Physiology, Hemostasis


Article Author:
Heeransh Dave


Article Editor:
Andrew LaPelusa


Editors In Chief:
Casey Ciresi


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
8/1/2019 11:53:56 PM

Introduction

Definition. Hemostasis is the mechanism that leads to cessation of bleeding from a blood vessel. It is a process that involves multiple interlinked steps. This cascade culminates into the formation of a “plug” that closes up the damaged site of the blood vessel controlling the bleeding. It begins with trauma to the lining of the blood vessel.

Stages. The mechanism of hemostasis can divide into four stages. 1) Constriction of the blood vessel. 2) Formation of a temporary “platelet plug." 3) Activation of the coagulation cascade. 4) Formation of “fibrin plug” or the final clot.

Purpose. Hemostasis facilitates a series of enzymatic activations that lead to the formation of a clot with platelets and fibrin polymer.[1] This clot seals the injured area, controls and prevents further bleeding while the tissue regeneration process takes place. Once the injury starts to heal, the plug slowly remodels, and it dissolves with the restoration of normal tissue at the site of the damage.[1]

Issues of Concern

Hyper-coagulation. The hemostatic cascade is meant to control hemorrhage and be a protective mechanism. At times, this process is triggered inadvertently while the blood is within the lumen of the blood vessel and without any bleeding.[1] This situation leads to a pathologic phenomenon of thrombosis, which can have catastrophic complications by obstructing blood flow leading to ischemia and even infarction of the tissues supplied by the occluded blood vessels. In this way, a physiologic process becomes a pathologic process leading to morbidity and/or mortality. Some of the examples include Antiphospholipid antibody syndrome, Factor 5 Leiden mutation, Protein C deficiency, protein S deficiency, Prothrombin gene mutation, etc.

Hypo-coagulation. When there is any defect in the functionality of any component of this hemostatic cascade, it can lead to ineffective hemostasis and inability to control hemorrhage; this can lead to severe blood loss, hemorrhage and also complications that can hence ensue due to the inhibited blood supply to vital organs. Some of the examples include Von Willebrand disease, hemophilia, disseminated intravascular coagulation, deficiency of the clotting factors, platelet disorders, collagen vascular disorders, etc.

Iatrogenic Coagulopathy. Medicine is currently in the era of widespread use of antiplatelet agents like aspirin, clopidogrel, ticagrelor and anticoagulants like warfarin, heparin, low molecular weight heparin, rivaroxaban, apixaban, dabigatran, fondaparinux amongst others for various commonly encountered clinical conditions like cardiac stenting/ percutaneous coronary intervention, atrial fibrillation, deep venous thrombosis, pulmonary embolism, and many more. The way these medications affect the functionality of the various components of clotting cascade can help patients with their clinical conditions. However, it can lead to bleeding/thrombosis in cases of inappropriate dosage, non-compliance, medication interactions, and result in significant morbidity and mortality. 

Cellular

There are various cellular components in the process of coagulation. Most notably are those processes associated with the endothelium, platelets, and hepatocytes.

Endothelium. Clotting factors III and VIII originate from the endothelial cells while the clotting factor IV comes from the plasma.[2][3] Factor III, IV, and VIII all undergo K dependent gamma-carboxylation of their glutamic acid residues, which allows for binding with calcium and other ions while in the coagulation pathway.[4]

Platelets. These are non-nucleated disc-like cells created from megakaryocytes that arise from the bone marrow. They are about 2 to 3 microns in size. Some of their unique structural elements include plasma membrane, open canalicular system, spectrin and actin cytoskeleton, microtubules, mitochondria, lysosomes, granules, and peroxisomes.[5] These cells release proteins involved in clotting and platelet aggregation.

Hepatocytes. The liver produces the majority of the proteins that function as clotting factors and as anticoagulants.

Development

Embryology. The development of the coagulation system begins in the fetus. The various clotting factors and the coagulation proteins initially get expressed in the endothelial cells during early gestation. They usually are undetectable in the plasma until after the first trimester. There is a transient gap in the development and maturation of the hemostatic proteins from the early second trimester until term due to some unclear mechanisms. Due to the similar structure and functionality of the hemostatic coagulative proteins in the fetus and the similarity in the platelet expression, there is a rarity in the occurrence of any thrombotic/hemorrhagic complications in the healthy fetus unless there is any form of uteroplacental insufficiency due to any maternal or fetal factors.[6]

Organ Systems Involved

The physiology of hemostasis involves the:

  • Vasculature
  • Liver
  • Bone marrow

All of these systems help with the production of the clotting factors, vitamins, and cells for appropriate functionality of hemostasis.

