Lecture 18 - Coagulation Flashcards
what is hemostasis
the ability to maintain blood in a fluid state and prevent loss from sites of vascular damage
what are the three major components of the hemostatic system?
- vascular wall
- platelets
- coagulation proteins
vascular injury exposes subendothelial collagen, which results in platelet activation (primary hemostatic plug), followed by what?
activation of coagulation proteins to produce a more stable meshwork associated with the platelet plug to seal off the damaged site and prevent further blood loss
when a fibrin clot results it is subject to regulatory control to limit the extent of what?
thrombus formation to the damaged site
there is a delicate hemostatic balance composed of what?
opposing “forces” of procoagulant proteins and regulatory proteins
what is the first response to vascular injury?
adhesion of platelets to the damaged endothelial site
in platelet adhesion, there is activation of:
surface membrane receptor (what is it?)
adhesive protein (what is it?)
appropriate surface (what is it?)
- surface membrane receptor: glycoprotein Ib/IX)
- adhesive protein (von Willebrand factor)
- appropriate surface (subendothelial collagen)
in platelet response to vascular injury, what mediates the adherence of platelets (glycoprotein Ib/IX) to the subendothelial collagen?
vWF
In the activation stage of platelet response to vascular injury, in order to effectively form a hemostatic plug, additional platelets are recruited into the local site, as platelets are activated by binding to vWF, there is release of second messenger molecules within the platelet that lead to what four things?
- shape change from discoid to spherical
- secretion of cytoplasmic ADP
- Activation of the glycoprotein IIb/IIIa receptor
- contraction of the platelet mediated through actin fibers
in the aggregation phase of the platelet response to vascular injury, platelets interact with other platelets, release of cytoplasmic ADP into the local millieu causes activation of what three things?
- adjacent platelets
- platelet-platelet binding mediated through fibrinogen
- gp IIb/IIIa receptor
in secondary hemostasis, soluble coagulation proteins within plasma are activated to generate what in an amplification reaction
thrombin
thrombin converts fibrinogen to fibrin which adds stability to the clot after fibrin monomers are covalently cross-linked by what factor?
factor XIII
the intrinsic pathway refers to what sequence of activation?
sequence of activation of factor XII by kallikrein, followed by activation of factor XI by factor XIIa
-Factor XIa activates factor IX
the extrinsic pathways refers to the sequence of what?
activation of factor VII by tissue factor
the common pathway involves activation of what followed by what?
X to Xa, followed by conversion of prothrombin (II) to thrombin, followed by conversion of fibrinogen (I) to fibrin monomers
a fibrin clot is formed when what happens?
fibrin monomers generated by thrombin polymerize to form a long strand
the fibrin monomers are made more stable by covalent crosslinking by what factor?
Factor XIII
Primary hemostasis involves the regulation of what?
platelets
in secondary hemostasis, what inhibits the activity of thrombin and other serine proteases (factors IXa, Xa, XIa, and XIIa) of the coagulation cascade in forming an inactive enzyme-inhibitor complex?
antithrombins
What system regulates the major cofactors of the coagulation cascade, factors Va and VIIIa?
Protein C
what is the major effector enzyme?
activated protein C (APC)
what protein is a major cofactor?
protein S
fibrinolysis limits generation of what?
a fibrin clot
In the presence of ____, tissue plasminogen activator (TPA) can bind to plasminogen and convert it to an active enzyme, plasmin
fibrin
plasmin breaks down previously cross-linked fibrin monomers into what?
fibrin degradation products (FDP)
the infusion of TPA can be used therapeutically in patients who have had recent _____ ______, since the activation of plasmin is limited to the site of a fibrin clot
myocardial infarcts
uncontrolled activation of plasmin can result in bleeding complications as what two things occur?
fibrinolysis and fibrin(ogen)olysis occurs
Shift in the balance that favor the procoagulant side result in _____, whereas shifts that favor the regulatory side can result in ____ _____
favor the procoagulant side result in THROMBOSIS
shifts that favor the regulatory side can result in BLEEDING DISORDERS
What is the most important part of defining the cause of a bleeding disorder?
careful clinical history
what should the clinical history include in a bleeding patient?
