Hemostasis and Coagulation (Exam IV)-Mordekai Flashcards
What is hemostasis?
Normal hemostasis is a balance between clot generation, thrombus formation, and regulatory mechanisms that inhiibit uncontrolled thrombogenesis.
What are the goals of hemostasis?
- To limit blood loss from vascular injury
- To maintain intravascular blood flow
- To promote revascularization after thrombus
Label the stages pf coagulation
What are the 2 stages of hemostasis?
- Primary hemostasis
- Secondary hemostasis
What is primary hemostasis?
- Immediate platelet deposition at the endovascular injury site.
- Leads to the initial platelet plug formation
- This is only adequate for minor injuries.
What is secondary hemostasis?
- Clotting factors activated
- Stabilized clot formed and secured with crosslinked fibrin
What is the vascular endothelial role?
Vascular endothelial cells have antiplatelet, anticoagulant, and fibrolytic effects to inhibit clot formation.
What are the anti-clotting mechanisms of endothelial cells?
- They are negatively charged to repel platelets
- They produce platelet inhibitors such as prostacyclin and nitric oxide.
- They excrete adenosine diphosphate (ADP), which degrades the ADP, a platelet activator.
- They increase protein C, which is an anticoagulant.
- They produce tissue factor pathway inhibitor (TFPI), which inhibits factor Xa and tissue factor VIIa complex
- They synthesize tissue plasminogen activator (t-PA)
What plays a critical role in hemostasis?
Platelets
Where are platelets derived from?
Bone-marrow megakaryocytes
Inactive platelets circulate as _______ with a lifespan of _____days
- disc-shaped anuclear cells
- 8-12 days
- What percent of platelets are consumed to support vascular integrity daily?
- How many new platelets are formed daily?
- 10%
- 120-150 billion
- Damage to the endothelium exposes what?
- Which contains what 3 things?
- It exposes the underlying extracellular matric (ECM).
- The ECM cotnains collagen, vWF, and other glycoproteins.
What are the 3 phases of alteration that platelets undergo upon exposure to contents in the ECM?
- Adhesion
- Activation
- Aggregation
Label the 3 phases of alteration in primary hemostasis
What is adhesion in primary hemostasis?
Occurs upon exposure to the ECM proteins
What is activation in primary hemostasis?
- Stimulated when platelets interact with collagen and tissue factor (TF) causing the release of geranular contents.
What is aggregation in primary hemostasis?
Occurs when the granular contents are released from the 2 storage granules in the platelets, which activate additional platelets, which propogates plasma-mediated coagulation.
What are the 2 types of storage granules platelets contains?
- Alpha granules
- dense bodies
What are alpha granules?
A storage granule of the platelet that contains fibrinogen, albumin, Ca++, K+, PO4+++, factors V and VIII, vWF, and platelet derived growth factor.
What are dense bodies?
storage granules of the platelet that contains ADP, ATP, Ca++, K+, PO4+++, serotonin, histamine, adrenalin, and epinephrine
Each stage of the clotting cascade requires assembly of what?
Membrane-bound activted tenase-complexes
What are the 4 things that each membrane-bound activated tenase-complex is composed of?
- A substrate (inactive precursor)
- an enzyme (activated coagulation factor)
- A cofactor (accelerator or catalyst)
- Calcium
What is factor I?
Fibrinogen
What is factor II?
Prothrombin
What is factor III?
Tissue thromboplastin
What is factor IV?
calcium ions
What is factor V?
labile factor
What is factor VII?
stable factor
What is factor VIII?
Antihemolytic factor
What is factor IX?
- Christmas factor
- Plasma thromboplastin component (PTC)
What is factor X?
Stuart-Prower factor
What is factor XI?
Plasma thromboplastin antecedent (PTA)
What is factor XII?
Hageman factor
What is factor XIII?
Fibrin stabilizing factor
Label the intrinsic pathway
Label the extrinsic pathway
About how long can clot dissolution occur after it has formed?
- minutes to days later
The extrinsic pathway is the is the initiation phase of what?
plasma mediated homeostasis
What starts the extrinsic pathway?
Begins with endothelial injury that exposes tissue factor to plasma.
Describe the steps of the extrinsic pathway
- Tissue factor forms an active complex with VIIa
- The tissue factor/VIIa complex binds to and activates factor X, converting it to Xa.
