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77 Cards in this Set
- Front
- Back
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What do Heparin-like molecules do? What happens from there?
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1. Enhance antithrombin III (ATIII) activity
2. Neutralize activated serine protease coagulation factors * Factors XII, XI, IX, and X; thrombin (activated prothrombin) |
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Where is prostacyclin synthesized? What is the precursor? What is its function? What is the effect of aspirin?
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1. Synthesized by intact endothelial cells
2. PGH2 is converted by prostacyclin synthase to PGI2. 3. Vasodilator; inhibits platelet aggregation 4. Aspirin does not inhibit synthesis of PGI2 by endothelial cells. |
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How are proteins C and S made? What is their function?
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1. Vitamin K-dependent factors
2. Inactivate factors V and VIII 3. Enhance fibrinolysis |
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Where is tPA synthesized? What is its function? What results?
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1) Synthesized by endothelial cells
2) Activates plasminogen to release plasmin 3) Plasmin degrades coagulation factors and lyses fibrin clots (thrombi) |
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Where is factor VIII synthesized?
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liver and reticuloendothelial tissues
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What activates factor VIII? What happens from there? Is factor VIII in the intrinsic or extrinsic pathway?
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When VIII:c is activated by thrombin, it dissociates from the VIII:vWF complex and performs its procoagulant function in the intrinsic coagulation cascade system.
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where is TXA2 synthesized? what is the precursor? What prevents its formation?
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Synthesized by platelets
1) PGH2 is converted into TXA2 by thromboxane synthase. 2) Aspirin irreversibly inhibits platelet cyclooxygenase. o Prevents formation of PGH2, the precursor for TXA2 3) Other NSAIDs reversibly inhibit platelet cyclooxygenase. |
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Is Prostacyclin synthase affected by NSAIDs? Where is the enzyme found?
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endothelial cells is minimally affected by NSAIDs.
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Where is TXA2 synthesized?
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Vasoconstrictor, enhances platelet aggregation
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Where is Von Willebrand factor synthesized? Where is stored?
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Synthesized by endothelial cells and megakaryocytes
1) Synthesized in Weibel-Palade bodies in endothelial cells 2) Platelets carry vWF in their α-granules |
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What is the function of vWF? If vWF is low what else is low?
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1) Platelet adhesion molecule
a) Binds platelets to exposed collagen b) Platelets have glycoprotein (Gp) Ib receptors for vWF. 2) Complexes with factor VIII coagulant activity in the circulation a) VIII:vWF complexes with VIII:c in the circulation. o Prevents degradation of factor VIII:c b) Decrease in vWF secondarily decreases VIII:c activity |
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When platelets adhere to vWF what happens to factor VIII in plasma?
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platelet adhesion; prevents degradation of VIII:c in plasma
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tissue thromboplastin is also known as? Is it normally found in circulation? What is its function? What pathway is it in?
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factor III
1. Noncirculating ubiquitous substance * Released from injured tissue 2. Activates factor VII in the extrinsic coagulation system |
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in peripheral blood how long do platelets survive?
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(live for ∼9-10 days
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How much of the total platelets are stored in the spleen?
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one third of the total platelet pool is stored in the spleen
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What are platelet receptors and what do they bind?
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1 Glycoprotein (Gp) receptors for vWF are designated GpIb.
2 Glycoprotein receptors for fibrinogen are designated GpIIb-IIIa |
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How do Ticlopidine and clopidogrel interfere with platelets?
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a) Inhibit adenosine diphosphate (ADP)-induced expression of platelet GpIIb-IIIa receptors
b) Prevents fibrinogen binding and platelet aggregation |
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What is the MOA of Abciximab?
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Monoclonal antibody that is directed against the GpIIb-IIIa receptor
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Where is platelet factor 3 (PF3) located and what is its function?
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1. Located on the platelet membrane
2. Phospholipid substrate required for the clotting sequence |
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What is the structure of the platelet? What is inside? What is the function?
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1. Contractile element
a) Called thrombosthenin b) Helps in clot retraction 2. Dense bodies contain: a) ADP, an aggregating agent b) Calcium, a binding agent for vitamin K-dependent factors 3. α-Granules contain: a) vWF, fibrinogen 2) Platelet factor 4 (PF4) o Heparin neutralizing factor |
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What is a heparin neutralizing factor?
