Episode 5 - Hemostasis: Physiology, Assessment and Common Disorders Flashcards
Any local bleeding is arrested by an interaction between ____ and ____, followed by a cascade of ____.
platelets and blood vessel endothelial cells
coagulation factors
____ is designed to ensure that there is no major leakage of blood following injury and consists of a complex system of proteins and enzymes.
Hemostasis
Hemostasis starts with ____.
platelets
Platelets are not really cells, but instead fragments of cells. They split from huge cells in the bone marrow called ____ and then enter the circulation.
megakaryocytes
A single megakaryocytic can generate around ____ platelets, of which ____% are pooled in the spleen.
3000
20-30%
A normal level of platelets is between _____ per cubic millimeter of blood.
250,000 - 400,000
Platlets have not nucleus or organelles but contain many ____.
Granules (granules are required for normal platelet function)
Platelets possess an average life span of ____ days.
5-20 days
3 layers of a typical artery
Tunica intima
Tunica media
Tunica externa
Compare the width of the tunicae of veins and arteries.
Veins have thinner tunica media
Anatomy of a ‘typical’ capillary
Tunica intima only contains endothelial cells and some collagen
No tunica media or externa (very thin walled)
3 Phases of Hemostasis
Vasoconstrictive Phase (Vascular Spasm) Platelet Plug Formation Coagulation Phase (Blood Clotting)
Explain the vasoconstrictive phase of hemostasis
Smooth muscle in damaged vessels contracts immediately producing local vasoconstriction. (capillaries don’t constrict)
Triggered by injury itself and SNS
Explain Platelet Plug Formation
Aggregation of platelets that stick to exposed collagen, swell and form spiked processes. Prevent blood loss in small injuries
Collagen is found in the tunica ____ of arteries
intima (also found in externa but it is particularly important to know that it is in the tunica intima)
Platelets stick to the exposed collagen of damaged endothelium via _____.
GPIa receptors
____ is a protein found in plasma, platelets and the walls of blood vessels. Via ____, it specifically causes platelets to attach firmly to and spread across the damaged endothelial surface.
von Willebrand’s Factor (vWF)
GPIb receptors
During adhesion, platelets will undergo major structural changes and deformations. Adhesion also triggers the secretion of multiple factors from the platelets:
These factors bind to specific receptors on other platelets making them more sticky causing aggregation.
ADP (adenosine diphosphate)
Thromboxane A2 (TA2; TXA2; a prostaglandin)
Serotonin (5-HT)
Aggregation occurs as a consequence of another platelet glycoprotein receptor called ____ onto which ____ and other macromolecules bind tightly.
GPIIb/IIIa
fibrinogen
Explain the coagulation phase
occurs to either reinforce a platelet plug or stop bleeding when the platelet plug fails.
Involves numbers clotting factors
Most clotting factors are ___ synthesized by the ___.
proteins
liver
Most of the clotting factors are present in the circulation as ___ to prevent unwanted clotting.
inactive proteins (zymogens)
Clotting Factor I
Fibrinogen
Clotting Factor II
Prothrombin
Clotting Factor III
Tissue Factor or thromboplastin
Clotting Factor IV
Calcium
Clotting Factor V
Proaccelerin (Labile factor)
Clotting Factor VII
Proconvertin (Stable factor)
Clotting Factor VIII
Antihemophilic factor A,
Antihemophilic globulin
Clotting Factor IX
Antihemophilic factor B, Plasma thromboplastin component, Christmas factor
Clotting Factor X
Stuart-Prower factor
Clotting Factor XI
Plasma thromboplastin antecedent, Hemophilia C, Rosenthal syndrome
Clotting Factor XII
Hageman factor
Clotting Factor XIII
Fibrin stabilizing factor, Laki-Lorand factor
Factors __, __, __ and __ are vitamin K-dependent clotting factors.
II, VII, IX and X
Blood clotting cascade comprises ___ and ___ pathways.
Both of those terms are somewhat outdated. Both pathways are initiated simultaneously and lead to a “_____”
extrinsic and intrinsic (initiated outside and inside the blood)
Final Common Pathway
In addition to coagulation factors, the plasma contains several ____ that rapidly inactivate coagulation factors that escape the site of injury.
protease inhibitors
There additionally needs to be an _____ system in place to maintain the homeostatic balance.
anti-coagulant
Examples of ‘natural’ anti-coagulants are:
Thrombomodulin
Antithrombin III
Heparin cofactor II
____ is a glycoprotein present on endothelial cells that combines with thrombin.
Thrombomodulin
Thrombomodulin-thrombin complex activates ____.
Protein C
Protein C and its cofactor ____ degrade factors V and VIII
Protein S
Antithrombin is a glycoprotein produced by the liver that binds to and subsequently inhibits ____ and ____.
factor X and thrombin
Heparin cofactor II is aplasma protein synthesized by the liver and inhibits ___.
thrombin
Breaking down of a blood clot is initiated by the enzyme ____ which is synthesized from an inactive plasma protein from the liver called ____.
