Unit 6 Flash Cards Hematology coagulation
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Transcript of Unit 6 Flash Cards Hematology coagulation
Disseminated intravascular coagulation (DIC)(consumptive coagulopathy)
a pathological activation of coagulation (blood clotting) mechanisms that happens in
response to a variety of diseases.
* DIC leads to the formation of small blood clots inside the blood vessels throughout the body* The small clots consume coagulation proteins and platelets, normal coagulation is disrupted and abnormal bleeding occurs from the skin, the gastrointestinal tract, the respiratory tract and surgical wounds. The small clots also disrupt normal blood flow to organs* DIC can occur acutely slower, chronic basis, and may participate in the development of multiple organ failure, which may lead to death.* In acutely ill and shocked with widespread hemorrhage (common bleeding sites are mouth, nose and venipuncture sites), extensive bruising, renal failure and gangrene.
Activation of Platelets
Thrombin activates platelets via protease activated receptors PAR Thrombin cleaves PAR PAR ‘plugs itself in’ Activation of PAR signals intracellular events to begin - Shape change and Granule release
Three Phases of Hemostasis
_ Primary hemostasis_ Formation of a platelet plug_ Vasculature and platelets
_ Secondary hemostatis_ Consolidation of the platelet plug by fibrin_ cascade and inhibitors
_ Fibrinolysis_ Cleanup_ cascade and inhibitors
Acute Phase Response
a group of physiological processes occurring soon after the onset of infection, trauma, inflammatory processes, and some malignant conditions;
increase in acute phase proteins in serum, fever, increased vascular permeability, and metabolic and pathologic changes.
These reactions aim to prevent ongoing tissue damage, isolate and destroy the infective organism and activate the repair processes necessary to restore the host/organism’s normal function
leukocytosis, fever, alterations in the metabolism of many organs as well as changes in the plasma concentrations of various acute-phase proteins made by hepatocytes in the liver
main mediator of the acute phase reaction is IL6 regulated by IL1
Start of Common Pathway Factor 10
Primary Hemostasis Formation of a platelet plug - Vascular system and platelets_ Activation in response to stimuli (Thromboplastin)
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_ Damaged vessel releases_ Epinephrine, collagen, thrombin, ADP, serotonin
_ Adherence to the margins of the lesion - platelets_ Cell membrane receptors _ GpIIb/IIIa, GpIb
_ Release of granule content (caused by GpIIb/IIIa, GpIb)_ Alpha granule _ Dense granule
_ Aggregation into a primary platelet plug
Start of Intrinsic PathwayActivated by
contact activation of factor XII (12)HMWK – high molecular weight kiniageninitiated by components entirely contained within the vasculaturethe contact system-various electronegative surfaces, such as collagen fibers, skin, or sebum
Start of Extrinsic PathwayActivated by
F - III (3) – Tissue ThromboplastinActivated by tissue trauma
factors circulate in the form of inactive precursors called
zymogens
von Willebrand Disease
symptoms include nosebleeds, skin bruises, and hematomas. oral cavity bleeding
excessive menstrual bleeding, easy bruising. Prolonged bleeding after minor trauma to skin or mucous Severe hemorrhage after major surgery delayed bleeding, up to several weeks after surgery. Heavy bleeding is common after tooth extraction or other oral
surgery Bleeding symptoms are often exacerbated by aspirin and oral
contraceptives.
High molecular weight kininogen(HMWK) is also known as what Factor?
Fitzgerald Factoracts as a cofactor for the activation of Factor XI,
prekallikrein, and Hageman factor
Factor (I): Fibrinogen - acted on by thrombin to form fibrin
Factor (II): Prothrombin - Coverts into thrombin
Factor (III): Tissue Thromboplastin - Activates Factor VII when exposed to tissue fluids.
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Factor (IV): Ionized Calcium - Assists in the activation of other factors.
Factor (V): Proaccelerin - Accelerates the conversion of Prothrombin to Thrombin.