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PF4
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What is the function of a platelet? What is their effect on smooth muscle?
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1. Fill gaps between endothelial cells in small vessels
a) Prevents leakage of RBCs into the interstitium b) Platelet dysfunction causes leakage of RBCs, producing petechiae. 2. Formation of the hemostatic plug in small vessel injury 3. Platelet-derived growth factor stimulates smooth muscle hyperplasia. * Important in the pathogenesis of atherosclerosis |
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How does the extrinsic pathway work?
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1. Factor VII is activated (factor VIIa) by tissue thromboplastin.
2. Factor VIIa activates factor X in the final common pathway. |
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How does the intrinsic pathway work?
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1. Factor XII (Hageman factor) is activated by:
a) Exposed subendothelial collagen b) High-molecular-weight kininogen (HMWK) 2. Functions of factor XIIa a) Activates factor X b) Activates plasminogen (produces plasmin) c) Activates the kininogen system (produces kallikrein and bradykinin) 3. Factor XIa activates factor IX to form factor IXa. a) Four-component complex is formed (IXa, VIII, PF3, calcium). b) Complex activates factor X in the final common pathway. c) Calcium binds factor IXa, a vitamin K-dependent coagulation factor. |
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What is the common clotting pathway and how does it work?
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1. Includes factors X, V, prothrombin (II), and fibrinogen (I)
2. Prothrombin complex a) Four-component system consisting of factor Xa, factor V, PF3, and calcium b) Calcium binds factor Xa, a vitamin K-dependent coagulation factor. c) Complex cleaves prothrombin into thrombin (enzyme). 3. Functions of thrombin a) Acts on fibrinogen to produce fibrin monomers plus fibrinopeptides A and B b) Activates fibrin stabilizing factor XIII c) Factor XIIIa converts soluble fibrin monomers to insoluble fibrin. d) Enhances protein-protein cross-linking to strengthen the fibrin clot e) Activates VIII:c in the intrinsic system |
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How can fibrin cross links be detected?
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Cross-links are detected in d-dimer assay
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What factors are vitamin K dependent? Where are they synthesized? What can vit K dependent factors bind in the plasma?
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1) Factors II, VII, IX, X, protein C, and protein S
2) Synthesized in the liver as nonfunctional precursor proteins 3) Function of vitamin K a. Vitamin K is activated in the liver by epoxide reductase. b. Majority of vitamin K is synthesized by colonic bacteria. 4) Activated vitamin K γ-carboxylates each factor. o Carboxylated factors can bind to calcium and PF3 in the cascade sequence. |
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Which factors are consumed in the formation of a fibrin clot?
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Consumed factors are fibrinogen (I), factor V, factor VIII, and prothrombin (II)
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What is the function of tPA? What are recombinant forms?
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1. tPA activates plasminogen to release the enzyme plasmin.
2. Alteplase and reteplase are recombinant forms of tPA used in thrombolytic therapy |
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Besides tPA what can activate plasminogen?
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(1) Factor XIIa
(2) Streptokinase ■Derived from streptococci (3) Anistreplase ■Complex of streptokinase and plasminogen (4) Urokinase (derived from human urine) |
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What is the function of Aminocaproic acid?
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■Competitively blocks plasminogen activation, thereby inhibiting fibrinolysis
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What are the functions of plasmin? What is synthesized in the liver that deactivates plasmin?
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1) Cleaves insoluble fibrin monomers and fibrinogen into fibrin(ogen) degradation products (FDPs)
■Fragments of cross-linked insoluble fibrin monomers are called d-dimers. b.Degrades factors V, VIII, and fibrinogen c.α2-Antiplasmin inactivates plasmin. ■Synthesized in the liver |
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What is the entire clotting sequence after small vessel injury?
