Hemostasis – Causes, Symptoms, Diagnosis, Treatment

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Hemostasis is the mechanism that leads to the cessation of bleeding from a blood vessel hemostasis is the process that stops blood loss from a damaged vessel. Blood clotting is achieved by a cascade of enzymatic reactions, which involves a series of factors. Among them are the zymogens prekallikrein, prothrombin, factors VII, IX, X, XI, and XII, which are converted to active proteases by hydrolysis. 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.

Hemostasis or hemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, blood changing from a liquid to a gel. Intact blood vessels are central to moderating blood’s tendency to form clots. The endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin and prevent platelet aggregation with nitric oxide and prostacyclin. When the endothelial injury occurs, the endothelial cells stop the secretion of coagulation and aggregation inhibitors and instead secrete the von Willebrand factor, which initiates the maintenance of hemostasis after injury.

Hemostasis has three major steps:

  • 1) vasoconstriction,
  • 2) temporary blockage of a break by a platelet plug, and
  • 3) blood coagulation or formation of a fibrin clot. These processes seal the hole until tissues are repaired.

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.

Types of Hemostasis

Some main types of hemostasis used in emergency medicine include:

  • Chemical/topical– This is a topical agent often used in surgery settings to stop bleeding. Microfibrillar collagen is the most popular choice among surgeons [recent source?] because it attracts the patient’s natural platelets and starts the blood clotting process when it comes in contact with the platelets. This topical agent requires the normal hemostatic pathway to be properly functional.[9]
  • Direct pressure or pressure dressing– This type of hemostasis approach is most commonly used in situations where proper medical attention is not available. Putting pressure and/or dressing to a bleeding wound slows the process of blood loss, allowing for more time to get to an emergency medical setting. Soldiers use this skill during combat when someone has been injured because this process allows for blood loss to be decreased, giving the system time to start coagulation.[10]
  • Sutures and ties– Sutures are often used to close an open wound, allowing for the injured area to stay free of pathogens and other unwanted debris to enter the site; however, it is also essential to the process of hemostasis. Sutures and ties allow for skin to be joined back together allowing for platelets to start the process of hemostasis at a quicker pace. Using sutures results in a quicker recovery period because the surface area of the wound has been decreased.[rx]
  • Physical agents (gelatin sponge)– Gelatin sponges have been indicated as great hemostatic devices. Once applied to a bleeding area, a gelatin sponge quickly stops or reduces the amount of bleeding present. These physical agents are mostly used in surgical settings as well as after-surgery treatments. These sponges absorb blood, allow for coagulation to occur faster, and give off chemical responses that decrease the time it takes for the hemostasis pathway to start.[rx]

Causes of Hemostasis

  • 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. 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 the 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.
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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. 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.
  • 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. 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.

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 the appropriate functionality of hemostasis.

Functions of Hemostasis

  • Hemodynamic Stability – Under normal circumstances, there exists a fine balance between the procoagulant and anticoagulant pathways. 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. 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, an avascular 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.
  • 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. 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.
  • 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.
  • 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 VIIa), 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 a thrombin.
  • 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 VIIa) 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.
  • 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.
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Commonly used tests to detect toxic effects on blood and bone marrow in clinical and preclinical toxicology

Name of test Usefulness Comments
Complete blood count (CBC): PCV, MCV, MCHC, WBC count, Differential leukocyte count, platelet count Routine blood analysis for screening effect of toxic chemicals Modern blood analyzers report these erythrocyte indices as part of a full blood count, and manual evaluation may be necessary to confirm findings and detect unusual red cell abnormalities
Hemolysis testing (e.g. osmotic fragility test and Heinz bodies) To confirm if hemolysis is responsible for lowered red blood cell count Look for Heinz bodies, methemoglobinemia, and eccentrocytes to detect oxidant-induced changes
Hemostatic tests (e.g. platelet numbers, PT, PTT, ACT, bleeding time) To detect abnormalities of coagulation in the extrinsic (PT) and intrinsic (PTT, ACT) pathways and platelet function (bleeding time) Special tests like D-dimer assay, antithrombin, platelet function tests, and individual factor assays are available in some commercial research laboratories
Special blood tests Reticulocyte count, Coombs, Platelet associated immunoglobulin G (PAIgG) These tests are based on the routine CBC bindings and are considered “problem-driven” tests Reticulocyte evaluation will determine bone marrow response to anemia; Coombs and PAIgG tests determine the immune-mediated component in anemia and thrombocytopenia
Bone marrow cytology (evaluate myeloid: erythroid ratio) Confirm blood findings and to evaluate marrow function This is an elaborate and time-consuming procedure. Cytochemical staining can be performed to differentiate abnormal cells in cases of leukemia
In vitro stem cell assays using clonogenic (CFU-E, CFU-GM, CFU-GEMM) assays Possible to examine effects on the myeloid, erythroid and megakaryocytic lineages in a fashion where the concentration of the chemical and duration of exposure are tightly controlled In vitro, clonogenic assays have proven useful in understanding mechanisms of toxicity and in formulating strategies for treatment

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:

  • 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.

