Flashcards in Hemostasis and Coagulation Deck (92):
What is hemostasis?
the ability to maintain blood in a fluid state (bleeding/clotting) and prevent loss from sites of vascular damage
What are the three major components of the hemostatic system?
1. vascular wall
3. coagulation proteins
_______ results in platelet activation.
vascular injury that exposes subendothelial collagen
The hemostatic balance consists of opposing actions of ______ and _______.
What are the three phases of Primary Hemostasis?
Platelet adhesion involves activation of the surface membrane receptor ______, the adhesion protein _______, and the appropriate surface, which is _________.
receptor: glycoprotein Ib/ IX
protein: von Willebrand factor
surface: subendothelial collagen
What does vWF do?
mediates the adherence of platelets to the subendothelial collagen
As platelets are activated by binding to vWF, there is a release of second messenger molecules within the platelet that leads to ____(4 events)____.
1. shape change from discoid to spherical
2. secretion of cyctoplasmic ADP
3. activation of the glycoprotein IIb/IIIa receptor
4. contraction of the platelet (mediated through active fibers)
What occurs during the aggregation stage of primary hemostasis?
-platelets interact with other platelets
-cytoplasmic ADP is released into the local milieu causing activation of adjacent platelets
-platelet to platelet binding (mediated through fibrinogen and the gpIIB/IIIa receptor)
______ formation occurs with Primary Hemostasis, _______ formation occurs with Secondary Hemostasis.
Describe the actions of thrombin.
Thrombin is generated through an amplification reaction via proteins within the plasma. Thrombin then converts fibrinogen to fibrin....fibrin adds stability to the clot after fibrin monomers are covalently cross-linked.
Fibrin monomers are covalently cross-linked by _____.
Describe the sequence of activations in the intrinsic pathway.
Factor Xii is activated by Kallikrein
Factor Xi is activated by Xiia
Factor iX is activated by Xia
The extrinsic pathway refers to the sequence of activation of ______ by ______.
by Tissue Factor
True or False: Calcium is a key element to the coagulation cascade.
The "common pathway" involves activation of _____, followed by conversion of ______. and then conversion of ______.
X to Xa
Prothrombin to Thrombin
Fibrinogen to Fibrin
How is a fibrin clot formed?
fibrin monomers are generated by thrombin and polymerize to form a long strand; monomers then cross-link due to actions of Factor Xiii (thirteen)
What is Antithrombin III?
a molecule which is activated in the presence of heparin and forms a complex with thrombin...by forming a complex, it destroys the ability of thrombin to participate in generation of fibrin monomers
What are the actions of the Protein C System?
Activated Protein C (APC) and Protein S (cofactor) will regulate/inactivate the major cofactors (Factors Va and Viiia) of the coagulation cascade
Deficiencies of Protein C or Protein S will result in ________ states.
What is the Factor V Leiden Mutation?
-resistance to enzymatic inactivation by the Protein C/S complex
What does plasmin do?
breaks down previously cross-linked fibrin monomers into fibrin degradation products (FDP) and thus provides a mechanism for breaking down a previously formed clot during wound healing
How is plasmin activated?
TPA (tissue plasminogen activator)
True or False: TPA can be used therapeutically in patients who have had recent MIs since activation of plasmin is limited to the site of the clot.
What does antithrombin inhibit?
What are four (five) common laboratory screening tests used to evaluate hemostasis?
1. Prothrombin Time (PT)
2. International Normalised Ratio (INR)
3. Partial Thromboplastin Time (PTT)
4. Platelet Count
Bleeding Time (no longer used)
______ is a measurement of the time needed for plasma to form a clot in the presence of added tissue thromboplastin and calcium ions.
Prothrombin Time (PT)
Prolonged PT can result from decreases or abnormalities in Factors ________ and/or _______. These proteins are all important in which pathway?
What is the International Normalised Ratio?
a ratio of the patient PT time compared to a "control-PT time" that allows for comparison between laboratories
*also used to monitor anticoagulant patients
_____ screens for activity within the INTRINSIC pathway which includes Factors ______ and fibrinogen.
Partial Thromboplastin Time (PTT)
(fibrinogen 10, 5, and 2 are in both! 7 is in extrinsic only)
(12, 11, 10, 9, 8, 5, 2)
What does the "platelet count" measure?
a measurement of platelet number in ANTIcoagulated blood; quantified by an automated instrument
What is the normal range for platelet count?
