Homeostasis Flashcards
what is the normal hemostatic process (3)
1. vasoconstriction: local neurohumoral factors induce a transient vasoconstriction
1. primary hemostasis: platelets adhere to exposed extracellular matrix (ECM) via von Willebrands factor and are activated undergoing shape change and granule release. released ADP and thromboxane A2 –> further platelet aggregation to form the primary hemostatic plug
3. secondary hemostasis: local activation of coagulation cascade results in fibrin polymerization, cementing platelets into definitive secondary hemostatic plug
how do platelets cause coagulation
cell membrane has phospholipids
enzymes in phospholipids is where coagulation will occur
what are the regulatory mechanisms in normal hemostatic process
- thrombus and antithrombotic events: release of tissue type plasminogen activator (t-pa) (fibrinolytic) and thrombomodulin (interfering with coagulation cascade), limit the hemostatic process to the site of injury
good control of clot formation
what are the activities of endothelial cells that favour thrombosis
damage –> allows platelet adhesion –> held together by fibrinogen
injury or activation of endothelial cells results in a procoagulant phenotype that augments local clot formation
membrane bound tissue factor: extrinsic coagulation sequence
what are endothelial cell activities that inhibit thrombosis
antithrombin III inactivates thrombin and factors Xa and IXa
tissue factor pathway inhibitor: inactivates tissue factors VIIa and Xa
intact endothelial cells serve primarily to inhibit platelet adherence and blood clotting
what are the 3 mechanisms that platelets undergo after injury and encounter of the ECM
- adhesion and shape change
- secretion
- aggregation
what stimulates the formation of a primary hemostatic plug
released ADP
what stabilizes and anchors the aggregated platelets
fibrin deposition
what do platelets expose
phospholipid complexes that are important in the intrinsic coagulation pathway
what do injured or activated endothelial cells expose
tissue factor which triggers extrinsic coagulation cascade
what is the process of coagulation
series of enzymatic conversions turning inactive proenzymes into activated enzymes
produces thrombin –> converts plasma fibrinogen into insoluble fibrin
how is the coagulation cascade divided
- instrinsic
- extrinsic
- common pathway
what does activation of the coagulation system also activate
the fibrinolytic system
what does the fibrinolytic system generate
plasmin
plasmin breakdown fibrin and interferes with its polymerization
what are the fibrin split products produced when plasmin breaks it down
D-dimers
fibrin degradation products
what is free plasmin converted to
rapidly complexes to alpha2-plasmin inhibitor and is inactivated
what is thrombocytopenia
decreased circulating platelets in the peripheral circulation
at risk for spontaneous hemorrhage
what are the clinical presentations of thrombocytopenia
- epitaxis
- ecchymoses: hemorrhagic bruises
- petechiae: pin point hemorrhages
- hematuria
- hematochezia: fresh blood in feces
- hyphema: bleeding in chamber of eye
- melena: partially digested blood in feces
when does hemorrhage soley due to thrombocytopenia occur
not usually until Plt = <50 x 10^9/L
pretty low before there is clinical signs
(reference is 200-500x 10^9/L)
how is thrombocytopenia diagnosed
- CBC
- smear examination: check for platelet aggregates, morphology and size
- manual platelet count: if numbers fall below the sensitivity of automated machine
what are the causes of thrombocytopenia (4)
- increased destruction (primary (idiopathic) or secondary immune mediated destruction)
- decreased production: marrow disorders
- increased consumption: DIC, thrombosis
- increased sequestration: hypersplenism (rare)
what are platelet disorders
have enough platelets but can’t do their job properly
what are the clinical signs of platelet disorders
mucosal bleeding, hematuria, petechiae (not typical of vWD), ecchymoses
clinical signs may vary
but platelet numbers are normal
how are platelet disorders diagnosed
platelet function test
buccal mucosal bleeding time (should stop in <4mins)
what is factor VIII-von Willebrand factor (vWF) complex and how does it form and wherei is it present
factor VIII is synthesized in the liver and kidney and vWF is made in endothelial cells and megakaryocytes
the two associate to form a complex in the circulation
also present in the subendothelial matrix of normal blood vessels and the alpha granules of platelets
