Analysis of Coagulation Cascade and Cell-Based Hemostasis Models

This report provides a comprehensive overview of hemostasis, the body's process of stopping blood loss. It begins by explaining the mechanism of hemostasis, which involves vascular spasm, platelet plug formation, and clot formation. The report then delves into two key models: the classic cascade model and the cell-based model. The classic cascade model describes blood clotting as a series of sequential steps, involving intrinsic and extrinsic pathways leading to fibrin formation. The cell-based model, in contrast, views coagulation as a process occurring on cell surfaces, encompassing initiation, amplification, and propagation phases. The report highlights the differences between the two models, discusses the value of each, and explores their relevance to laboratory testing and diagnosis of hemostasis disorders, including the roles of various factors and pathways. Ultimately, the report aims to compare and contrast these models to provide a clear understanding of the complex process of blood clotting.

Runninghead: COAGULATION CASCADE MODEL
COAGULATION CASCADE MODEL
Name of the student
Name of the university
Author Note

1
COAGULATION CASCADE MODEL
Table of Contents
Introduction:...............................................................................................................................3
Discussion:.................................................................................................................................4
Mechanism of Hemostasis:....................................................................................................4
Classic-Cascade Model..........................................................................................................4
The Cell-based model of blood clotting:................................................................................7
Differences between the classic cascade model and cell-based model:.................................8
Value of each model :............................................................................................................9
Which model is better:...........................................................................................................9
Relation of different models to lab testing and diagnosis:...................................................10
Conclusion:..............................................................................................................................10
References:...............................................................................................................................11

2
COAGULATION CASCADE MODEL
Introduction:
Hemostasis is a process of the body to stop bleeding from any cut or injury to heal a
wound. The primary phase of hemostasis is to convert blood from its liquid form into a gel-
like form. The name Hemostasis came from two Greek words, “heme,” that means blood, and
the word “stasis” means halting. The first reference of hemostasis is found in the Ancient
Greek time during the Battle of the Troy. The need for artificial hemostasis was
acknowledged in that battle, as a massive number of lives were lost due to loss of blood. The
advancement of Egyptian mummification practices enhanced the knowledge of hemostasis.
The developed study of human physiology made the physicians understand that the blood
flows through arteries and veins, which is present all over the body. Although, the first note
about the medical history of hemostasis is found in the fifteen century after printed media
invented. Hemostasis is a very important procedure to keep the blood inside the body flowing
and keep the physiological process of body ongoing. Hemostasis immediately stops the blood
loss inside the body in any kind of injury by its acting mechanism. The laboratory test of
hemostasis disorder (thrombotic and hemorrhagic disorder) is an integral part of most of the
medical treatment nowadays (Gresele et al. 2017). The tests includes fibrin clot formation,
platelet plug formation and fibrinolysis tests, which are the measures of blood clotting. This
report will discuss the mechanism of Hemostasis, different models of hemostasis, similarity,
and dissimilarity between the old classic and new cell-based models, value of the models and
importance of Hemostasis in laboratory testing including different laboratory tests done to
understand blood clotting according to different models (Palta, Saroa and Palta 2014).

3
COAGULATION CASCADE MODEL
Discussion:
Mechanism of Hemostasis:
The mechanism of blood clotting differs in different models. They are discussed as
follows.
Classic-Cascade Model:
The Mechanism of Hemostasis in the classic cascade model includes three major steps,
which take place one after another. The three steps are Vascular spasm or vasoconstriction,
Platelet plug formation, and clot formation (Potze 2014).
 The first step is the Vascular spasm or vasoconstriction. This is the first response by
the blood vessels to an injury. The injured endothelial cell releases signalling
molecules, activates the inactive blood platelets(Schiro et al. 2014). At the same time,
the nervous system starts to reflex with the help of local pain receptors. In normal
conditions, intact blood vessels prevent blood coagulation by expressing fibrinolytic
heparin and thrombulins. In injured condition, collagen comes in contact with the
wound and activate platelets to adhere in the wound. Platelets release granules of
cytoplasm, which includes serotonin, Adenosine diphosphate (ADP), and
thromboxaneA2. These compounds of cytoplasmic granules enhance the
vasoconstriction effect. The effect of vasoconstriction is higher in the case of small
blood vessels. The response of spasm is directly proportional to the amount of
damage. Vasoconstriction also changes the normal blood pressure of affected vessels
by increasing the blood pressure
 Platelet plug formation is the next step of the cascade. The active platelets adhered to
the injured endothelium to form a plug; this process is named primary hemostasis.
The next step is the degranulation of the platelets. The thromboregulation mechanism