Plasmin
Plasminogen
____ converts plasminogen to the active plasmin, thus allowing fibrinolysis to occur.
Tissue Plasminogen Activator (t-PA)
t-PA is released into the blood very slowly by the ____ of the blood vessels. After several days, the clot is broken down because plasminogen was trapped within the clot when it formed and is slowly activated to break down the fibrin mesh.
damaged endothelium
____ are required in vivo to prevent prolonged or unwanted degradation of fibrinogen.
Fibrinolysis inhibitors
Some natural fibrinolysis inhibitors:
Plasminogen activator inhibitor 1
Plasminogen activator inhibitor 2
alpha2-antiplasmin
alpha2-macroglobulin
____ is a low platelet count and causes an increased risk for bleeding.
Thrombocytopenia
Often low platelet levels do NOT lead to clinical problems. Occasionally, there may be:
bruising, particularly purport in the forearms, petechia (pinpoint hemorrhages on skin and mucous membranes), nosebleeds and/or bleeding gums.
To perform a coagulation test, blood is taken from the patient and put in tubes containing ____ which prevents clotting because it binds ____.
Sodium Citrate
Calcium
Explain the Prothrombin Time (PT); Pro-Time
A test used to asses the extrinsic pathway. Calcium is added to replace the removed calcium and brain thromboplastin is added to substitute for tissue factor (III). Clotting is compared with the standard normal (12-15 seconds) control in a ratio.
The ___ was devised to standardize results due to the variation of tissue factor (III).
Each manufacturer gives an ____ for any tissue factor they make.
International Normalized Ratio (INR)
International Sensitivity Index (ISI)
Clinically, the INR is most often used to monitor the effectiveness of drugs such as ____ which is an ____.
warfarin (coumadin)
anti-coagulant
Patients should have an INR of ____ for basic ‘blood-thinning’ needs.
Some patients who have a high risk of clot formation need an INR of about ____.
- 0-3.0
2. 5-3.5
Explain the Activated Partial Thromboplastin Time (APPT)
Used to assess the intrinsic pathway. Calcium is added to plasma to replace what was removed by citrate and then kaolin and phospholipids are added to substitute for contact factor. Clotting is compared with the standard normal (25-36 seconds) control in a ratio.
Clinically used to monitor Heparin therapy. Therapeutic levels of UFH will typically prolong the aPTT to 2-2.5 times that of the normal value.
Explain Thrombin Clotting Time
Used to assess the common pathway. Calcium is added to plasma to replace that removed by citrate and then thrombin is added to substitute for the products of the intrinsic and extrinsic pathways. This assesses the conversion of fibrinogen to fibrin.
Clinically used when a PT and/or aPTT test is prolonged, particularly if abnormal fibrinogen level or function is considered.
Why would you do a coagulation factor assay.
To determine actual deficiencies of specific clotting factors.
Hemophilia A is an X-linked disorder from mutations in factor ____ gene.
factor VIII
What results would you expect from an APTT and a PT in a patient with Hemophilia A
Prolongation of APTT and normal PT
___% of Hemophilia A patients have no family history; their disease is presumably caused by new mutations.
30%
Hemophilia B (aka ____) is an X-linked disorder caused by mutations in factor ___ gene.
Christmas Disease
Factor IX
What results would you expect from an APTT and a PT in a patient with Hemophilia B
Prolongation of APTT and normal PT
Hemophilia often leads to superficial bleeding but by far the most serious sites of bleeding are:
Joint Capsules
Skeletal Muscles
GI Tract
Brain
Though not life threatening, ___ bleeds are one of the most serious symptoms of hemophilia because while the blood in the joint is being broken down, the bone in the area is also degraded.
joint
Patients with very low factor levels who experience repeated and painful bleeds to their joints and skeletal muscles are given ___.
IV(intravenous) factor replacement
_____ is the most common inherited bleeding disorder that affects 125 per million and leads to a mild bleeding disorder affecting males and females equally.
Von Willebrand’s Disease (vWD)
vWF has 2 major roles:
- Mediating platelet adhesion
2. Stabilizing factor VIII
In Von Willebrands Disease bleeding is typically seen in ___ and ___ because of the high capillary density. These tissues depend on the efficient formation of platelet plugs to stop bleeding.
skin and mucous membranes
What results would you expect from an APTT and a PT in a patient with Von Willebrand’s Disease and why?
Prolonged aPTT - reduced factor VIII clotting activity (factor VIII linked to vWF)
Prolonged PT - failure in platelet-vessel wall interaction
Thrombocytopenia can be caused by ____ or ____.
Impaired production of platelets (drug induced or bone marrow failure)
Increased destruction of platelets (Idiopathic Thrombocytopenic Purpura - autoimmune)
_____ are conditions associated with excessive clotting.
Thrombophilias
A defect of deficiency in one of the natural anticoagulants will swing the balance towards a _____ state and potential ____.
hypercoagulable
venous thromboembolism (VTE)
4 Examples of inherited thrombophilias are
Activated Protein C Resistance (most common)
Protein C Deficiency
Protein S Deficiency
Antithrombin III Deficiency (least common)
Activated Protein C Resistance is not a protein C deficiency but instead a poor response by _____ to protein C
Factor V