General Principle. 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:

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

Pharmaceutical agents currently used to treat hemostatic disorders

Drug Trade name Targeted molecule/system Clinical use
acetylsalicylic acid Aspirin cyclo-oxygenase, TXA2 synthesis block platelet aggregation, arterial thrombosis
clopidogrel Plavix ADP receptor P2Y12 block platelet activation, arterial thrombosis
prasugrel Effient ADP receptor P2Y12 block platelet activation, arterial thrombosis
abciximab ReoPro integrin αIIbβ3 block platelet aggregation, arterial thrombosis
eptifibatide Integrilin integrin αIIbβ3 block platelet aggregation, arterial thrombosis
tirofiban Aggrastat integrin αIIbβ3 block platelet aggregation, arterial thrombosis
dipyridamole Persantine adenosine reuptake block platelet activation, arterial thrombosis
unfractionated heparin Heparin thrombin, factor Xa blocks coagulation, venous thrombosis
low molecular weight heparin several names, e.g. Lovenox factor Xa blocks coagulation, venous thrombosis
fondaparinux Arixtra factor Xa blocks coagulation, venous thrombosis
rivaroxaban Xarelto factor Xa blocks coagulation, venous thrombosis
argatroban Argatroban thrombin prevent thrombosis during percutaneous coronary intervention (PCI)
dabigatran Pradaxa thrombin prevent thrombosis during/after joint surgery
bivalirudin Angiomax thrombin prevent thrombosis during PCI
lepirudin Refludan thrombin prevent thrombosis in patients with heparin- induced thrombocytopenia
desirudin Iprivask thrombin venous thrombosis during/after joint surgery
coumarin derivatives several names, e.g. Coumadin vitamin K antagonist venous thrombosis, long-term prophylaxis
factor VIII multiple names replace factor VIII hemophilia A
factor IX multiple names replace factor IX hemophilia B
desmopressin several names, e.g. DDAVP von Willebrand factor von Willebrand disease
tranexamic acid Lysteda fibrinolysis von Willebrand disease
von Willebrand factor Humate-P von Willebrand factor von Willebrand disease
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Hemostatic and fibrinolytic proteins, characteristics and physiological roles/pathological processes

Protein Plasma (mcg ml−1) Chromosome loci Physiological pathway Pathological process (deficiency or mutation)
α2-Antiplasmin 70 18p11.1-q11.2 Anti-fibrinolysis Hemorrhage
Antithrombin 150–400 1q23-q25 Anticoagulation Thrombosis
Endothelial protein C receptor 20q11.22 Anticoagulation Thrombosis
Factor V 5–10 1q21-q25 Coagulation Hemorrhage
Factor VII 0.5 13q34 Coagulation Hemorrhage
Factor VIII 0.1–0.2 Xq28 Coagulation Hemorrhage
Factor IX 4–5 Xq27.1-q27.2 Coagulation Hemorrhage
Factor X 8–10 13q34 Coagulation Hemorrhage
Factor XI 5 4q32-q35 Coagulation Hemorrhage
Factor XII 30 5q33 Inflammation
Factor XIII 10–22 6p24-p25 and 1q31-q32.1 Coagulation Hemorrhage
Fibrinogen 2000–4000 4q23-q32 Coagulation Hemorrhage
High-molecular-weight kininogen 70 3q26 Inflammation
Plasminogen 10–16 6q26-27 Fibrinolysis Thrombosis
Plasminogen activator inhibitor-1 0.012–0.014 q21.3-q22 Anti-fibrinolysis Hemorrhage
Prekallikrein (PK) 20 4q35 Inflammation
Protein C 4–5 2q13-q14 Anticoagulation Thrombosis
Protein S 25 3p11.1-q11 Anticoagulation Thrombosis
Protein Z 2–3 13q34 Anticoagulation Thrombosis
Protein Z-dependent protease inhibitor (ZPI) 1–1.6 14q32 Anticoagulation Thrombosis
Prothrombin 100–150 11p11-q12 Coagulation Hemorrhagic
Thrombin activatable fibrinolysis inhibitor (TAFI) 6 13q14 Anti-fibrinolysis Hemorrhage
Thrombomodulin 20p12-cen Anticoagulation Thrombosis
Tissue factor 1p21-p22 Coagulation Hemorrhage
Tissue factor pathway inhibitor 0.1 2q31-q32.1 Anticoagulation Thrombosis
Tissue-type plasminogen activator 0–0.012 8p11.21 Fibrinolysis Thrombosis
von Willebrand factor 10 12p13.2 Coagulation Hemorrhage

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 an 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 the 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.

References

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