4
COAGULATION CASCADE MODEL
controls the step of degranulation. Von Willebrand Factor (vWF), a glycoprotein,
activate the plug formation (Lenting et al. 2015). vWF is found in plasma. When the
platelets come in contact with the damaged endothelium, they start to change their
shape and the degranulation process to become sticky. The aggregation and attraction
between platelets occur by the interaction of a glycoprotein receptor expressed by the
platelet. Platelets release granules to help the aggregation and coagulation process in
the injured area. The granules secreted by platelets are adenosine diphosphate, or
ADP which helps more platelets to aggregate in the injured area, serotonin, which is a
vasoconstrictor, and thromboxane A2, which assisting molecule of platelets (Fritsma
2015).
 The third and final step of hemostasis is the clot formation. Blood clotting factors are
a cascade of twelve factors that are present in the blood in an inactive form. The
factors get activated in a series of events after the platelet plug formation. The cascade
of reaction is called “coagulation Cascade.” The last product form in the cascade of
reaction results to the formation of Fibrin from its inactive precursor fibrinogen
plasma protein (Tosenberger et al. 2016). A fibrin mess covers up the platelet plug
and keeps it in the place. This step is called secondary hemostasis. During the long
network of reaction, some amount of red and white blood cell is produced and takes
part in hardening the platelet plug. The final product of the cascade includes primary
hemostasis plug and blood cells altogether called “clot” or ‘thrombus.”(Posma et al.
2016).
The formation of fibrin in the coagulation cascade is done by two distinct pathways. The
two paths are Intrinsic pathway or contact activated pathway and the Extrinsic pathway or
tissue factor pathway. The importance of the tissue factor is more as it is the primary
coagulation pathway.

5
COAGULATION CASCADE MODEL
Tissue factor pathway:
The major function of the intrinsic pathway is to produce “thrombin burst.”This
thrombin burst is a procedure to release thrombin, an important constituent of blood
coagulation. FVII comes out in the circulation following damage, and in the bloodstream,
it comes in contact with tissue factor (TF), which are expressed in the tissue-factor –
bearing cells(Grover and Mackman 2018). TF-FVIIa factor then activates the FIX and FX
factors. Thrombin, FXIa, and FXII together activate FVII. TF and FVIIa complex
activates FX, but the TFPI or tissue factor pathway inhibitor inhibits the activation
procedure immediately. The prothrombinase complex is formed, which includes FXa and
FVa, the cofactor of FXa (Wood et al. 2014). The other components of the coagulation
cascade, which includes FV and FVII, get activated by the action of thrombin. The
activated factors then help the release of FVIII, which were attached to vWF. “Tenase
compound “is formed by the complex formation of FVIIIa and FIXa, a cofactor of FVIIIa
(Howard et al. 2015).
The intrinsic pathway or contact activation pathway:
This pathway starts with the formation of a primary complex of high-molecular-
weight kininogen or (HMWK), FXII or Hageman factor, and Prekallilkrein. This primary
complex forms in the collagen. Prekallikrein and FXII are then converted to Kallikrein
and FXIIa, respectively. The role of this intrinsic pathway is found to be minor in clot
formation. People with the Prekallikrein, HMWK and FXII deficiency do not show
bleeding disorders. The major role played by the pathway is in the case of inflammation
and innate immunity (Wu 2015).
The common pathway:

6
COAGULATION CASCADE MODEL
The final pathway states than the generation of prothrombin to thrombin happen only
after the action of the intrinsic or extrinsic pathway. This pathway is the oversimplified
version. Moreover, the thrombin generated by the activated platelets.
The Cell-based model of blood clotting:
This model states that the coagulation of blood occurs in the cell surface and includes
four steps that do not occur in sequences but overlap with each other (Ho and Pavey 2017).
 The first step is the initiation phase. This step occurs in cells, which express TF on the
surface, comes in contact with the blood components in the injury site. The TF
activates FVII and forms a complex of FVIIa/TF. These compound further activates
FIX and FX. FXa gets associated with FVa, which is a cofactor and forms a
prothrombinase complex, which then gets expressed in the surface of the cell, also
expressing TF. Fxa or nom-coagulating agents activate FV, which then releases FVa,
a necessary compound for the prothrombinase complex. Prothroombinase complex
then converts the prothrombin, also called Factor II to thrombin. The initial amount of
produced thrombin is very low, so it cannot take part in coagulation but plays a chief
role in the amplification phase. The small amount of thrombin is always present in the
cell as the chains of reaction never stop inside the cell, but the amplification step only
takes place in the case of vascular damage, when the linked molecule of von
Willebrand factor, FVII and platelets come in contact of each other.
 The next stage is the amplification phase. In a case of large vascular injury platelets,
FVIII and platelets can only pass through the extravascular compartment due to their
large size. Platelets leave the injured vessels and bind to the collagen as well as the
other compounds present in the extracellular matrix at the injured site(Bye et al.
2016). There they get activated partially and forms platelet plugs which are the chief

