Platelets are fragments of what other cells?
Megakaryocytes
What is the role of Hemostasis
Designed to ensure that there is no major leakage of blood following injury
A single megakaryocyte can generate how many platelets?
3000 of which 20-30% are pooled in the spleen
- A normal level of platelets is between 250,000-400,000 per cubic millimeter of blood
Which of these can be found in a platelet?
- Nucleus
- Organelles
- Granules
Just Granules. They are needed for normal platelet function
What is the average life span for a platelet?
5-20 days
Describe the endothelial wall of a capillary
- Only contains the Tunica Intima
- Tunica Intima contains endothelial cells and small amount of collagen
What are the three phases of Hemostasis
- Vasoconstriction
- Platelet plug formation
- Blood Clotting
What is the first phase of Hemostasis and what two things trigger it?
Vasoconstrictive phase (Vascular spasm)
- Direct injury itself
- Sympathetic Nervous System
What is the second phase of Hemostasis?
Platelet Plug Formation
What is the first step in Platelet Plug Formation?
Adhesion
- Platelets stick to exposed collagen of damaged endothelium via GP1a receptors
What are GP1a receptors used for?
These receptors are used by platelets to stick to exposed collagen of damaged endothelium
What is von Willebrand’s Factor (vWF)?
a protein found in plasma, platelets and the walls of blood vessels. Via GP1b receptors, it specifically causes platelets to attach firmly to and spread across the damaged endothelial surface
Where is vWF found?
In plasma, platelets and the walls of blood vessels
What receptors are associated with vWF?
GP1b receptors
T or F, During adhesion, platelets will undergo major structural changes and deformations
True
Adhesion of platelets to damaged endothelial surface also triggers what 3 factors from the platelets?
- ADP (adenosine diphosphate)
- Thromboxane A2 (TXA2, a prostaglandin)
- Serotonin (5-HT)
What to ADP, AXA2 and 5-HT do after released from platelets upon adhesion to the endothelial surface?
They bind to specific receptors on other platelets. Stimulation of these receptors will activate these platelets by making them more sticky and cause platelets to adhere to each other and aggregate.
What is the role of GPIIb/IIa receptors?
Glycoprotein receptors found on platelets that ultimately cause aggregation. Fibrinogen binds to these receptors and ultimately bind platelets together
What is the third and final phase of Hemostasis?
Coagulation or Blood Clotting phase
When does a blood clot form?
To reinforce a platelet plug or stop bleeding when a platelet plug fails
Most clotting factors are what type of macromolecule and synthesized where?
Proteins
Synthesized in the liver
Clotting Factor I
Fibrinogen
Origin: Liver
Clotting Factor II
Prothrombin
Origin: Liver
Clotting Factor III
Tissue factor or Thromboplastin
Origin: Perivascular tissue
Clotting factor IV
Calcium
Origin: Plasma
Clotting Factor V
Proaccelerin (Labile Factor)
Origin: Liver
Clotting Factor VII
Proconvertin (Stable factor)
Origin: Liver
Clotting Factor VIII
Antihemophillic Factor A or Antihemophillic globulin
Origin: Liver
Clotting Factor IX
Antihemophilic Factor B, Plasma thromboplastin component or Christmas factor
Origin: Liver
Clotting Factor X
Stuart-Prower Factor
Origin: Liver
Clotting Factor XI
Plasma thromboplastin antecedent, Hemophilia C or Rosenthal Syndrome
Origin: Liver
Clotting Factor XII
Hageman factor
Origin: Liver, Platelets
Clotting Factor XIII
Fibrin stabilizing Factor or Laki-Lorand factor
Origin: Platelets, Plasma
Which clotting factors are considered the Vitamin K-dependent clotting factors?
II, VII, IX and X
In what form are most of the clotting factors in the blood?
Inactive (Zymogen) to prevent unwanted clotting. They require activation by other clotting factors
What things are involved in Extrinsic pathway of cascade?
Thromboplastin (Factor III) –> Factor VII
What things are involved in the Intrinsic pathway of cascade?
Factor XII –> Factor XI –> Factor IX –> Factor VIII
What is needed to convert Thromboplastin to Factor VII in the extrinsic pathway? Factor VII to Factor X?
Ca 2+
Factor V
What is needed to convert Factor IX to Factor VIII in Intrinsic pathway?
Ca2+
PF3
What initiates the intrinsic and extrinsic pathways respectively?
Intrinsic: Platelets
Extrinsic: tissue thromboplastin
What are three examples of natural “anticoagulants”used in our body as protease inhibitors to inactivate clotting factors:
- Thrombomodulin
- Antithrombin III
- Heparin cofactor II
What is Thrombomodulin and where is it present?
A glycoprotein present on the endothelial cells
What is the mechanism of Thrombomodulin in 3 steps
- Thrombomodulin combines with Thrombin
- Thrombomodulin-thrombin complex activates Protein C
- Protein C and its cofactor Protein S, degrades Factors V, VIII
What is Antithrombin and where is it produced?
Glycoprotein produced in the Liver
What is the mechanism of Antithrombin?
Binds to and inhibits Factor X and Thrombin
What two things does Antithrombin III bind to and inhibit?
Factor X
Thrombin
What is Heparin Cofactor II and where is it made?
A plasma protein
Synthesized by liver
What does Heparin Cofactor II inhibit?
Thrombin
What enzyme is used to degrade a blood clot so that normal blood flow can return to a blood vessel?