- The tissue factor and VIIa complex also activates factor Ix, turning it into IXa in the instrinic pathway. (IXa and calcium convert factor X to Xa)
- Factor Xa begins the final common pathway.
What factor begins the final common pathway?
Factor Xa
Coagulation proteins are typically found in what form?
- inactivated form
What are two reasons why clotting factors do not attach to the endothelium of the vessel?
- Endothelium is smooth
- Undamaged endothelium doesn’t express tissue factor or collagen
If the endothelium becomes damage or is injured what does that cause?
- Tissue Factor and Collagen expression → platelet plug formation and coagulation cascade.
What are the three layer of a blood vessel?
- Intima → endothelial layer
- Media → subendothelial layer (middle)
- Adventitia → outer layer
Which clotting mediators/factors belong to the intima (endothelial) layer?
- VWF
- Tissue factor
- Prostacyclin
- Nitric oxide
Which clotting factors belong to the Media (subendothelial) layer?
- Collagen
- Fibronectin
How do the endothelial cells of the intima modulate hemostasis?
Synthesize and secrete:
- Procoagulants
- Anticoagulants
- Fibrinolytics
Which two vascular mediators are released by the Intima endothelial cells?
- Vasoconstrictors
- Vasodilators
What does vWF do?
vWF → help platelets adhere to subendothelial layer
What does Tissue Factor (TF) do?
- TF → activates clotting cascade when vessel is injured
Which mediators that are released by the endothelial cells cause vasoconstriction? Which cause vasodilation?
- Constrict → thromboxane A2 and ADP
- Dilate → NO and PGI₂
What are the functions of the following Procoagulants:
- Coagulation factors
- Collagen
- vWF
- Fibronectin
- Thrombomodulin
- Coagulation factors → coagulation
- Collagen → tensile strength & plt adhesion
- vWF → plt adhesion
- Fibronectin → cell to cell adhesion
- Thrombomodulin → anticoagulation
What are the functions of the following Anticoagulants:
- Antithrombin IlI
- Tissue pathway factor inhibitor (TFPI)
- Antithrombin IlI → Degrades factors XII XI X IX II (2, 9, 10, 11, 12)
- TFPI → Inhibits TF
What are the functions of the following Fibrinolytics:
- Plasminogen
- tPA
- Urokinase
- Plasminogen →Converts to plasmin
- tPA → Activates plasmin
- Urokinase → Activates plasmin
Besides vasodilation what other function does Prostacyclin provide?
- Inhibits aggregation
Which layer of a blood vessel is extremely thrombogenic and very active?
- Media (subendothelial)
Which two substances does the media contain that play important roles in clotting? What does each substance do?
- Collagen → potent stimulus for platelet attachment to vessel wall
- Fibronectin → Facilitate anchoring of fibrin during hemostatic plug formation
How does the adventitia control blood flow?
- Influences blood flow via vessel contraction using NO and prostacyclin
How does vasodilation of the adventitia limit the activity of procoagulant mediators?
- ↑ BF washes the procoagulants away
Briefly explain how NO enables vasodilation?
NOS → L-arginine to NO → NO activates sGC in muscle → sGC activates cGMP → relaxation/dilation
- Nitro Oxide Synthaze converts L-arginine to NO
- NO diffuses into VSM and activates soluble guanylate cyclase (sGC)
- sGC activates cGMP which then causes VSM relaxation
What are Eicosanoids?
PGs and other compounds such as:
- Prostacyclin
- Leukotriene
- Thromboxane
What are the 4 phases of Hemostasis and Coagulation?
- Vascular phase (Vascular spasm)
- Primary hemostasis (Formation of platelet plug)
- Secondary hemostasis (Coagulation and formation of fibrin)
- Fibrinolysis (Lysis of clot)
What happens during the Vascular Phase of hemostasis and coagulation?
- Damaged blood vessels cause vascular spasm of smooth muscle in vessel wall
- Localized to the injured area
What are the primary hormones involved in the Vascular Phase of hemostasis and coagulation? What do they do?
- Endothelins → stimulate VSM and cell division of endothelial smooth muscle and fibroblast cells which help repair damaged site
Vasospasm MAY slow down/stop bleeding depending on what?
BP
What phase occurs after vascular contraction causes tamponade?
- Primary hemostasis
What two things occur during Primary Hemostasis?