7
COAGULATION CASCADE MODEL
component of primary hemostasis. In this procedure, a minor amount of thrombin
produced by TF expressing cells. This small amount of thrombin can interact with the
FVIII/vWF complex. These begin the process, which leads to the reaction climax of
the formation of fibrin, and secondary hemostasis. Fibrin and secondary hemostasis
form the final plug of hemostasis (Monroe and Hoffman 2014)
 The major characteristic of the next step, which is called the propagation step is the
migration of huge amount of platelets in the site of injury. These step also includes the
production of tenase complex and prothrombinase, on the cell surface of activated
platelets. FIX activated in the initiation step binds to the FVIIIa of the surface of the
platelet to form a tenase complex. FIX also produce FXa. After a sufficient amount of
FXa produced, FXa associate to platelet bound cell to form prothrombinase complex.
This prothrombinase complex helps in the conversion of prothrombin to
thrombin(Colombini et al. 2014). Thrombin then cleaves fibrinogen to produce
fibrin., which polymerise to form a platelet plug.
 The main function of the next step, the Termination step is to limit the clotting of
blood cells in the site of injury. The spread of coagulation is inhibited by four natural
anti-coagulating agents, which are tissue factor inhibitor or TFPI, antithrombin or AT,
protein C or PC, and protein S or PS. TFPI form TF/FVIIa/FXa/TFPI inactivates the
activated factors to limit the coagulation process. PS and PC inactivate the pro-
coagulating cofactors, FVa and FVIIIa.
Differences between the classic cascade model and cell-based model:
The major difference of the cell-based model and cascade model is that the cell-based
model has an overlapping series of reactions, whereas the classic cascade model has a

8
COAGULATION CASCADE MODEL
sequence of reactions (Smith et al.2015). In a cell-based model, all the intermediate comes in
the scenario in a chain-like mechanism, which is not the case of the cascade model.
The cascade model was not challenged and accepted for a long time; still it has some
flaws which can be cleared by the new cell-based model. The cascade model is not a perfect
model to explain in vivo hemostasis. Many factors are needed in the cascade pathway like
HMWK and prekallikrein but do not show any serious disorder of coagulation if they are
absent (Moore, Knight. and Blann 2016). Whereas, factor X or factor IX deficiency causes
some serious disorders. The old classic model fails to answer the reason behind the different
consequences. The consistency of the cell-based model is with the aspect of clinical
observation of clotting disorder is higher than the old model as well as the new model gives a
better explanation of in vivo hemostasis.
Value of each model :
The classic cascade model is widely accepted and answers almost all the questions
related to hemostasis. Although the cell-based model well explains the in vivo hemostasis,
The cell-based model has a drawback, as it is not well investigated to improve the
understanding of the different steps.
Which model is better:
The new classic cascade model is accepted widely due to its clear explanation action
of all the steps. It is still relatable to modern days blood screening process. Whereas the new
cell-based model has a different approach towards the blood clotting system and fills the gaps
of the old model. The cell based model can be defined as a step forward but surely it can not
be stated as the better model due to lack of investigation and research.

9
COAGULATION CASCADE MODEL
Relation of different models to lab testing and diagnosis:
 The classic cascade screening includes a Global test, which includes testing blood
components that are part of the classical cascade pathway and their concentrations, to
know hypo-coagulation and hyper-coagulation. The specific global test includes
Thromboelastography, Thrombin generation test and Thrombodynamic tests(Hunt et
al. 2015). Another set of test known as Local tests is done to measure the work result
of different factors individually and in the cascade (Ong et al. 2018).
 The cell-based model implements the function of cellular structure in controlling and
directing the clotting process, and the lab tests include the screening of cellular
components.
Conclusion:
The study about hemostasis gives a vivid idea about the mechanism, different models,
flaws, advances and clinical application of the models. The history of hemostasis shows that
the importance of the process was well understood in ancient times and shows that modern
artificial hemostasis is a result of the research that has a root in the ancient time. The cascade
model of blood clotting has a complex mechanism, which includes a dozen of components.
The model has a drawback to present itself as an in vivo model. The new cell-based model
demands the pathway to be the result of some overlapping steps. The model is an advanced
step of the old model and explains many unanswered questions of the cascade model. The
cell-based model also explains in vivo hemostasis but more experiments and studies are
needed to done to support and establish the cell-based model.