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1.Vascular phase
a.Transient vasoconstriction occurs directly after injury. b.Factor VII (extrinsic system) is locally activated by tissue thromboplastin. c.Exposed collagen activates factor XII (intrinsic system). d.Thrombin produced changes fibrinogen holding platelets together into fibrin at the end of the platelet phase. 2.Platelet phase a.Platelet adhesion ■Platelet GpIb receptors adhere to exposed vWF in damaged endothelial cells. b.Platelet release reaction (1) Release of ADP (2) Produces conformational changes in GpIIb-IIIa receptor c.Platelet synthesis and release of TXA2 ■(1) TXA2 is a vasoconstrictor, which reduces blood flow. ■(2) TXA2 is a platelet aggregator. ■Enhances fibrinogen attachment to GpIIb-IIIa receptors d.Temporary platelet plug stops bleeding. Temporary platelet plug: held together by fibrinogen ■(1) Unstable plug that can easily be dislodged ■(2) Only held together by fibrinogen (no cross-links) ■(3) Correlates with the end of the bleeding time (BT) 4.Coagulation phase a.Fibrinogen attached to GpIIb-IIIa receptors is converted by thrombin to insoluble fibrin monomers (cross-linked). b.Stable platelet plug is formed. ■Held together by fibrin, not fibrinogen |
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What are the effects of TXA2 on coagulation?
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■(1) TXA2 is a vasoconstrictor, which reduces blood flow.
■(2) TXA2 is a platelet aggregator. ■Enhances fibrinogen attachment to GpIIb-IIIa receptors |
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What is the normal platelet count?
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150,000 to 400,000 cells/mm3
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What is normal bleeding time?
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■(1) Normal reference interval is 2 to 7 minutes
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What are aggregating molecules used to check platelet aggregation?
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Aggregating agents include ADP, epinephrine, collagen, and ristocetin.
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What are tests used to evaluate vWF?
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a.Ristocetin cofactor assay
(1) Classic von Willebrand disease (deficiency of vWF) (b) Bernard-Soulier disease (absent GpIb receptor) 2.vWF antigen assay a) Measures the quantity of vWF regardless of function 3) Decreased in classic von Willebrand disease |
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Does warfarin or heparin mess slow the PT or PTT time?
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Whether the patient is anticoagulated with heparin or warfarin, both the PT and PTT are prolonged, because both inhibit factors in the final common pathway. Experience has shown that the PT performs better in monitoring warfarin, while the PTT performs better in monitoring heparin
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What does the PT evaluate?
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Evaluates the extrinsic system down to formation of the fibrin clot
* Factors evaluated include VII, X, V, II, and I. |
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What is the normal PT time?
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11 to 15 seconds
Note: Only prolonged when a factor level is 30% to 40% of normal |
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What does the INR evaluate? What is the range for the INR?
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1) Standardizes the PT for use in warfarin therapy
2) Results are the same regardless of the reagents used to perform the test. 3) Usual range for INR is 2 to 3. |
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The PT interval can be used for what?
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1) Follow patients who are taking warfarin for anticoagulation
2) Evaluate liver synthetic function o Increased PT indicates severe liver dysfunction 3) Detect factor VII deficiency |
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What does the PTT evaluate? What is the normal reference range?
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1) Evaluates the intrinsic system down to formation of a fibrin clot
* Factors evaluated include XII, XI, IX, VIII, X, V, II, and I. 2) Normal reference interval for PTT is 25 to 40 seconds. * Only prolonged when a factor level is 30% to 40% of normal |
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What is the PTT used for? Which type of therapy is it not required for?
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1) Follow heparin therapy
o (a) Heparin enhances ATIII activity. o (b) PTT is not required to follow low-molecular-weight heparin therapy. 2) Detect factor deficiencies in the intrinsic system |
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What does the d-dimer test detect? What won't it detect?
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1) Detects cross-linked insoluble fibrin monomers in a fibrin clot
2) Does not detect fibrinogen degradation products (not cross-linked) |
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What is the d-dimer the most specific test for?
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1) Thrombolytic therapy for coronary artery thrombosis
* Thrombus is composed of platelets held together by fibrin 2) Screening test for pulmonary thromboembolism * Thrombus is composed of RBCs, platelets, WBCs held together by fibrin 3) Screening test for disseminated intravascular coagulation (DIC) * Thrombus is composed of RBCs, platelets, and WBCs held together by fibrin |
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What is the defect in Bernard-Soulier syndrome? What are clinical and lab findings?