- Injured blood vessel attracts platelets
- Initiates the phases of platelet formation
What are the three phases of platelet plug formation?
- Adherence
- Activation
- Aggregation
What effect causes the platelet circulating in the blood to be positioned near the vessel wall?
- Platelets are smaller than RBCs/WBCs and get pushed to the sides of the vessel
What shape do platelets have that allow them to circulate freely in the blood?
They are round and disk-like
Where are platelets formed?
In the bone marrow from megakaryocytes
According to our class what is the normal concentration of platelets in the blood? How long do they live?
- 150000 to 300000 /mm3
- 1-2 wk lifespan
Which 2 systems clear old platelets from the blood?
How much of the circulating platelets are stored in the spleen?
- Macrophages in the reticuloendothelial system
- Spleen (holds ⅓ of circulating plts)
In general what do the glycoproteins on the external membrane of the platelet do? What about GpIb and GpIIb-IIIa?
- Adheres to injured endothelium collagen and fibrinogen
- GPIb → attaches platelet to vWF
- GPIIb-IIIa → links activated platelets together to form plug
What do the phospholipids on the surface of the platelet do?
- Substrates to PG synthesis
- Produce TXA2 which activates platelet
Which platelet surface glycoprotein doesn’t have a lot of options to reverse its effects?
- GPIIb-IIIa
What are the 5 platelet surface receptors for antiplatelet therapy?
- ADP
- GP1b
- GPIIb-IIIa
- Thrombin
- TXA2
Describe the role of each of the following substances/structures found inside a platelet:
- Actin and myosin
- ADP
- Calcium
- Fibrin-stabilizing factor
- Growth factor
- Serotonin
- Thrombosthenin
- Actin and myosin → Contraction to form the PLT plug
- ADP → PLT activation and aggregation
- Calcium → Plays a role in the coagulation cascade
- Fibrin-stabilizing factor → Cross links fibrin
- Growth factor → Repairs damaged vessel walls
- Serotonin → Activates nearby PLT
- Thrombosthenin → PLT contraction
Explain the process by which platelets adhere to each other?
- vWF released from endothelial cells onto the endothelial lining
- GPIb receptors emerge from platelet surface
- GPIb binds to vWF and this process attracts other platelets
What change does the presence of TF cause to the platelet?
- Platelet has conformational change and is activated
- GPIIb-IIIa projects outward from platelets and links them to each other → purpose is to create a platelet plug
- Seal it and heal it…
During aggregation which mediators are released from the platelets themselves (when they are activated)?
- alpha and dense granules
- contractile granules
- thrombin
During aggregation what is the role of the mediators released from the activated platelets?
- Promote procoagulant activity
- Form a primary unstable clot
What is the difference between a primary clot and a secondary clot?
- Small injury → primary clot (or plug) is enough to provide hemostasis
- Large injury → clotting cascade must be activated to create/stabilize secondary clot for hemostasis
During secondary hemostasis fibrin production requires which clotting factors in order to proceed?
- all of them
Which protein is probably the single most important protein in the clotting cascade?
- Fibrin
What is a very general explanation of the clotting cascade?
- A series of enzymatic reactions (clotting cascade) that ultimately activate prothrombin to thrombin which then converts soluble fibrinogen to fibrin
What are the 2 paths of the clotting cascade? They ultimately join together to form…?
- Intrinsic
- Extrinsic
- Common path
What are the Vitamin K dependent clotting factors?
- Factors II, VII, IX, X
What is the name and source of factor I? Is it Vitamin K dependent?
- Name: Fibrinogen
- Source: Liver
- Vit K: no
What is the name and source of factor III? Is it Vitamin K dependent?
- Name: Tissue Factor (TF) or Thromboplastin
- Source: vascular wall/extracellular membrane/released from injured cells
- Vit K: No
What is the name and source of factor II? Is it Vitamin K dependent?
- Name: Prothrombin
- Source: Liver
- Vit K: Yes
What is the name and source of factor IV? Is it Vitamin K dependent?
- Name: Calcium
- Source: Diet
- Vit K: n/a
What is the name and source of factor V? Is it Vitamin K dependent?
- Name: Proaccelerin
- Source: Liver
- Vit K: No
What is the name and source of factor VII? Is it Vitamin K dependent?
- Name: Proconvertin
- Source: Liver
- Vit K: Yes
What is the name and source of factor VIII:C? Is it Vitamin K dependent?