Factor (VI) Not assigned
Factor (VII): Stable Factor - activated by Factor IIIEnzyme involved transforming
prothrombin to thrombin
Factor (VIII): Antihemophilic A Passed on from father to son, loss of this factor leads to
inability to clot.essential for the formation of blood thromboplastin
Factor (IX): 2 names and what it does? plasma thromboplastin componentChristmas Factor
Helps activate Factor X
Factor (X): Stuart /Prower enzyme for common pathway activation
of prothrombin
Factor (XI): Plasma Thromboplastin Antecedentprecursor to Plasma Thromboplastin, which is one of the
proteins that alters the shape of blood platelets
Factor (XII): What pathway?Activated when?
Hageman Factor Intrinsic Activated when a foreign substance is in the body.
Factor (XIII): Fibrin Stabilizing Factor(FSF)Helps to further stabilize the clot.
Prekallikren is also known as what Factor? Fletcher Factor
Factor V Leiden: this mutated gene leads to what?
Increase in clot formation which results in a degradation of Factor (V), by Protein C.
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AdhesionPlatelet adhesion is primarily mediated
by binding of
_ the platelet glycoprotein GpIb to subendothelialvon Willebrandfactor(vWF) carries Factor 8
_ it is rapidly followed by release of granule content
Release of granules
_ Dense granules - _ ATP, ADP, serotonin, Calcium_ Alpha granules_ Albumin, fibrinogen, factor V, vWF, HWMK_ Platelet specific - _ β-thromboglobulin, PLT-factor 4, PLT-derived growth factor_ Lysosomal granules - Acid hydrolase
Secondary hemostasis
“Blood coagulation” – coagulation factors Activated by primary hemostasisChange in platelet surface upon aggregation A secondary hemostatic plug is formed The primary platelet plug is reinforced Further bleeding from the lesion is prevented Primary and secondary hemostasis occur simultaneously Interactive mechanism
Physiologic control mechanisms
Blood flow Feedback inhibition Liver clearance Inhibitors
Anti-thrombinsTissue factor pathway inhibitorProtein CProtein S
Types of coagulation factors
ZymogensCirculate in inactive forms Activated to proteasesBecome activated to enzyme formFactors II, VII, IX, X, XI, XII, XIII
Accelerators - ‘Gas pedals’ Factors V and VIII
Others - Fibrinogen (Factor I)
Inhibitors (* Vitamin K dependent) Put the ‘brakes’ on clot formation by
slowing down and regulating the process
Protein S* Protein C*ATIII TFPI
Alpha-2-antiplasminPAI (plasminogen activator factor)
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Fibrinolysis2 actions
_ Keeps blood clots from growing andcausing problems_ Leads to the breakdown of fibrinclots
FibrinolysisPrimary and Secondary
_ 1o - _ Normal clot breakdown _ Occurs naturally_ 2o - _ Clot breakdown due to medications_ tPA, streptokinase, urokinase_ Another disorder _ DIC, Bacterial infections_ Intense exercise, inadequate oxygenation, low blood sugar
3 types of disorders of HemostasisCause bleeding or thrombosis problems
Platelet disordersCoagulation factor disordersFibrinolytic disorders
*Many more deaths occur from thrombosis problems than bleeding
Formation of Platelets
_ Formed in bone marrow_ Begin as megakaryoblasts mature to megakaryocytes_ 4-5 days maturation_ Thrombocytes - _ In circulation 8-12 days_ Normal range: 150,000-450,000 uL_ 10-30 PLTs/HPF
Thrombocytopenia
Most common cause of bleeding_ Range - 50-150 x 109/L
_ Bleeding unexpected_ May imply qualitative disorder
_ 10-50 x 109/L_ Bleeding may follow trauma, surgery, dental_ <10 x 109/L_ Spontaneous bleeding requiring treatment
ThrombocytopeniaCauses
Inherited Marrow hypoplasia
ChemotherapyDrug or ethanol
Immune-mediated consumptionAcute or chronic AITT, neonatal alloimmune,post-transfusion purpura
Non-immune mediated consumption
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TTP, HUS, DIC, HIT, type 2B vWD