10
COAGULATION CASCADE MODEL
References:
Bye, A.P., Unsworth, A.J. and Gibbins, J.M., 2016. Platelet signaling: a complex interplay
between inhibitory and activatory networks. Journal of Thrombosis and Haemostasis, 14(5),
pp.918-930.
Colombini, A., Ceriani, C., Banfi, G., Brayda-Bruno, M. and Moretti, M., 2014. Fibrin in
intervertebral disc tissue engineering. Tissue Engineering Part B: Reviews, 20(6), pp.713-
721.
Fritsma, G.A., 2015. Platelet structure and function. Clinical laboratory science, 28(2),
p.125.
Gresele, P., Kleiman, N.S., Lopez, J.A. and Page, C.P. eds., 2017. Platelets in Thrombotic
and Non-Thrombotic Disorders: Pathophysiology, Pharmacology and Therapeutics: an
Update. Springer.
Grover, S.P. and Mackman, N., 2018. Tissue factor: an essential mediator of hemostasis and
trigger of thrombosis. Arteriosclerosis, thrombosis, and vascular biology, 38(4), pp.709-725.
Ho, K.M. and Pavey, W., 2017. Applying the cell-based coagulation model in the
management of critical bleeding. Anaesthesia and intensive care, 45(2), pp.166-176.
Howard, B.M., Miyazawa, B.Y., Dong, W., Cedron, W.J., Vilardi, R.F., Ruf, W. and Cohen,
M.J., 2015. The tissue factor pathway mediates both activation of coagulation and
coagulopathy after injury. The journal of trauma and acute care surgery, 79(6), p.1009.
Hunt, H., Stanworth, S., Curry, N., Woolley, T., Cooper, C., Ukoumunne, O., Zhelev, Z. and
Hyde, C., 2015. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM)

11
COAGULATION CASCADE MODEL
for trauma-induced coagulopathy in adult trauma patients with bleeding. Cochrane Database
of Systematic Reviews, (2).
Lenting, P.J., Christophe, O.D. and Denis, C.V., 2015. von Willebrand factor biosynthesis,
secretion, and clearance: connecting the far ends. Blood, The Journal of the American Society
of Hematology, 125(13), pp.2019-2028.
Monroe, D.M. and Hoffman, M., 2014. Theories of blood coagulation: basic concepts and
recent updates. Hemostasis and Thrombosis, p.1.
Moore, G., Knight, G. and Blann, A.D., 2016. Haematology. Oxford University Press.
Ong, C.C., Gopinath, S.C., Rebecca, L.W.X., Perumal, V., Lakshmipriya, T. and Saheed,
M.S.M., 2018. Diagnosing human blood clotting deficiency. International journal of
biological macromolecules, 116, pp.765-773.
Palta, S., Saroa, R. and Palta, A., 2014. Overview of the coagulation system. Indian journal
of anaesthesia, 58(5), p.515.
Posma, J.J.N., Posthuma, J.J. and Spronk, H.M.H., 2016. Coagulation and non‐coagulation
effects of thrombin. Journal of thrombosis and haemostasis, 14(10), pp.1908-1916.
Potze, W., 2014. Hemostasis and anticoagulant therapy in liver diseases. PLoS One, 9(2),
p.e88390.
Schiro, A., Wilkinson, F.L., Weston, R., Smyth, J.V., Serracino-Inglott, F. and Alexander,
M.Y., 2014. Endothelial microparticles as conveyors of information in atherosclerotic
disease. Atherosclerosis, 234(2), pp.295-302.
Smith, S.A., Travers, R.J. and Morrissey, J.H., 2015. How it all starts: Initiation of the
clotting cascade. Critical reviews in biochemistry and molecular biology, 50(4), pp.326-336.

12
COAGULATION CASCADE MODEL
Tosenberger, A., Ataullakhanov, F., Bessonov, N., Panteleev, M., Tokarev, A. and Volpert,
V., 2016. Modelling of platelet–fibrin clot formation in flow with a DPD–PDE
method. Journal of mathematical biology, 72(3), pp.649-681.
Wood, J.P., Ellery, P.E., Maroney, S.A. and Mast, A.E., 2014. Biology of tissue factor
pathway inhibitor. Blood, The Journal of the American Society of Hematology, 123(19),
pp.2934-2943.
Wu, Y., 2015. Contact pathway of coagulation and inflammation. Thrombosis journal, 13(1),
p.17.

13
COAGULATION CASCADE MODEL