Function

Hemodynamic Stability. Under normal circumstances, there exists a fine balance between the procoagulant and anticoagulant pathway. This mechanism ensures control of hemorrhage as needed and cessation of pro-coagulant pathway activation beyond the injury site/or without any bleeding. When this equilibrium becomes compromised under any condition, this may lead to thrombotic/bleeding complications.[4] The hemostatic system also helps in wound healing.

Cardiovascular System. PGA1 and PGA2 cause peripheral arteriolar dilation. Prostacyclin produces vasodilation, and thromboxane A2 causes vasoconstriction. Prostacyclin inhibits platelet aggregation and produces vasodilation whereas thromboxane A2 and endoperoxides promote platelet aggregation and cause vasoconstriction. The balance between the prostacyclin and thrombox­ane A2 determines the degree of platelet plug forma­tion. Thus, prostaglandins greatly influence temporary hemostasis. 

Mechanism

Vaso Constriction. Within about 30 minutes of damage/trauma to the blood vessels, vascular spasm ensues, which leads to vasoconstriction. At the site of the disrupted endothelial lining, the extracellular matrix (ECM)/ collagen becomes exposed to the blood components.[7]

Platelet Adhesion. This ECM releases cytokines and inflammatory markers that lead to adhesion of the platelets and their aggregation at that site which leads to the formation of a platelet plug and sealing of the defect. The platelet adhesion is a complex process mediated by interactions between various receptors and proteins including tyrosine kinase receptors, glycoprotein receptors, other G-protein receptors as well as the von Willebrand Factor (vWF). The von Willebrand Factor functions via binding to the Gp 1b-9 within the platelets.[7]

Platelet Activation. The platelets that have adhered undergo very specific changes. They release their cytoplasmic granules that include ADP, thromboxane A2, serotonin, and multiple other activation factors. They also undergo a transformation of their shape into a pseudopodal shape which in-turn leads to release reactions of various chemokines. P2Y1 receptors help in the conformational changes in platelets.[7]

Platelet Aggregation. With the mechanisms mentioned above, various platelets are activated, adhered to each other and the damaged endothelial surface leading to the formation of a primary platelet plug.

Extrinsic Pathway. The tissue factor binds to factor VII and activates it. The activated factor VII (factor VIIa) further activates factor X and factor IX via proteolysis. Activated factor IX (factor IXa) binds with its cofactor – activated factor VIII (factor VIIIa), which leads to the activation of factor X (factor Xa). Factor Xa binds to activated factor V (factor Va) and calcium and generates a prothrombinase complex that cleaves the prothrombin into thrombin.[4]

Intrinsic Pathway. With thrombin production, there occurs conversion of factor XI to activated factor XI (factor XIa). Factor XIa with activated factor VII and tissue factor converts factor IX to activated factor IX (factor IXa). The activated factor IX combines with activated factor VIII (factor VIIIa) and activates factor X. Activated factor X (factor Xa) binds with activated factor V (factor Va) and converts prothrombin to thrombin. Thrombin acts as a cofactor and catalysis and enhances the bioactivity of many of the aforementioned proteolytic pathways.[4]

Fibrin Clot Formation. The final steps in the coagulation cascade involve the conversion of fibrinogen to fibrin monomers which polymerizes and forms fibrin polymer mesh and result in a cross-linked fibrin clot.  This reaction is catalyzed by activated factor XIII (factor XIIIa) that stimulates the lysine and the glutamic acid side chains causing cross-linking of the fibrin molecules and formation of a stabilized clot.

Clot Resolution (Tertiary Hemostasis). Activated platelets contract their internal actin and myosin fibrils in their cytoskeleton, which leads to shrinkage of the clot volume. Plasminogen then activates to plasmin, which promotes lysis of the fibrin clot; this restores the flow of blood in the damaged/obstructed blood vessels.[4]

Related Testing

Indications. The assessment of platelet function as well as its dysfunction has become vital in the current era in multiple clinical scenarios; several examples are:

  • For patients with clotting or bleeding disorders
  • For patients after cardiac stenting or stroke to monitor the activity of the antiplatelet agents
  • For perioperative evaluation.