Factors that alter automatedplatelet counts
_ False decreases _ Platelet satellitism _ Platelet aggregates_ Giant platelets
_ False increases_ Cell fragments (schistocytes)_ Extreme microcytosis
Chemical that activates platelet receptors seratonin
1. clot stabilizing factor XIII (13)
5. % HCT level where anticoagulant needs adjustment 55%
8. fragments D & E are measured by this test D dimer
10. inactivation of cyclo-oxygenase Aspirin
11. caused by; viruses, antibodies, overactive spleen and unknown etiological agents
ITP (autoimmune)Immune Thrombocytopenic Purpura
Antibodies bind to platelets, shorting platelet lifespan
13. anticoagulant of choice for coag tesing Sodium Citrate
14. intrinsic pathway is activated by Contact Factor
16. plt satellitism, giant plts, and plt clumps all cause falsely "blank" automated platelet counts decreased
18. large molecule that helps platelets bind Von Willibrand Factor
21. Factors X, V, II, and I are in this pathway Common pathway
23. factor VIII deficiency Hemophilia A
27. APTT is the test of choice monitoring "blank" therapy Heprin
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29. Vitamin K antagonist Rat Poison (Coumadin)
28. deficiency causes deep vein thrombosis & hypercoagulabilty
Protein C
31. factor XII deficiency demonstrates no "blank" manifestations
Hemorrahaic
30. Factors II, VII, IX, & X are "blank" dependent Vitamin K
2. factors in this pathway are XII, XI, IX, VIII, X, V, II, & I Intrinsic
3. 170-410 mg/dl is reference range Fibrinogen
4. treatment is Factor IX concentrate Hemophilia B
6. for bleeding time the blood pressure cuff is kept at "blank" mm/Hg
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7. the platelet stores and synthesizes this factor Von Willibrand
9. measured by the FSP test (X, Y, D, & E) Monomers
12. individuals are clinically asymtomatic for most of their life
Factor V Leiden
15. extrinsic pathway is activated by Thromboplastin
17. PT is the test of choice for monitoring "blank" therapy
Coumadin
19. disease state indicated by elevated FSP and D-dimer fragments
DIC
20. non-correction in a mixing study indicates the presence of
inhibitor
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25. 2.0-3.0 is standard therapeutic range INR
26. 27-36 sec is reference range APTT
22. factors in this pathway are VII, X, V, II, & I Extrinsic
24. two weeks is average life span in circulation
Platelet
Thrombus is A Blood clot
Vitamin K coagulation inhibitors Protein C and protein S
plasmin Meat cleaver that chops up clot into smaller pieces
Regulators of the coagulation cascade
Identify substances that are contact activators
G. Describe the physiologic controls of hemostasis
3 actions and 4 inhibitors
• Blood flow • Feedback inhibition• Liver clearance
• Inhibitorso antithrombins o tissue factor pathway inhibitor (TFPI)o protein C o protein S
Primary Hemostasis involves (2) Smaller injuries to blood vessels, platelet plug
Secondary Hemostasis involves (2) Large injuries to blood vessels/tissueInvolves platelets and plasma coagulation
Fibrinolysis - definition Breakdown of fibrin clots caused by enzymes
Man made clot busters for ER TPA, streptokinase, urokinase
Tissue factor (in all cells) does Activates the plasma coag system through F 7
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Coagulation occurs in steps
1. Reactions in 2 pathways activate serine proteaseenzymes and form prothrombin activator(V and X)
2. Prothrombin activator cleaves prothrombin into 2 fragments
3. Thrombin cleaves small peptides to give rise to an insoluble fibrin polymer (also activates F 13 – catalyzes formation of covalent bonds between fibrin molecules, cross-linking)
vWF binds during platelet adhesion to Glycoprotein receptor for platelet surface membrane (GPIb)
Protein C
prevents blood clottinga major physiological anticoagulant.