- Name: Antihemophiliac factor
- Source: Liver
- Vit K: No
What is the name and source of factor VIII:vWF? Is it Vitamin K dependent?
- Name: vonWillibrand Factor
- Source: Vascular endothelial cells
- Vit K: n/a
How can we compensate for vWF deficiency?
- DDAVP infusion
What is the name and source of factor IX? Is it Vitamin K dependent?
- Name: Christmas Factor
- Source: Liver and other tissues
- Vit K: Yes
What is the name and source of factor X? Is it Vitamin K dependent?
- Name: Stuart-Prower Factor
- Source: Liver
- Vit K: Yes
What is the name and source of factor XI? Is it Vitamin K dependent?
- Name: Plasma thromboplastin antecedent
- Source: Liver
- Vit K: No
What is the name and source of factor XII? Is it Vitamin K dependent?
- Name: Hageman Factor
- Source: Liver
- Vit K: No
What is the name and source of factor XIII? Is it Vitamin K dependent?
- Name: Fibrin Stabilizing Factor
- Source: Liver
- Vit K: No
Which clotting factors come from the liver?
- All of them except III IV and vWF (VIII:vWF)
Explain how the Extrinsic pathway works up to the common path.
For37cents you can purchase theextrinsicpathway
* TF released from subendothelium during injury → TF or factor 7 activates extrinsic path
* TF activates factor 7
* Factor 7 activates factor Xin the presence of factor 4 (Ca++)
* Prothrombin activator and platelet phospholipids activate factor 2 (thrombin) → this leads to common path
* Note: Factor 5 ↑ the production of prothromin activator (+ feedback)
If the patient is low on Ca++ how will this effect the extrinisic path of the clotting cascade?
- It won’t work as well
How long does it take a clot to form via the extrinsic path?
- 12 to 15 sec
Explain how the Intrinsic pathway works up to the common path.
If you can’t buy theintrinsicpathway for $12 you can buy it for $11.98.
* Blood trauma or exposure to Collagen → activates factor XII
* Factor XIIa activates factor XI → this step needs HMW kininogen and accelerated by prekalllikrein
* Factor XIa activates factor IX
* Factor IXa and VIII activate factor X
* Prothromin activator and phospholipids activate factor IIa (thrombin) → leads to common path
Which pathologies will prevent factor X from being activated in the intrinsic path?
- Hemophilia A → Factor VIII missing
- Thrombocytopenia → Platelets (phospholipids) missing
How long does it take to creat a clot via the intrinsic path?
- 6 minutes
Explain how the Common pathway works.
The final common pathway can be purchased at the five(V) and dime(X) for 1(I) or 2(II) dollars on the 13th (XIII) of the month
* Prothrombin activator changes prothrombin (II) to thrombin (lla)
* Thrombin changes fibrinogen to fibrin in the presence of Ca++
* Fibrin is added to platelet plug
* Activated fibrin-stabilizing factor (XIlla) cross-links fibrin-fibers to complete the clot
When the clotting cascade gets activated what else does the body activate?
- Fibrinolysis
What is fibrinolysis?
- Prevents clotting from going out of control (+ feedback loop)
- Prevents excessive deposition of fibrin
What is the primary mechanism that begins Fibrinolysis? What is a secondary activator?
- tPA released by damaged endothelial cells
- urokinase
Where is urokinase produced and what is its purpose?
- Produced by kidneys → helps prevent small clots from clogging up kidneys
What are two fibrinogenic factors involved in fibrinolysis? What do they do?
- Kallikrein
- Neutrophil elastase
- Convert plasminogen to plasmin → plasmin breaks down fibrin
Explain how fibrinolysis works?
- Plasminogen is converted to Plasmin via tPA and UPA
- Plasmin degrades fibrin into “split” products
What is a normal platelet values for our class?
- 150,000 to 300,000/mm3
What is a normal bleeding time (BT) for our class?
- BT = 3-10 min
What is a normal PT for our class?
- PT = 12-14 sec
What is a normal aPTT for our class?
- aPTT = 25-35 sec
What is a normal thrombin time (TT) for our class?
- TT = 30 secs
What is a normal activated clotting time (ACT) for our class?
- ACT = 80-150 secs
What is a normal fibrinogen level for our class?
- Fibrinogen ≥ 150 mg/dL