Platelet Specific. Various tests have undergone development for platelet testing; they include[8][9]:

  • Bleeding time (BT)
  • Light transmission platelet aggregation
  • Impedance platelet aggregation
  • Global thrombosis test
  • PFA-100/200
  • VerifyNow system
  • Thromboelastography (TEG)
  • Flow cytometric analysis of platelet function

Coagulation Cascade Specific. There has been the development of various tests that evaluate specific events in the coagulation cascade.

  • They help in the determination of where the deficiency exists in the intrinsic, extrinsic, or the final common pathways as well as identification of qualitative or quantitative defects of the specific clotting factors.
  • Prothrombin time, developed in 1935, assesses the extrinsic and common coagulation cascade function.
  • Activated partial thromboplastin time assesses the intrinsic and the common pathways of coagulation. 
  • Thrombin time evaluates the formation of fibrin in the final common pathway of coagulation.
  • The reptilase time and the various fibrinogen assays assess the fibrin formation step.
  • Mixing studies, factor activity assays, and factor inhibitor assays are special tests for further evaluation of the presence of inhibitors or antibodies as well as deficiency of factors. 

Pathophysiology

General Principle. The Virchow’s triad of hypercoagulability, vascular stasis, and vascular trauma, described in 1856, remains a true predictor of thrombosis.

  • Hypercoagulability
  • Stasis
  • Trauma

Etiologies. The physiology of coagulation undergoes alteration due to various factors, including:

  • Genetics
  • Medications
  • Procoagulant
  • Anticoagulation defects of the coagulation cascade
  • Quantitative defects of the integral components of the coagulation
  • Qualitative defects of the integral components of coagulation.

Clinical Presentations. With the altering of hemostatic physiology, various clinical outcomes including:

  • Pulmonary embolism
  • Deep vein thrombosis
  • Stroke
  • Myocardial infarction

Coagulopathies. Few of the disorders of coagulation include:

  • Anti-thrombin 3 deficiency,
  • Protein C deficiency,
  • Hyperhomocysteinemia,
  • Anti-phospholipid antibody syndrome

Risk Factors. Some acquired factors influencing the coagulation include[10]:

  • Pregnancy
  • Trauma
  • Malignancy-related hypercoagulable state
  • Hormone replacement therapy
  • Inflammation
  • Infection
  • Heparin-induced thrombocytopenia

Clinical Significance

As discussed above, there are various hypercoagulable and hypercoagulable conditions resulting from defects in the coagulation pathways. The full extent is beyond the scope of this topic. Here are several examples:

  • Cardiovascular. There has been increased incidence of bleeding while on antiplatelet agents and anticoagulant agents for recent myocardial infarction, stroke, cardiac stents, peripheral vascular stenting, atrial fibrillation, pulmonary embolism, deep venous thrombosis as well as many other conditions; this has led to the development and use of reversal agents.
  • Renal. Pathological conditions like end-stage renal disease can lead to uremic platelet dysfunction which can be corrected with dialysis and renal replacement therapy.
  • Immunological. Replenishing the deficient clotting factors, removing the antibodies against the clotting factors, use of medications to enhance or ameliorate functionality of the clotting cascade- these newer developments have led to significant advances in the field of medicine and provided treatment options for various challenging to manage clinical scenarios. Transfusion of blood products such as packed red blood cells, platelets, and clotting factors aid further in management. Prothrombin complex concentrate and other formulations are available to replace the deficient clotting factors.
  • Pharmacological. Prudent use of the antiplatelet agents such as aspirin, clopidogrel, prasugrel, ticagrelor as well as the anticoagulant agents such as unfractionated heparin, low molecular weight heparin, fondaparinux, warfarin, rivaroxaban, apixaban, dabigatran, argatroban, lepirudin, as well as use of vitamin K, transfusion of blood products and specific modalities like hemodialysis, plasmapheresis and others are recommended as indicated for the management of various hemostatic disorders and can enhance patient care and improve clinical endpoints significantly. 

Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Physiology, Hemostasis - Questions

Take a quiz of the questions on this article.

Take Quiz
A 65-year-old male with a history of diabetes mellitus, hypertension, end-stage renal disease on hemodialysis, and ischemic stroke presents with prolonged bleeding from the skin after an accidental fall. His vitals are stable. On physical examination, he is found to have large bruises on his feet and a petechial skin rash. He does not have transportation assistance and unfortunately misses dialysis multiple times. What is the most likely cause of his prolonged bleeding after minor trauma?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 65-year-old female presents with bleeding from her gums after a prolonged hospital stay for hospital-acquired pneumonia. Her medical history includes diabetes mellitus type 2 and cardiovascular accident. What test can be done to determine if the cause of her bleeding is a deficiency of clotting factors or the presence of inhibitors or antibodies?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 17-year-old soccer player sustains an abrasion on his knee while playing. There is a significant amount of bruising and some bleeding on the skin surface. He is taken to the emergency department where, after an initial evaluation, it is determined that he does not have any fractures or ligament injury. The skin wound is cleaned and dressed and he is sent home. A clot is formed in the area. Over the next few weeks, the clot disappears and the wound is replaced by normal skin. What is the name of this last stage of hemostasis which leads to the dissolution of the clot?

(Move Mouse on Image to Enlarge)
  • Image 3968 Not availableImage 3968 Not available
    Contributed by Wikimedia Commons,"Medical gallery of Mikael Häggström 2014" (Public Domain)
Attributed To: Contributed by Wikimedia Commons,"Medical gallery of Mikael Häggström 2014" (Public Domain)



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 65-year-old male is brought to the emergency department with right-sided weakness and seizures. CT scan of the brain reveals a hemorrhagic stroke. Emergent neurosurgical consultation and critical care consultation is called. The patient has a history of atrial fibrillation and is taking warfarin on a daily basis. Which of the following clotting factors are affected by the action of warfarin on vitamin K metabolism?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 17-year-old male has a history of excessive bleeding with minor trauma. He quit playing soccer due to multiple episodes of hemarthrosis from minor falls that resulted in arthritis. Name the clotting factor that originates in the subendothelial cells and participates in the intrinsic pathway of the clotting cascade?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Physiology, Hemostasis - References

References

Smith SA,Travers RJ,Morrissey JH, How it all starts: Initiation of the clotting cascade. Critical reviews in biochemistry and molecular biology. 2015;     [PubMed]
Thon JN,Italiano JE, Platelets: production, morphology and ultrastructure. Handbook of experimental pharmacology. 2012;     [PubMed]
Palta S,Saroa R,Palta A, Overview of the coagulation system. Indian journal of anaesthesia. 2014 Sep;     [PubMed]
Holthenrich A,Gerke V, Regulation of von-Willebrand Factor Secretion from Endothelial Cells by the Annexin A2-S100A10 Complex. International journal of molecular sciences. 2018 Jun 13;     [PubMed]
Swieringa F,Spronk HMH,Heemskerk JWM,van der Meijden PEJ, Integrating platelet and coagulation activation in fibrin clot formation. Research and practice in thrombosis and haemostasis. 2018 Jul;     [PubMed]
Periayah MH,Halim AS,Mat Saad AZ, Mechanism Action of Platelets and Crucial Blood Coagulation Pathways in Hemostasis. International journal of hematology-oncology and stem cell research. 2017 Oct 1;     [PubMed]
Paniccia R,Priora R,Liotta AA,Abbate R, Platelet function tests: a comparative review. Vascular health and risk management. 2015;     [PubMed]
Senst B,Tadi P,Basit H,Jan A, Hypercoagulability 2019 Jan;     [PubMed]
Manco-Johnson MJ, Development of hemostasis in the fetus. Thrombosis research. 2005 Feb;     [PubMed]
Lordkipanidzé M,So D,Tanguay JF, Platelet function testing as a biomarker for efficacy of antiplatelet drugs. Biomarkers in medicine. 2016 Aug     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Nurse-Corrections (CCN). The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Nurse-Corrections (CCN), it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Nurse-Corrections (CCN), you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Nurse-Corrections (CCN). When it is time for the Nurse-Corrections (CCN) board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Nurse-Corrections (CCN).