- description of bleeding manifestations
- age of onset of symptoms
- bleeding frequency
- family history
- medication history
- any predisposing causes
what lab screening test used to evaluate hemostasis is described: a measurement of the time needed for plasma to form a clot in the presence of added tissue thromboplastin (to initiate extrinsic coagulation cascade) and calcium ions
prothrombin time (PT)
- Prolonged PT can result from decreases or abnormalities in factors VII, X, V, II and/or fibrinogen
- Routinely used to measure degree of anticoagulation in patients receiving oral anticoagulants (Coumadin/Warfarin)
what lab screening test used to evaluate hemostasis is described: a measurement of the time needed for plasma to form a clot in the presence of added ground glass or kaolin (to activate contact-dependent Factor XII), cephalin (phospholipid), and calcium ions; it primarily accesses the intrinsic coagulation cascade
Partial thromboplastin time (PTT)
prolonged PTT can result from decreases or abnormalities of what factors?
factors XII, XI, IX, VIII, V, X, II and fibrinogen
which lab screening test is routinely used to measure degree of anticoagulation in patients receiving heparin (anticoagulant) therapy
partial thromboplastin time (PTT)
what lab screening test used to evaluate hemostasis is described: measurement of platelet number in anticoagulated blood quantitated by an automated instrument
platelet count
what is the normal range for a platelet count?
150,000 to 400,000/ uL
What term refers to a decrease in platelet number?
thrombocytopenia
what two terms denote an increase in platelet number?
thrombocytosis and thrombocythemia
what lab screening test used to evaluate hemostasis is described: a measurement of platelet function, as determined by the time taken for a standardized skin incision (5mm long x 1 mm deep) to stop bleeding
bleeding time
*The bleeding time is no longer available, it has been replaced by the PFA-100 which performs like an in vitro bleeding time
what is the normal range of time for a standardized skin incision to stop bleeding in the lab test bleeding time?
2-8 mins
*The bleeding time is prolonged when there are abnormalities of platelet number or function
when either the PT or PTT is prolonged, a mixing study with what ratio of normal plasma:patient plasma can be performed?
1:1
what percent of any given factor should be enough to have a normal PT or PTT?
50% of any given factor
if the mixing study corrects the clotting time, a deficiency of some ____ is felt to be present
factor
if the mixing study does not correct the clotting time, what is felt to be present
inhibitor
*Either factor-specific or lupus anticoagulant type
more specialized tests may be necessary to precisely define a coagulation defect, what are some of these specialized tests?
- Assays for specific coagulation factors
- Measurement of fibrinogen quantity and function
- Platelet aggregation tests
congenital disorders are usually _____, and are present at birth
hereditary
Acquired disorders occur after birth, and are often related to what?
medication or other pathologic processes
the type of bleeding provides diagnostic clues, if the bleeding is primarily mucosa it suggests a problem with what?
platelet problem
the type of bleeding provides diagnostic clues, if there are deep tissue hematomas present this suggests what?
a defect in coagulation proteins
If screening laboratory tests are normal, disorders of what may be expected?
regulatory system
in disorders of primary hemostasis, what are the clinical and laboratory manifestations?