150,000 to 400,000 microliters
What is thrombocytopenia?
a decrease in platelet NUMBER
What is thrombocytosis (or thrombocythemia)?
an increase in platelet number
Which laboratory test is used to measure the degree of anticoagulation in patients receiving oral anticoagulants such as coumadin/warfarin?
PT (prothrombin time-measures time to form a clot)
What does PTT (partial thromboplastin time) measure?
PTT measures the time needed for plasma to form a clot in the presence of added ground glass(Kaolin), cephalin, and calcium ions
*The glass activates "contact dependent" Factor Xii
PTT is routinely used to measure degree of anticoagulation in patients receiving _______ therapy.
PTT measures intrinsic path and heparin
PT measures extrinsic path and warfarin/coumadin
(WEPT = warfarin, extrinsic, prothrombin time)
What has "bleeding time" been replaced by?
-performs like an in vitro bleeding time
If either the PT or PTT is prolonged, what is to be done?
a mixing study
-using a 1:1 ratio of normal plasma to patient plasma
-by mixing in 50% of a given factor, there should be a normalized PT or PTT
-if the mixing study is corrective of clotting time = deficiency of some FACTOR exists
-if the mixing study does not correct clotting time = an INHIBITOR is thought to be present (antibody)
What are three specialized tests that may be performed after an un-corrected mixing study?
-Factor Assays (for specific coagulation factors)
-Circulating Anticoagulant (fibrinogen amount and fxn)
-Platelet Aggregation Testing
What is the difference between a Congenital bleeding disorder and an Acquired disorder?
Congenital: present at birth, usually
Acquired: occur after birth and are often related to mediation or other pathologic processes
Bleeding that is primarily mucosal suggests a ______ problem; whereas, presence of deep tissue hematomas would suggest ________.
a defect in coagulation proteins
What type of disorder is suspected if screening lab tests are normal?
disorders of the regulatory system
What are the clinical manifestations of Primary Hemostasis Disorders? What are the lab findings?
-excessive bleeding with trauma
-Prolonged bleeding time (PFA-100)
What are the clinical manifestations of Secondary Hemostasis Disorders? What are the lab findings?
-Soft tissue bleeding
-Excessive bleeding with trauma
-Prolonged PT and PTT
-Prolonged Thrombin Time (TT)
What are the clinical manifestations associated with Disorders of the Regulatory System? What are the lab findings?
-soft tissue bleeding
-excessive bleeding with trauma
-normal PT and PTT
-normal bleeding time
-normal platelet counts
What are the three mentioned Congenital Bleeding Disorders?
1. von Willebrand Disease
2. Factor VIII deficiency (hemophilia A)
3. Factor IX deficiency (hemophilia B)
______ functions as both a carrier molecule for Factor VIII and as the "glue" between damaged endothelium and platelets.
Where is Factor VIII synthesized? Where is vWF located?
VIII = in the liver
vWF = platelets and endothelial cells
What is the Factor VIII Complex composed of?
vWF (large molecule composed of associated multimers)
Factor VIII Procoagulant
von Willebrand Disease is an autosomal _____ disorder that is associated with production of _______ amounts of a normal protein OR production of a protein with abnormal function (quantitative, qualitative, both).
(most common form of this disease is decreased amounts of vWF)
What is the dominant clinical manifestation of von Willebrand Disease?
(nosebleeds, bruises, excess menstrual flow, etc)
True or False: von Willebrand Disease is the most common inherited bleeding disorder and occurs in approximately 1% of the US population.
True or False: Symptoms of von Willebrand disease often get worse after adolescence.
False, often improve
What are the three types of vWD?
Type 1: quantitative deficiency (partial)
Type 2: qualitative deficiency
Type 3: quantitative deficiency (total)- most severe
What are the laboratory features of vWD?
-decreased Factor VIII
-prolonged bleeding time (PFA-100)
(BEND: bleeding time prolonged, endothelium derived, normal to low platelets, desmopressin for treatment)
________ releases vWF from endothelial cells and is the common drug for treating vWD. What is the most recent treatment option for vWD?
Recombinant Factor VIII
Hemophilia A is a(n) __________ disorder that occurs due to decreased production of Factor ____.
True or False: Hemophilia A is the most common hereditary cause for serious bleeding.
What is the clinical hallmark of Hemophilia A?
