18 and 19 - Hematological Agents I and II Flashcards
Define thrombosis
Thrombosis = inappropriate clot formation
- Clot becomes too big and begins to significantly inhibit blood flow
- Clots form at inappropriate sites in the vasculature
- Clots embolize and block distant areas of vasculature
Describe a venous thrombosis
- Platelet poor clots (AKA “red thrombus”) because much more RBCs are in these clots than platelets
- Often occur at valve cusps in deep veins where there is stasis (slow/sluggish blood flow) –> DVT
- This can lead to venous thromboembolism (VTE) which can cause pulmonary embolism (PE)
- Note that antiplatelet therapies are NOT as useful
Describe an arterial thrombus
- Arterial thrombi often occur on top of a ruptured artherosclerotic plaque ***
- There is thrombogenic material at the center of the plaque which is now exposed to blood
- Often rich in platelets, so it is called a “white thrombus”
- Antiplatelets are VERY useful
- This is the most common cause of myocardial infarction and ischemic strokes
List the causes of thrombosis
- Sluggish blood flow
- Atherosclerosis
- Hereditary thrombophilia
- Cancer
- Atrial fibrillation
- Mechanical heart valves
- Major surgery (especially lower limb surgery)
- Prolonged bed rest
- Oral contraceptives (especially in women with other risk factors)
Describe hereditary thrombophilia
Factor V Leiden
- Quite severe, requires medication for life
- Mutation and deficiency in protein C or S leads to decreased control of thrombin generation
Antithrombin deficiency
- Deficiency in antithrombin (AT) leads to decreased neutralization of thrombin
Define hemostasis
Hemostasis is a physiological process that halts bleeding that involves the following systems:
- Vasculature, platelet, coagulation, anti-coagulation, and fibrinolytic
- Balance between theses systems reduces blood loss due to vessel injury while keeping blood in fluid state allowing tissue perfusion.
Describe the basic steps of platelet activation
- Glycoprotein binds to von Willebrand Factor (vWF)
- This complex binds to collagen which activates platelets
- Platelets secrete factors which activate more glycoproteins
- Prothrombin is activated into thrombin
- Thrombin cleaves fibrinogen into fibrin
- Thrombin further activates platelets by binding to and activating the protease activated receptor (PAR)
Now more specifically describe the firs step
- Glycoprotein 1b (GP 1b) binds to von Willebrand Factor (vWF) and other glycoproteins
- This complex then binds to collagen, which activates platelets
This means that GP 1b initially tethers the platelets to the site of injury
Describe what platelets secrete next
NEED TO KNOW
Platelets secrete three factors
- ADP
- TXA
- 5-HT
These factors bind to platelets and activate another glycoprotein called GP iib/IIIa
What is the role of GP IIb/IIIa once activated?
GP IIb/IIIa bind to fibrinogen
Describe the role of the intrinsic and extrinsic coagulation pathway
- The intrinsic and extrinsic coagulation pathways activate prothrombin into thrombin
What is the role of thrombin?
Cleaves fibrinogen into fibrin
Recall that fibrin promotes blood clotting
What else does thrombin do?
Thrombin further activates platelets by binding to and activating the protease activated receptor (PAR)
Describe the anticoagulation system
- Antithrombin is a circulating plasma protease produced by the liver and is present in blood plasma
- Antithrombin inactivates thrombin and factor Xa
Describe the role of heparin sulfate in the anticoagulation system
- Normally antithrombin slowly inactivates thrombin and factor Xa through proteolysis
- Heparin sulfate present on surface of vascular endothelial cells can bind antithrombin
- Significantly increases rate of thrombin and factor Xa inactivation
- Heparin sulfate has no direct anticoagulation effect by itself
Describe how thrombin binds to fibrin and how it converts fibrinogen to fibrin
- The active site of thrombin is where fibrinogen is converted into fibrin.
- The (E1) site on thrombin binds fibrin.
- This limits the diffusion of thrombin away from the clot, which facilitates clot propagation.
- Importantly, the antithrombin/heparin complex does is not inhibit thrombin bound to fibrin.
- This prevents thrombin from being inactivated at site of clot.
- Once thrombin is there, there is a lot of feedback
What is hemostasis balance?
Deficiencies in any of the 5 systems can lead to uncontrolled hemorrhaging or clotting
Describe the fibrinolytic system
- Fibrin present in clots and fibrinogen is degraded by a plasma protease called plasmin.
- The inactive form of plasmin is called plasminogen. Plasminogen is synthesized by the liver.
- Both tPA and plasminogen have a high affinity for fibrin, which reduces the circulating levels of plasmin.
- Circulating plasmin is quickly inactivated by α2plasmin inhibitor
Describe the use of antiplatelet drugs
- Used in the primary prevention in patients at high risk for myocardial infarction or stroke
- Secondary prevention to prevent recurrence
What is dual antiplatelet therapy?
- Dual antiplatelet therapy (DAPT) with aspirin and P2Y12 antagonist
- DAPT often administered for some period of time after coronary angioplasty (surgical repair or unblocking of a blood vessel)
- DAPT shown to reduce myocardial infarction and cardiac death
What is triple antiplatelet therapy?
Triple therapy with warfarin, aspirin, and clopidogrel is used in some patients with atrial fibrillation and coronary artery disease.