Clinical: mucocutaneous bleeding and/or bleeding associated with trauma
Laboratory: prolonged bleeding time and thrombocytopenia
in disorders of secondary hemostasis what are the clinical and laboratory manifestations?
clinical manifestations: soft tissue bleeding and/or bleeding associated with trauma
Laboratory: prolonged PT and/or PTT and/or thrombin time
in disorders of the regulatory system what are the clinical and laboratory manifestations?
clinical: soft tissue bleeding and/or bleeding associated with trauma
laboratory: normal in screening tests
what are the two most frequent congenital bleeding disorders?
von Willebrand disease and hemophilia A
the factor VIII complex is composed of ______ which it itself is a large molecule composed of associated smaller multimers, and _____ procoagulant
vWF which itself is a large molecule composed of associated smaller miltimers and FACTOR VIII procoagulant
Both vWF and factor VIII are produced by different _____ on different _____, and the molecules associate with each other to form the complex in the plasma
different GENES on different CHROMOSOMES
What functions as both the carried molecule for factor VIII and as the “glue” between damaged endothelium and platelets (primary hemostasis)
vWF
what procoagulant is released from its associated with vWF when a clot is formed, and also participates in the generation of Factor X (secondary hemostasis)
Factor VIII
the half life of Factor VIII not bound to ____ is very short
vWF
Factor VIII is believed to be synthesized where?
in the liver
vWF is present in what two cells?
platelets and endothelial cells
what disease is described: an autosomal dominanat disoder associated with production of decreased amounts of a normal protein (quantitative abnormality) or production of a protein with abnormal function (qualitative abnormality) or both, it is fairly common in the US - approximately 1% of population is affected
won Willebrand Disease
what is the most common inherited bleeding disorder?
von Willebrand disease
what is the predominant clinical manifestation of von Willebrand disease?
mucocutaneous bleeding
- This can include:
- Nosebleeds (epistaxis)
- Eccymoses (bruises)
- mucosal bleeding
- bleeding with trauma or surgery
- excessive menstrual blood flow
what is the most common form of vWD?
production of decreased amounts of vWF
Because vWF is a carrier for ____, the measured level of _____ is also decreased
factor VIII
what are the laboratory manifestations of von Willebrand disease?
- prolonged bleeding time
- prolonged PTT (due to decreased factor VIII)
- deceased vWF
- decreased factor VII
- Platelt aggregation studies may be abnomral in 1/3
what are the therapeutic options in von Willebrand disease?
-desmopressin (releases vWF from endothelial cells) and antifibrinolytic agents in mild cases, factor VIII concentrates containing vWF and cryoprecipitate in more severe cases
what congenital disorder is described: sex-linked recessive disorder that is due to decreased production of factor VIII and the most common hereditary cause for SERIOUS bleeding
hemophilia A
what is the clinical hallmark of hemophilia A?
recurrent soft tissue bleeding, and symptoms usually start early in life
what are the clinical manifestations of hemophilia A?
- hemarthrosis
- soft tissue bleeding
- bleeding with trauma
- intramuscular hematomas
- intracranial hemorrhage
- excessive bleeding
what are the laboratory features of hemophilia A
- normal bleeding time
- prolonged PTT
- decreased VIII
- normal vWF
- normal IX
there is a high rate (30%) of spontaneous __________ responsible for appearance of new cases in non-carrier families
gene mutations
what is the % of factor VIII in:
severe, moderate, and mild forms of hemophilia A
severe: 5%
the severity of bleeding is proportional to what?
the amount of VIII present
what is the therapy for hemophilia A?
replacement of factor VIII in the form of concentrates; desmopressin may be used in mild forms with minor bleeding along with fibrinolytic inhibitors
what are the complications in hemophilia A?
joint disease, pseudotumors (hematomas), fatal hemorrhage
what are therapy related complications in hemophilia A?
transfusion-transmitted diseases, formation of antibodies to transfused VIII, allergic reactions, hemolysis
what congential disease is described: sex-linked recessive disorder that is due to decreased production of factor IX; the clinical picture is similar to factor VIII deficiency, and mild, moderate, and severe forms are recognized depending on the quantity of IX present
hemophilia B
*Mild cases can be difficult to diagnose
what laboratory features are found in hemophilia B?
- normal bleeding time
- prolonged PTT
- normal VIII and vWF
- decreased factor IX
- Complications are similar to those in VIII defiency
generally thrombocytopenia is present when the platelet count is less than what?
