Erythrocyte clotting Flashcards
Life span of RBC
~120 days
Anemias caused by:
Iron deficiency, B12 deficiency, folate deficiency, thalassemia, RBC loss
Erythrocyte metabolism is dependent on ___.
They also require ___.
glucose (glycolysis) (because RBCs do not have mitochondria)
NADPH reducing equivalents for glutathione
Erythrocytes use ___ to reduce ferric iron to ferrous iron.
NADH (from glycolysis)
Erythrocytes use __ to modulate oxygen binding to hemoglobin, which stabilizes deoxy-hemoglobin.
2,3-bisphosphoglycerate
Glucose-6-phosphate dehydrogenase deficiency results in ___.
hemolytic anemia (NADPH keeps glutathione reduced, helps prevent buildup of ROS, low NADPH results in hemolysis, deficiency decreases NADPH)
What are some sources of oxidative stress for red blood cells?
primaquine for malaria, aspirin, sulfonamide antibiotics (folic acid inhibitors), and fava beans
What causes microcytotic anemia?
iron deficiency, lead poisoning, or thalessemia
(They cause impaired hemoglobin synthesis)
Microcytic anemia is also known as hypochromic anemia
What causes macrocytic anemia?
B12 or folate (B9) deficiency
This causes impaired DNA synthesis
Macrocytic anemia is also known as normochromic anemia
What causes normocytic anemia?
Severe bleeding, sickle cell anemia, pyruvate kinase deficiency, or glucose-6-phosphate dehydrogenase deficiency
This causes red blood cell loss
Normocytic anemia is normochromic anemia
Hemostasis
The process of clot formation and susequent dissolution
Four major events associated with hemostasis
Vascular constriction, Platelets activated by thrombin and aggregate at injury site, fibrin clot formation: intrinsic and extrinsic pathways, dissolution of clot: action of plasmin
Platelets are derived from ___.
megakaryocytes
Hormone that controls platelet formation
thrombopoeitin
True or false: Platelets contain mitochondria.
True
Life span of platelet
7-10 days
Platelet activation
Adhesion, aggregation, and activation
adhesion: At damaged site, glycoprotein IA (GPIa) binds collagen and GPIb binds VonWillebrand factor (vWF) that is attached to collagen
Aggregation: glycoprotein IIb/IIIa molecules on platelets bind other platelets through fibrin
Activation: Release of hemostasis chemicals from intracellular granules
Phospholipase A
Stimulation of platelet membrane receptors triggers activation of platelet membrane phospholipase A2 (PLA2)
Hydrolyzes membrane phospholipids, platelets release arachidonic acid
PGI2
prostacyclin, major arachidonic acid metabolite formed by vascular cells (potent vasodilator, inhibitor of platelet aggregation)
Platelet-related bleeding disorders
Congenital bleeding disorders:
Bernard-Soulier syndrome: GPIb-IX deficiency causes bleeding disorder
Acquired platelet disorders:
Thrombocytopenia (low platelet count): defective formation of platelets by megakaryocytes, bone marrow neoplasia; excessive destruction of platelets - anti-platelet antibodies
Platelet inhibition drugs
Plavix (inhibits ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex
Antiplatelet drugs (examples)
dipyridamole, ticlopidine, clopidogrel (plavix)
Less gastric bleeding than aspirin
Dipyridamole
inhibits uptake of adenosine, leading to increased platelet A2 receptor stimulation and suppression of ADP receptor action
Blood Clotting cascade (intrinsic)
Prekallikrein -->Kallikrein Factor XII --> Factor XIIa Factor XI --> Factor XIa Factor IX --> Factor IXa Factor X ---> Factor Xa (uses VIIIa) Factor II / Prothrombin --> IIa /Thrombin Factor I / Fibrinogen --> Factor Ia / Fibrin and XIII ---> XIIIa Crosslinked fibrin clot/XIIIa
Blood Clotting cascade (extrinsic)
Factor VII –> Factor VIIa
Factor X —> Factor Xa (uses VIIIa)
Factor II / Prothrombin –> IIa /Thrombin
Factor I / Fibrinogen –> Factor Ia / Fibrin and XIII —> XIIIa
Crosslinked fibrin clot/XIIIa
Fibrin is synthesize as ___ and cleaved by ___.
fibrinogen,
thrombin (A serine protease)
What does Transglutaminase do?