Plasmin (active form of Plasminogen)
What activates Plasminogen to Plasmin?
Tissue Plasminogen Activator (t-PA)
Where is plasminogen synthesized?
Liver
Explain the process behind the plasminogen to plasmin mechanism
Plasminogen is an inactive plasma protein in blood clots. t-PA is released slowly into the blood by the damaged endothelial cells so that after the bleeding has stopped (several days), the clot can be broken down by activating plasminogen to plasmin
Name four Fibrinolysis inhibitors
- Plasminogen activator inhibitor 1
- Plasminogen activator inhibitor 2
- alpha-2 antiplasm
- alpha-2 macroglobulin
T or F, Low platelet count normally lead to serious clinical problems
False, they do not lead to clinical problems
Low platelet count may lead to what four things?
Bruising
Petechia (pinpoint hemorrhages on skin and mucous membranes)
Nosebleeds
Bleeding gums
In coagulation tests, blood is collected in a tube containing what? WHy?
Sodium citrate
- The normal functioning of the coagulation cascade needs calcium. Citrate binds calcium. Blood will not form clot in tube until further calcium is added
Prothrombin time coagulation test is used to assess what pathway?
Extrinsic
Describe the mechanism behind the Prothrombin time coagulation test:
Calcium is added to plasma to replace calcium that was removed by citrate. Brain thromboplastin is added to substitute for tissue factor. Clotting normally takes 12-15 seconds and is compared to a standard normal control.
What is the INR?
International Normalized Ratio - It is the ratio of a patient prothrombin time to a normal (control) sample. This is then raised to the ISI value which is simple the index of the tissue made by a certain company.
What is the INR most often used for?
To monitor the effectiveness of drugs such as warfarin (coumadin). In other words, anticoagulants.
What type of patients may have long-term anticoagulants prescribed to them?
People with:
- Heart attacks, strokes, deep venous thrombosis
- Also may be a preventative measure for patients with an artificial heart valve or short-term for knee surgeries.
Why must anticoagulants be measured carefully?
to maintain a balance between blood clotting and causing excessive bleeding
What is the Active Partial Thromboplastin Time (APPT) used to assess?
The intrinsic pathway
What is the mechanism of APPT?
- Add calcium to plasma to replace calcium removed by citrate.
- Kaolin and Phospholipids are added to substitute for contact factor
- Usually takes 25-36 seconds for clot
When is the APTT normally used?
It is most often used to monitor Heparin therapy. Therapeutic levels of of heparin prolong the normal APTT clot time to 2-2.5 times the normal value
What is Thrombin Clotting Time used for?
To assess the Common Pathway
What is the mechanism of Thrombin Clotting Time (TT)
- Calcium is added to plasma to replace removed calcium by citrate
- Thrombin is added to substitute for the products of the intrinsic and extrinsic pathways
- This assesses the conversion of fibrinogen to fibrin
When is TT typically used?
When a PT or APTT test is prolonged, particularly if abnormal fibrinogen level or function is considered
When is a Coagulation Factor Assay used?
To determine actual deficiencies of specific clotting factors
What type of deficiency is Hemophilia A deficiency?
Factor VIII Defiecency
What are the test results of PT and APTT in Hemophilia A deficiency?
Prolonged APTT, Normal PT
Who mainly suffer from Hemophilia A deficiency?
Males, It is an X-linked disorder and males only have one
- 30% of cases are not family related but by new mutations
Hemophilia B (christmas disease) is a disorder of what factor?
A mutation in Factor IX gene (X-linked)
What are the test results for PT and APTT in the Hemophilia B (Christmas Disease)
Prolongation of APTT, Normal PT
Who mainly are affected by Hemophilia B?
Males, 1-30,000 are affected
What are the main clinical features of hemophilia?
Increased risk of prolonged bleeding from common injuries
- In severe cases, bleeding may be spontaneous and without obvious cause
What are the most serious sites of bleeding for hemophilia?
- Joint Capsules
- Skeletal Muscles
- GI Tract
- Brain
Although joint bleeding is not life threatening, what can occur if joint bleeding repeats?
- Can cause permanent joint damage and disfigurement resulting in chronic arthritis and disability
What causes joint damage?
It is not the bleeding but rather the healing process. When blood in joint is broken down it is broken down by enzymes and bone in that area is also degraded
What is the treatment with patients with hemophilia?
IV factor replacement
- Extra factor replacement can be given around surgical procedures and after trauma
What is the most common bleeding disorder?
von Willebrand’s Disease
Does von Willebrand’s disease affect men or women?
Both equally
2 major roles of vWF
- Mediating platelet adhesion
2. Stabalizing Factor VIII
What are the test results for von Willebrand’s disease?
Prolonged APTT - link to factor VIII
Prolonged PT - Failure in platelet-vessel wall interaction
Thrombocytopenia can be cause by what two things?
- Impaired production of platelets (Drug induced or Bone Marrow failure)
- Increased destruction of platelets (ITP)
What is Idiopathic Thrombocytopenia Purpura (ITP)
Autoimmune response to platelets, which are removed prematurely by reticuloendothelial system
What is Thrombophilia?
Conditions associated with excessive clotting
4 examples of inherited thrombophilia
Protein C deficiency
Protein S deficiency
Activated Protein C Resistance
Antithrombin III deficiency
Describe Activated Protein C Resistance
- No Protein C deficiency, rather a poor response from Factor V to protein C occurs
- Factor V gene mutation