process called platelet activation or secretion.

Platelets undergo a profound structural transformation. Membranes dense granules bind with the plasma membrane, releasing their contents to the outside and α granules release their contents. The released substances have very different types of biological activity:

• Stimulate changes estrucuturales own platelets.

• Increase in platelet adhesion and platelet granule secretion more.

• Increase the recruitment and activation of additional platelets.

• favor the aggregation and coagulation.

• Platelets possess on its surface adhesion molecules belonging to integrin family, which serve as receptors for various substances involved in platelet adhesion and aggregation, such as von Willebrand factor (vWF) and fibrinogen (FIB). Either by their adhesion to collagen, in contact with thrombin (TB), or by the action of platelet activating factor (PAF) produced by monocytes / macrophages (MON / MF) and polymorphonuclear (PMN); platelet activating your metabolism producing ADP, serotonin and Ca ++ dense granules, and other pro and anticoagulant substance of their alpha granules. Alongside the path of Phospholipase A2 (FA2) which releases arachidonic acid (ACA) is activated. This AcA, is metabolized by cyclooxygenase resulting in a series of cyclic endoperoxides that form in the endothelium Prostacyclin (PGI) of antiplatelet effect; and platelets by the action of thromboxane synthetase will result in thromboxane A2 (TXA2), potent platelet aggregating local and vasoconstrictor. AcA share equally the lipoxygenase metabolites produced family of leukotrienes, which are activators of PMN and MF .In this activation process, platelets change their discoid shape to a spherical structure with internal extension and contraction pseudopodia his cotráctil actin-myosin system, after the release of Ca ++ and generation of prostaglandins (PG). Thus they served on platelet thrombus.

That is, stimulated platelets in their adherence to subendotelio, TB and PAF, free Ca ++ activates the system actin-myosin coupling. TXA 2 mobilizes and involves other circulating platelets; and these reactions release the contents of dense granules - secreción- initiating similar phenomena in the surrounding chain platelets. Later receivers exposed for FIB and platelet aggregation begin to form the thrombus. This primary plug must be stabilized by fibrin deposition, final product of the coagulation cascades that form the plasma phase

This discharge produces more changes in platelets adhered and attracts other platelets, gradually adding to leave. Platelets are held together by bridges link between their membranes and subendothelial tissue. Thus a barrier is established, yet permeable for the free spaces left between platelets, but forming an initial line of defense, platelet plug or thrombus blank for the subsequent performance of the process of coagulation.

3 - Secondary haemostasis or coagulation

It is a process that modifies the liquid state of the blood giving it a gel structure type. It is the transformation of a soluble protein, fibrinogen, into an insoluble protein: fibrin; forming a mesh or net enclosing formed elements (clot), thereby strengthening the bond between platelets in order to permanently prevent bleeding.

Schematically it can be represented as an enzymatic cascade by and plasma proteins.

It has several phases:

1. Formation of prothrombinase or prothrombin activator.

2. Formation of thrombin.

3. Formation of fibrin.

This plasma coagulation phase begins with the activation of the contact system factors: Factor XII (FXII), XI (FXI), IX (FIX). Prekallikrein (PK) and high molecular weight kininogen (HMWK), the latter resulting kallikrein (KK) and kinin (K) respectively. All of these factors are the intrinsic coagulation pathway, because its components are in the plasma. The extrinsic pathway begins with the expression of tissue factor (TF) which activates factor VII (FVII). Both routes lead to the common pathway with activation of factor X (FX) in the presence of Factor V and prothrombin transform Ca ++ (PTB) in TB, and this in turn IFF fibrin monomers and fibrinopeptide A and B. the factor XIII (FXIII), activated TB and FXII, stabilizes the soluble fibrin monomers in polymers and insoluble stable serine protease coagulation are activated with the help of cofactors - FV, Ca ++ and factor VIII by both tract, for cascade mechanism whose final product is the fibrin network, which together with platelets form the final haemostatic .Paralelamente to serine protease members coagulation pathways, a series of inhibitory proteins coagulation try to maintain a stable equilibrium, the final product is the blood flow and maintaining circulation. Thus, for the extrinsic pathway inhibitor of tissue factor (ftpi) produced in the endothelium, that seek to regulate this pathway is known. Endothelium also produce thrombomodulin (TRM), responsible for modulating the action of TB, which activates protein C (PC) which together with its cofactor Protein S (PS), exert anticoagulant and fibrinolytic action. Also described is an endothelial inhibitor PC (IPC) that regulate this anticoagulant mechanism.

3-1 prothrombinase Formation

You can follow two paths:

• extrinsic extravascular or exogenous pathway (see diagrams of the presentation in supplementary material).

• Intrinsic, intravascular or endogenous pathway (see diagrams of the presentation supplemental material).

The two-way match for activating the X factor from this point form the final common pathway. This factor along with platelet factor 3, calcium and factor V form an enzyme complex called prothrombinase and prothrombin activator.

3-2 Formation of thrombin

It is performed in a single reaction of prothrombin (Factor II).

3-3 in blood is present an inactive protein, Factor I or fibrinogen.

Thrombin catalyzes the splitting of this molecule to form fibrin monomers, soluble and unstable in the presence of Ca ++ and Factor XIII are polymerized activated; forming an insoluble polymer in the form of three-dimensional mesh network or closes the spaces between the platelets and seals definitively the platelet plug, resulting in the red thrombus or clot

Words cannot express my gratitude for the time, energy, and attention that I received after asking this question. Still: Thank you - you have allowed me to develop a deeper and more meaningful understanding of the coagulation process than I could have achieved without your generous help.