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1) Platelet adhesion defect
2) Autosomal recessive disease 3) Absent GpIb platelet receptors for vWF 4) Thrombocytopenia, giant platelets 5) Lifelong bleeding problem |
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What is defective in Glanzmann's disease? What is the clinical feature?
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1. Platelet aggregation defect
2. Autosomal recessive disease 3. Absent GpIIb-IIIa fibrinogen receptors 4. Absent thrombosthenin 5. life long bleeding disorder |
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How can renal failure cause prolonged bleeding? How can it be reversed?
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1) Platelet aggregation defect
2) Inhibition of platelet phospholipid by toxic products 3) Reversed with dialysis and desmopressin acetate |
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Scurvy may cause what?
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ecchymoses and hemarthroses
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When is someone considered to have thrombocytopenia and increased bleeding time?
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Increased bleeding time when platelet count < 90,000 cells/mm3
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What is defective in Von Willebrand disease? What is the clinical result?
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1) Platelet adhesion defect
2) Autosomal dominant disorder 3) Absent or defective vWF 4) Decreased VIII:c 5) Combined platelet and coagulation factor disorder |
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What are causes of thrombocytopenia?
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1. Decreased production
* Examples-aplastic anemia, leukemia 2. Increased destruction a) Immune o Examples-idiopathic thrombocytopenic purpura, drugs b) Nonimmune o Examples-thrombotic thrombocytopenic purpura, DIC 3. Sequestration in the spleen * Hypersplenism in portal hypertension |
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Why is there thrombocytopenia in TTP/HUS?
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platelet consumption + hemolytic anemia with schistocytes
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What are primary and secondary causes of thrombocytosis?
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1. Primary thrombocytosis
* Examples-essential thrombocythemia, polycythemia vera 2. Secondary (reactive) thrombocytosis * Examples-chronic iron deficiency, infections, splenectomy, malignancy |
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What are causes of qaulitative platelet disorders?
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Acquired (e.g., aspirin most common) or hereditary (e.g., Glanzmann's disease)
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What is a palpable purpura a sign of?
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small vessel vasculitis
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What is Epistaxis? What is it the most common finding in/
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1. nose bleed
2. platelet dysfunction |
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Describe petechiae and ecchymoses?
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1. Petechiae are pinpoint areas of hemorrhage in subcutaneous tissue
* RBCs leak through postcapillary venular gaps in the endothelium. 2. Ecchymoses are the size of a quarter. |
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Petechiae generally only occur with what?
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thrombocytopenia
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Who does Acute idiopathic thrombocytopenic purpura (ITP) typically occur in? What type of hypersensitivity is it? What does it proceed? What are symptoms? What is the treatment?
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1) Most common cause thrombocytopenia in children 2-6 years of age
2) IgG antibodies directed against GpIIb-IIIa receptors (type II reaction) 3) Abrupt onset 1-3 weeks after a viral infection. 4) Present with epistaxis, easy bruising, petechiae 5) Absence of lymphadenopathy and splenomegaly 6) Responds well to corticosteroids |
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chronic ITP primarily occurs in who? What type of hypersensitivity? What is treatment? What happens to newborns if mom has it? What are secondary causes?
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1) Most common cause of thrombocytopenia in adults
2) Most common in women 20-40 years of age 3) IgG antibodies directed against GpIIb-IIIa receptors (type II reaction) 4) Insidious onset 5) Often resistant to steroids and requires splenectomy; IV γ-globulin temporarily stops serious bleeding (IgG blocks macrophage Fc receptors) 6) Newborn infants of mothers with ITP may have transient thrombocytopenia due to transplacental passage of IgG antibodies 7) Secondary causes: SLE, HIV, lymphoproliferative diseases |
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Neonatal alloimmune thrombocytopenia occurs in who and from what? What type of hypersensitivity is it? What are signs in first few days of life?
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1) Accounts for 20% of cases of thrombocytopenia in neonates
2) Feto-maternal incompatibility for platelet specific antigens (e.g., PlA1); PlA1 is absent from the 2% of population 3) PlA1-negative mother develops IgG antibodies during pregnancy or from a previous pregnancy or transfusion 4) Transplacental passage of IgG antibodies targets fetal PlA1 positive platelets leading to macrophage destruction of platelets (type II hypersensitivity) 4) May produce petechial hemorrhages in first few days of life or CNS hemorrhages in severe cases |
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Post-transfusion purpura predominately occurs in who? why? when does it present?