a vitamin K-dependent serine protease enzyme that is activated by thrombin
Protein S
a vitamin K-dependent plasma glycoprotein synthesized in the endothelium
functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa
ThrombocytosisPlatelets still may not function right so you still
may have bleeding
_ PLT >450 x 109/L_ Reactive
_ Hemorrhage, surgery, iron def, inflammation_ Myeloproliferative disorders
_ ET, CML, PV_ May demonstrate bleeding or thrombosis
_ PLT >1 x 1010/L - _ Plateletphoresis may be required
Platelets
_ Normal - 2-4 um diameter_ Dense granules _ α-granules
_ Giant - >7um diameter_ MPD, MDS, May-Hegglin anomoly
_ Grey - _ Slightly inlarged_ Bernard-Soulier syndrome_ α-granule deficiency
Qualitative disordersDon’t work right
_ Storage pool deficiency_ Dense granules
_ Chediak-Higashi: albinism
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_ Wiskott-Aldrich: immunodef/severe eczema_ α granule_ Grey PLT syndrome: moderate bleeding_ Acquired - _ MDS, MDP
Metabolic PathwayDefects
_ Platelet release/secretion defects_ “Aspirin like”
_ Cycloxygenase_ Thromboxane synthetase
Qualitative disorders_ Receptor Defects
_ Mucocutaneous bleeding
Disorder Receptor lackingBernard-Soulier GP Ib/VGlanzmann’s thrombasthenia GPIIb/IIIa
Platelet Function “3A’s & 2R’s”_ Activation _ Adhesion _ Aggregation_ Release Reactions
_ Dense body and alpha granulecontents_ Retraction
Aspirin (3 things)blocks cycloxygenase
inhibits platelet activationaffects all platelets in circulation
General: Aspirinlike effect
_ Aspirin _ NSAIDs_ Antibiotics _ Herbs_ Garlic _ Vitamin E
Coumadin stays in system 2 months
Heparin stays in system 4 hours
The PFA-100 R System Assesses how aspirin affects platelet function
_ measures platelet plug formation_ small, whole blood sample (< 1 mL)_ reports a Closure Time in 4-8 minutes._ challenges platelets under highshear flow conditions_ hemodynamic conditions_ sensitivity of 95% following ingestion of a single 325 mg tablet of aspirin
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Platelet AggregometryMeasures aggregation
_ Qualitative function test_ Whole blood or PRP
_ Agonist (activator) is added_ Platelet clumping is recorder
Agonist aspirin/release defect
Membrane defect
storage pool defect
Thrombin normal normal ↓ Arachidonic
acid ↓ normal ↓
ADP, epi, collagen
↓ ↓ ↓
Specimen Collection_ Plasma
Lt Blue Tube9:1 blood to anticoag
_3.2% (0.109 M) Sodium Citrate - Buffered_Allow tube to fill_Short draws
• Excess anticoag • Erratic results_Invert to mix _Room temp_Centrifuge - _2500 x g for 10 min – we want plasma to be platelet free_Freeze rapidly at -70oC, then thaw rapidly too
Results of Hemolysis Activates clotting mechanism
Silicon coated and plastic tubes and pipets Prevent activationGlass and air can activate coag cascade
_ Whole bloodFor PFA 100 assay to replace bleeding time
Sodium Citrate_ Room temp _ No centrifugation
_ Run within 3 hours
_ Hct Adjustment
_ Hct >55%More anticoagulant goes into plasma
C=(1.85 x 103)([100-Hct]*V)C= Sodium Cit in mls V= whole blood in mls
Inhibitors of clotting
AT Heparin CofactorProtein C Protein STFPA Alpha 2 MacroglobulinAlpha 1 Antitrypsin C1 Inactivator
Inhibitors of Fibrinolysis PAI-1 PAI-2 PAI-3Alpha 2 Antiplasmin
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Specimen CollectionAvoid
_Hemolysis_Lipemia – can run on mechanical Fibromenter
(New analyzers have both mechanical and optical detection)_Traumatic draws
Activators of Coagulation Coagulation Factors PhospholipidsCa++
Job of activators and inhibitors To get clotting and fibrinolysis to balance
Activators of Fibrinolysis Factor X11a(12) Factor X1a(11)Kallikrein T-PA U-PA
Anticoagulant Therapy MonitoringMajor reason that we do coag testing in the lab
You want to
_ Oral: Warfarin (coumadin) - _PT with INR_ Standard unfractionated heparin - PTT, Chromogenic anti-
Xa_ LMWH(low molecular weight heparin): Enoxaparin, Tinzaparin - Chromogenic anti-Xa_ Direct thrombin inhibitors: Argatroban, Lepirudin,