what occurs to factor VIII-von Willebrand factor (vWF) complex when there is an endothelial injury (4)
- exposure of subendothelial vWF causes adhesion of platelets primarily via glycoprotein lb platelet receptor
- circulating vWF and VWF released from the alpha granules of activated platelets can bind exposed subendothelial matrix, further contributing to platelet adhesion and activation
- activated platelets form hemostatic aggregates; fibrinogen (and possibly vWF) participate in aggregation through bridging interactions with the platelet receptor gpIIb/III
- factor VIII takes part in the coagulation cascade as a cofactor in the activation of factor X on the surface of activated platelets
what is a platelet function disorder
Von Willebrands disease
what is von willebrands disease caused by
caused by quantitative and functional deficiencies in vWF
what are the 3 types of von willebrands disease
- partial quantitative disorder
- loss of large molecular weight
- abscence
what is the most common inherited disorder of hemostasis in dogs
von willebrands disease
how is VWD disease evaluated
- BMBT (not specific for VWD)
- quantitative assay –> ELISA for vWF;Ag, reported as percentage of normal (<50% indicates vWF deficiency)
- functional assays: ristocetin cofactor assay, VWF collagen binding assay
what is thrombocytosis
blood platelet concentration above reference interval
what causes thrombocytosis (3)
- reactive thrombocytosis –> increased production (inflammation, iron deficiency, blood loss, nonhemic neoplasia)
- redistribution: physiologic (exercise, epinephrine)
- hemic neoplasia (involves platelet line): primary essential thrombocythemia, acute megakaryocytic leukemia
what are the two types of clotting disorders
- acquired: vitamin K deficiency, severe hepatic disease, DIC
- hereditary: X-linked deficiency hemophilia A (FVIII) and B (FIX), FVII deficiency beagles
how can bleeding manigest as in clotting disorders
- hematomas
- GI tract and urinary bleeding
- hemarthrosis
what are examples of hereditary clotting disorders
- hemophilia A (FVIII) most common (dogs, cats, horses)
- hemophilia B (FIX): X-linked traits, males affected, hemarthrosis, hematomas
how are clotting disorders diagnosed
both types cause prolongation of intrinsic/common pathway tests
specific diagnosis can be achieved testing with specific factor deficient plasma
what are examples of acquired coagulopathies
- vitamin K deficiency: biliary obstruction, infiltrative bowel disease (inflammatory or cancer of bowel –> gut lining is thicker and makes it difficult for nutrients to be absorbed)
- vitamin K antagonism: coumadin (warfarin), 2nd generation anticoagulant rodenticides, affects FII, FVII, FIX, FX
how are acquired coagulopathies diagnosed
in vitro tests
prolongation of PT (prothrombin time) and aPTT (activated partial thromboplastin time)
normal TCT (thrombin clotting time)
what do in vitro clotting tests reqiure
- tissue factor for extrinsic pathway
- contact activator for intrinsic pathway
- exogenous source of phospholipids and calcium
what parts of the pathway do the following tests analyze:
- activated partial thromboplastin time
- thrombin clotting time
- prothrombin time
- intrinsic/common pathway
- common pathway
- extrinsic/common pathway
how is fibrinogen measured
modified claus method (thrombin initiated clotting rate)
rate of clot formation in diluted citrated plasma with addition of high concentration thrombin solution
what does it mean that fibrinogen is a positive acute phase protein
sensitive indicator of inflammation
fibrinogen is
whats virchow’s triad
what is disseminated intravascular coagulation
an acquired syndrome characterized by the intravascular activation of coagulation with loss of localization resulting from different causes
it can originate from and cause damage to the microvasculature which if sufficiently severe can produce organ dysfunction
DIC is always a secondary phenomenon
what are primary disease conditions that can lead to DIC
- neoplasia
- systemic inflammation
- endotoxemia
- sepsis
how is DIC initiated
massive tissue trauma causes exposure of huge amounts of tissue factor
some conditions can induce TF expression
abberant expression of TF by intravascular cells (monocytes, tumour cells)
what is the pathophysiology of disseminated intravascular coagulation
how is DIC diagnosed
CBC: thrombocytopenia
- clotting times: aPTT and PT clotting times prolonged, hypofibrinogenemia
- elevated D-dimers (dogs)