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1) Primarily occurs in multiparous women
2) Patient receiving blood has antibodies against PlA1 or other platelet antigens that are present on donor platelets 3) Severe thrombocytopenia with destruction of donor and patient platelets occurs 7-10 days after a blood transfusion |
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Heparin-induced thrombocytopenia is most common in who? What type of hypersensitivity?
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1) hospitalized patients
2) Macrophage removal of platelets surfaced by IgG antibody directed against heparin attached to PF4 (type II hypersensitivity) 3) Occurs 5-14 days after Rx; must stop heparin; release of PF4 (anti-heparin factor) after platelet destruction may result in vessel thrombosis |
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Thrombotic thrombocytopenic purpura occurs in who? What is the pathogenesis? What can enhance it? What are clincal findings? How is it treated?
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1) Occurs in adult females
2) Acquired or genetic deficiency in vWF-cleaving metalloprotease in endothelial cells 3) Increase in circulating multimers of vWF increases platelet adhesion to areas of endothelial injury at arteriole-capillary junctions 4) Platelets are consumed owing to production of platelet thrombi in areas of injury (not DIC) 5) Enhanced by other factors that damage endothelial cells (e.g., ticlopidine, clopidogrel, cyclosporine, oral contraceptives; hypertension, postpartum) 6) Clinical pentad: fever, thrombocytopenia, renal failure, microangiopathic hemolytic anemia with schistocytes (damage by platelet thrombi), CNS deficits 7) Treatment: plasma exchange; corticosteroids; vincristine Mortality rate, 10-20% |
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What is the clinical pentad of TTP?
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Clinical pentad:
1) fever 2) thrombocytopenia 3) renal failure 4) microangiopathic hemolytic anemia with schistocytes (damage by platelet thrombi) 5) CNS deficits |
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Who does HUS occur in? What are causes? What are clinical findings? how is it treated?
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1) Primarily occurs in children < 10 years old
2) Most often caused by endothelial damage at arteriole-capillary junction due to Shiga-like toxin of O157:H7 serotype of E. coli 3) Organisms proliferate in undercooked beef 4) May also be caused by drugs and other infections (e.g., Shigella, Salmonella) 5) Clinical findings similar to TTP; however, CNS findings are less frequent 6) Bloody diarrhea in 75% of cases Triad: thrombocytopenia, acute renal failure, microangiopathic hemolytic anemia 7) Treatment: plasma exchange transfusions; corticosteroids Mortality rate, 3-5% |
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what is the clinical triad of HUS?
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Triad: thrombocytopenia, acute renal failure, microangiopathic hemolytic anemia
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How is HUS treated? what is mortality rate?
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1) plasma exchange transfusions
2) corticosteroids 3) Mortality rate, 3-5% |
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How do hereditary vs acquired coagulation disorders generally differ?
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1) hereditary = single factor
2) acquired = single or multiple factors |
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In what conditions is there decreased production of coagulation factors? In which disorders is there pathologic inhibition? In which disorders is there increased consumption of clotting factors?
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1) decreased production:
a. hemophilia A b. cirrhosis 2) pathologic inhibition a. acquired circulating antibodies (inhibitors) against coagulation factors 3) consumption: a. DIC |
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A child goes to dentist and has a tooth removed that a few hours later begins to bleed. What is this an example of? Why?
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1) Coagulation disorder with Late rebleeding after surgery or wisdom tooth extraction
a. Temporary platelet plug is the only mechanical block preventing bleeding. b. Lack of thrombin prevents formation of a stable platelet plug held together by fibrin. |
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What are clinical findings in severe coagulation deficiencies?
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1) Hemarthroses
2) Retroperitoneal and deep muscular bleeding |
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What are clinical findings of coagulation disorders that are similar to platelet disorders?
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1. Ecchymoses, epistaxis
2. Menorrhagia, hematuria 3. Bleeding from tooth extraction sites 4. Easy bruiseability 5. Gastrointestinal and intracranial bleeding |
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left off with hemophilia A
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page 259
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