Bivalirudin - _PTT
Hemorrhage and Coagulopathy
_ Bleeding - Local tissue injuries (not from coagulopathies)_ Suspect Coagulopathy
_Multiple sites _Spontaneous_Excessive _Recurrent
_ Most are Acquired_Drug interactions _Underlying systemic disorder
ThromboplastinGold standard
ISI 1.0 – most sensitive, most expensiveDon’t use over ISI 2.0
Coagulopathy Missing a factor
Primary hemostasis_Von Willebrand tests
_ Factor VIII activity_vWD Activity (ristocetin cofactor)
_vWF Antigen (Is it there?)Aggregomentry – how platelets respond to different stumuluses
Von Willebrand Disease Deficiency or abnormality of VWF
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Involved in Primary and SecondaryHemostasis
Multimeric protein necessary for PLT adhesionCarrier of factor VIII (8)Ineffective platelet aggregationLevels vary with blood type, common in OAcute phase reactantHuge platelet
Incidence - 1-2% in general population (inherited and acquired) Treatment - Desmopressin (DDAVP) nasal spray – stimulates any stored VWF to go into peripheral blood
ScurvyIncidence on rise
_Marked capillarybleeding_Progressive anemia
_ Vitamin C deficiency
Systemic (mucoscutaneous) Bleeding implies defect in 1o hemostasis
Bleeding Due to Factor Deficiency implies defect in 2o hemostasis
Test Menu _Bleeding Disorders
_Intrinsic - _PTT_Extrinsic - _PT
_Common - _Fibrinogen, _TT, _Reptilase Time (not prolonged by heparin)
Most common factor deficiency Factor 8
PTT↑, PT normal – Missing? 12, 11, 9, 8
PT↑, APPT normal – Missing? 7
PT↑, APPT↑ – Missing? 10, 5, 2, 1
Covalently links loose fibrin into strong clot Factor 13
Test Menu_ Fibrinolysis
_Fibrinogen activity _Reptilase time_TT _Euglobulin clot lysis time_Plasminogen activator inhibitor-1 (PAI-1)
Test Menu_ DIC
_↑D-dimer (quantitative) – for D and E fragmentsSpecific for covalently linked clot
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(many fibin stands in circulation) _↑PT _↑PTT _↑Fibrinogen Schistocytes in blood smear
What you use up when you make a clot 1, 13, 8 , 5, platelets
Thrombosis disorders: implies defects in fibrinolysis
Lupus Anticoagulant _ScreensCan develop antibodies against their factors
APPT↑_LA sensitive PTT (PTT-LA)Have clotting problems because of inhibition in the
fibrinolytic pathway
Mixing study (PTT-LA mixing study)½ patients + ½ normal blood
APPT↑ after mixing = inhibitor Normal results after mixing = factor deficiency
Treatment for DIC Heparin
Factor V Leiden
Defect in Factor V _ Inherited Condition_Seen mostly in northern European populations
_ Results in hypercoagulation and thrombosisFactor V resistant to Proteins C and S
Process does not get slowed down
Factor V Leiden
_Factor V has increased resistance to inactivation by protein C_Normally Protein C along with Protein S binds to the surface of a platelet, which degrades Factors V and VIII, preventing premature clotting_When Factor V Leiden is present, degradation is prevented and clotting occurs inside the veins
Factor V LeidenWho is affected?
6% of populationPregnant women or on Birth Ctrl pills
Causes thrombosis, even death
Symptoms
_ Pain swelling, and discoloration in legs, and/or arms due to clotting in the veins_ Extreme difficulty breathing due to pulmonary clotting_ Severe headaches due to clotting in the brain_ *There is no evidence showing that Factor V Leiden is associated with clots in the heart because it has its effects in the veins and not the arteries
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Increased Risks For Clotting
_Smoking _Overweight_Sitting or standing for long periods of time_Women with Factor V Leiden should not take the contraceptive pill_Pregnancy also increases the risk of thrombosis
Factor V LeidenTreatment
_Treatment may or may not be needed, depending on severity of disease (Homozygous or heterozygous)_If treatment is needed, long term anticoagulants are used_Heparin _Warfarin_Low-molecular-weight heparins
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