<100,000/uL
in thrombocytopenia, spontaneous bleeding may not become manifest until the count falls below what
20,000
Bleeding due to thrombocytopenia typically appears as petechial hemorrhages where?
in skin and mucous membranes
what are the major mechanisms of thrombocytopenia?
increased destruction and decreased production
evaluation of thrombocytopenia ia made using what?
clinical information and peripheral blood smear morphology
what examination in thrombocytopenia may be critical to determine if platelets are being produced in adequate numbers?
bone marrow examination
*Platelet antibody tests are also helpful
a variety of conditions can result in increased destruction of platelets including what?
- immune-mediated conditions
- sepsis
- DIC
- TTP
- vasculitis
- burns
- drugs
- fat emboli
- hemorrhage
what platelet disorder is described: immune mediated destruction of platelets, platelets coated with antibody that is directed against platelet-specific antigens are sequestered in the sleep and reticuloendothelial system
immune thrombocytopenic purpura (ITP)
- Acute form occurs in childhood and there is severe thrombocytopenia with abrupt onset
- Chronic form is more typical in adults and the degree of thrombocytopenia is less
immune thrombocytopenia purpura (ITP) is self limited and resolves in how many weeks
2-6 weeks
who is more affected in immune thrombocytopenic purpura: A. males B. females C. A and B D. dogs
A and B
both males and females are equally effected in ITP
*females with autoimmune disorders predominant, and spontaneous remission is unusual
in immune thrombocytopenic, there is often a history of what?
recent viral infection
what does immune thrombycytopenic present as?
- petechial hemorrhage
- bruising
- gingival bleeding (YAY something to do with dentistry)
- increased risk of bleeding
what are the therapy options for immune thrombocytopenic purpura (ITP)?
corticosteroids (suppress antibody formation), IV immunoglobulin, and splenectomy
what platelet disorder is described: acute disorder characterized by intravascular platelet activation with formation of platelet-rich microthrombi throughout the circulation, the cause is now known to be due to deficiency of metalloproteinase, ADAMTS 13, that normally degrades very-high molecular weight multimers of von Willebrand facor
thrombotic thrombocytopenic purpra
In TTP deficiency of metalloproteinase, ADAMTS 13 results in accumulation of the abnormally large ____ in the plasma
vWF - if left untreated it is associated with high mortality
what are the classic manifestations of thrombotic thrombocytopenic purpura (TTP)
- fever
- marked thrombocytopenia
- microangiopathic hemolytic anemia
- acute renal failure
- neurologic changes (headache, mental status changes)
what are the laboratory manifestations of thrombocytopenic purpura?
- thrombocytopenia
- schistocytes in peripheral blood smear
- anemia
- reticulocytosis
- normal coagulation parameters
- increase bilirubin and LD
- reflecting intravascular hemolysis
what platelet disorder is described: uncontrolled activation of the hemostatic system; both systemic thrombin formation and systemic plasmin formation; coagulation factors are activated and consumed faster than they can be produced, resulting in bleeding and microvascular thrombi; platelets are consumed with resultant thrombocytopenia
disseminated intravascular coagulation (DIC)
what are the clinical manifestations of disseminated intravascular coagulation (DIC)
- bleeding form multiple sites
- thrombotic problems
- hypotension and shock
- respiratory dysfunction
- hepatic and renal dysfunction
- CNS dysfunction
what are clinical situations with increased risk of occurrence of DIC?
-infections (Gram negative sepsis)
-Tissue injury (trauma, surgery, burn)
-Obstetrical complications
-Malignancies
-Venomous snake bites
0Vascular lesions
-Hemolytic transfusion reaction
what is the therapy of disseminated intravascular coagulation?
directed at removing the initiating stimulus, and supporting that patient coagulation protein reserve with transfusions of plasma and platelets