Factor XIIIa (transglutaminase) links lysine side chains to glutamine side chains
What activates Transglutaminase?
Factor XIIIa is activated by Factor IIa (thrombin)
True or false: Factor XIIIa is a serine protease.
FALSE
What is prothrombinase?
Factor Xa and V form it and it catalyzes the proteolysis of prothrombin to thrombin.
What does thrombin do?
This thrombin catalyzes the activation of factors V, VII, VIII, and XIII (triggering VIII is key for starting the intrinsic path)
It also catalyzes the formation of fibrin from fibrinogen
___ inhibits thrombin.
Hirudin from leeches
Vitamin K is important for ___.
The synthesis of prothrombin and other clotting factors
Cofactor for the enzyme that carboxylates Glutamine
Gamma-carboxyglutamate binds ___.
Calcium
Antagonist of Vitamin K
warfarin
Vitamin K dependent clotting factors
X, II, VII, IX
also regulatory factor protein C
Activated partial thromboplastin time
Phospholipid and silica added (test of the intrinsic pathway)
Prolonged aPTT indicates a deficiency in VIII, IX, XI, XII (all except XIII and VII) (used to monitor IV heparin)
Prothrombin time
Used to test the extrinsic pathway
Factor III added to plasma. Specific for reduced factor VII but also X and II (used to monitor warfarin)
Common pathway for clotting (simplified)
10/5 = 2. Factor X goes to Factor V goes to Factor 2
Pnemonic for remembering extrinsic pathway
You do PT outside at 7 AM
Prothrombin time = extrinsic, uses Factor VII, then common pathway
Prothrombin time can reveal ___.
Acquired bleeding disorders:
Vitamin K deficiency
Oral anticoagulants (Warfarin)
and Liver disease (Reduced hepatic synthesis of Factor II, VII, IX, X)
Activated prothrombin time can reveal ___.
Hemophilia A (Factor VIII)
Hemophilia A is associated with ___.
Factor VIII
Antithrombin II
Serine protease inhibitor: inhibits activity of thrombin, Factos IXa, Xa, and XIa
What does heparin do?
It binds to antithrombin III and increases its affinity for thrombin (thereby reducing clotting)
Where is antithrombin synthesized?
In the liver
Deficiency of antithrombin can lead to __.
increased risk of venous thromboembolism
Factor V Leiden
Factor V variant that is resistant to protein C (increases clotting)
Thrombin binds ___ on the surface of endothelial cells and activates ___.
thrombomodulin,
protein C
Protein C forms a complex with ___ and provides selective proteolytic degradation of ___.
protein S,
Factor Va and VIIIa
____ (a serine protease), degrades fibrin clot.
Plasmin
Converts plasminogen to activated plasmin
tPA (tissue-type activator)
T-PA inactivators
Plasminogen activator-inhibitor types 1 and 2 (PAI-1, PAI-2)
t-PA
converts plasminogen to activated plasmin, made by endothelial cells, Has Kringle domains (binds fibrin), low basal concentrations in plasma
Hemophilia A
Classic hemophilia
Deficiency in factor VIII (cofactor activating Xa)
X-linked
prolonged bleeding from wounds, easy bruising
treat with human plasma or recombinant factor VIII
Von Willebrand Disease
Defective platelet adhesion (prolonged bleeding time)
different forms with different severity
more common than Hemophilia A
Antithrombin deficiency
Causes deep vein thrombosis and pulmonary embolism
Pyruvate Kinase deficiency
Separate isoforms in humans (one for erythrocyte; active tetramer)
Reduced ATP production results in failure to maintain cation gradient, loss of potassium and water, cell dehydration, hemolytic anemia
Hemolytic anemia has symptoms less severe than expected due to increased 2,3-bisphospholgycerate (2,3-BPG), results in greater release of oxygen to tissues
Partial block of PK increases 1,3-BPG and therefore 2,3-BPG
Wide range of severity, from infant death to asymptomatic adults
Treatment: transfusions and possible splenectomy (to prevent hemolytic anemia)