-recurrent soft tissue bleeding
*symptoms usually start early in life*
True or False: There is a high rate (30%) of spontaneous gene mutations responsible for the appearance of new vWD cases in non-carrier families.
False, that statement holds true for Hemophilia A
What is hemarthrosis associated with?
Hemophilia A (unusual course of bleeding into joint spaces, causing fibrosis)
Where does bleeding occur with Hemophilia A?
Joint spaces (hemarthrosis)
Which laboratory values are altered with Hemophilia A?
Factor VIII (decreased)
-the others are normal
Complications of Hemophilia A (or B) include ________, _______, and _______.
fatal hemorrhage (intracranial or retroperitoneal)
_____-______ complications of hemophilia A include transfusion-transmitted diseases, formation of antibodies to transfused VIII, allergic reactions, and hemolysis.
What type of disorder is hemophilia B? How does it differ from hemophilia A?
x-linked recessive disorder
B is less common and is associated with a decreased production of Factor IX (rather than Factor 8)
What is thrombocytopenia?
a decrease in platelet count; generally, when the platelet count is less than 100,000 microliters
*spontaneous bleeding manifests when the count falls below 20,000
How does bleeding due to thrombocytopenia typically appear? How else can thrombocytopenia be evaluated?
petechial hemorrhage in skin and mucous membranes
*peripheral blood smear
*bone marrow examination (megakaryocytes, etc)
*platelet antibody determination
By what mechanisms can thrombocytopenia develop?
1. Decreased production of platelets
2. Increased destruction of platelets (aplastic anemia)
3. Sequestration (pulled out of circulation)
4. Congenital or Acquired
____ ____ _____ is a disorder characterized by immune-mediated destruction of platelets (autoantibodies directed at the platelet membrane antigens)
Immune Thrombocytopenic Purpura (ITP)
Which platelet membrane antigens are commonly targeted in Immune Thrombocytopenic Purpura (ITP)?
With ITP, increased IgG bound to the platelet surface promotes increased sequestration by the ________ system and _______.
Describe the two forms of ITP.
Acute: occurs in childhood, common viral prodrome, sudden onset, severe thrombocytopenia, frequent spontaneous remission, affects males and females equally
Chronic: gradual onset, occurs in adults, infrequent spontaneous remission, moderate thrombocytopenia, no viral/antecedent infection, more common in females
What are the therapy options for ITP?
Clinical Features of ITP include bleeding with trauma, _______ and ______.
True or False: With ITP there are no microangiopathic changes on blood smear review.
True, no evidence of RBCs being sheared apart by thrombocytes
________ is an acute disorder characterized by intravascular platelet activation with formation of platelet-rich microthrombi throughout the circulation.
Thrombotic Thrombocytopenic Purpura (TTP)
TTP is now known to be caused by a deficiency of a metalloproteinase that normally degrades very-high molecular weight multimers of vWF. What is the name of this metalloproteinase?
What does ADAMTS 13 do?
degrades very high molecular weight vWF
True or False: Deficiency of ADAMTS 13 is an inherited disorder, not acquired.
False, TTP (enzyme deficiency) can be either inherited or acquired
True or False: TTP can be left untreated without major repercussions.
False, high mortality rate if untreated
Treatment of TTP involves _____ to replace the ADAMTS 13 enzyme.
What are the clinical manifestations of TTP?
microangiopathic hemolytic anemia
acute renal failure
neurologic changes (headache, mental status changes)
What cell will appear in the peripheral blood smear of a TTP patient?
In TTP, the increased ______ and ______ reflect intravascular hemolysis.
(body is breaking down RBC too quickly)
With DIC there is both systemic ______ formation and systemic ______ formation.
What is DIC?
unregulated, widespread intravascular activation of the hemostatic system; coagulation factors are activated and consumed faster than they can be produced which results in bleeding and microthrombi; platelets are also consumed which results in thrombocytopenia
What are four clinical situations with increased risk for occurence of DIC?
1. Infections (gram negative sepsis)
2. Tissue Injury (trauma, burn, surgery, venomous snake bites, vasculature lesions, etc.)
3. Obstetrical Complications
4. Certain Malignancies
How is DIC managed/treated?
therapy aims to:
1. remove or reverse the initiating stimulus,
2. support the patient's coagulation protein reserve
How is the patient's coagulation protein reserve "supported?"
-transfusions of blood products (plasma and platelets)