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94 Cards in this Set
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Platelet (lifespan, production, function, count, destruction) |
7-9 days maintain primary hemostasis (primary plug) 150k -450k/mm cubed and irrespective of age destruction in spleen and liver (reticuloendothelial system), endothelial cell junctions and subendothelium at sites of injury |
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Platelet production |
Thrombopoietin (liver)- Receptors for TPO are on all the cells but increasing action as matures stem cell, megakaryocyte progenitors, immature megakaryocyte, mature megakaryocyte (big) then platelets |
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TPO levels (liver failure, ITP, marrow failure states) |
Increased in marrow failure states (aplastic anemia) normal or slight decrease in ITP decreased in liver failure |
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Platelet kinetics (removed by, percent in spleen, young "reticulated" platelets) |
removed from circulation by monocyte/MO system 25-35% in spleen 15-25% of daily turnover of platelets for maintaining vascular integrity young platelets contain mRNA from megakaryocyte precursors and function is more potent) |
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Platelet structure and shape |
Pseudopods on activated (for adhesion) alpha and dense granules Mb with receptors round and flat discs- 1-2 micrometer
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alpha granules |
vWF, fibrinogen, PF4, PDGF |
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dense granules |
ADP, ATP, serotonin, Ca |
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Platelet in primary hemostasis |
Adhesion (subendothelial vWF/collagen with pseudopods/GPIb-IX0V and GPVI) Activation (change shape and expose GPIIb/IIIa receptors) Aggregation: cross linking of GPIIb/IIIa by fibrinogen or vWF degranulation formation of primary hemostatic plug Propagation of coagulation- activated platelet provide anionic aminophospholipid rich surface for assembly of procoagulant enzyme complexes |
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How to get platelet count |
Electronic (doesn't detect clumping or macrothrombocytes) so not accurate at low counts Peripheral blood smear- number, size, morphology |
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Platelet count of 100k vs 5 k |
100 k= no symptoms 5k - bleed can be severe, can involve CNS and internal bleeds |
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Clinical manifestations of thrombocytopenia |
hematuria spontaneous mucosal bleeding mucosal or cutaneous petechiae cutaneous ecchymoses and hematomas Petechiae is more specific uncommon to bleed in joints and intramuscular- more bleeds into mucocutaneous |
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pseudothrombocytopenia |
in vitro clumping of platelets often due to EDTA dependent antibodies against platelets suspect when thrombocytopenia is reported in non bleeding patient
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assessment of platelet function |
bleeding time: normal range is 2-10 minutes, but test poorly reproducible automated platelet function tests (e.g. PFA-100)- Mb coated with collagen and ADP or collagen and epi, and formation of platelet plug closes the aperture- if prolonged time then low platelets (aspirin) Platelet aggregation (requires a lot of blood): many agonists, measure change in light transmission, Platelet electron microscopy: evaluate dense granules with EM; evaluate alpha granules and morphology with transmission EM Flow cytometry: to measure surface glycoprotein levels |
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Thrombocytopenia (general causes) |
shortened platelet life span platelet sequestration or pooling platelet loss or dilution diminished/impaired production |
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Shortened life span (immune and non immune) |
Immune: Immune thrombocytopenia, neonatal alloimmune thrombocytopenia, drug/heparin induced thrombocytopenia Non Immune: DIC, Thrombotic thrombocytopenia purpura, hemolytic uremic syndrome |
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Immune thrombocytopenia (ITP) |
acute onset most children present with skin findings only bleeding is mucosal in nature severe hemorrhage is rare often after virus Platelet decreasedd but are very large autoantibody production Normal Hb/Hct, normal total and differential WBC BM biopsy: (usually not needed unless atypical features like anemia, or constitutional symptoms, or prior to steroid use) |
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ITP resolution |
rise in platelet count within 1-3 weeks normalization: 40% of cases within 6 weeks 80% within 12 months recurrences rare 20% after 12 months are chronic ITP |
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ITP Tx |
Observation- nature often solves it Anti D Ig (WinRho)- takes 1-2 days for response, sensitized erythrocytres occupy the Fc receptors (risk of hemolytic anemia), only give to patients with normal Hb IVIG: 1-2 days, blocks reticuloendothelial system steroids: take 3-4 days for response, blocks reticuloendothelial system, reduced Anti platelet Ab production |
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Chronic ITP treatment |
stepwise observation then steroid/IVIG/anti D then splenectomy, TPO receptor agonists then immunosuppressants/cytotoxic agents |
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neonatal alloimmune thrombocytopenia (diagnosis vs ITP) |
If moms platelet count low then maternal causes ie ITP, SLE, drugs if moms normal then do check up on baby- usually HPA-1a antigen on baby platelet while mother is negative; affects GpIIb/IIIa and hemorrhage is more severe than ITP differentiate between the two bc tx is different |
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Neonatal alloimmune thrombocytopenia |
neonate with platelet less than 50k requires anti platelet alloantibodies in mother and documentation of fetomaternal incompatibility Ab crossed placenta Check head ultrasound to check for intracranial hemorrhage |
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NAIT treatment |
gold standard is transfusion with maternal platelets HPA-1a negative platelets or donor platelets with IVIG/steroids subsequent pregnancies more affected |
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Drug/herapin induced thrombocytopenia |
Drug binds platelet and antibody forms withdrawal of drug leads to quick rise in platelets Heparin binds PF-4, then Ab binds complex and platelet activation (Fc receptor) and release of thrombin and clot formation low platelet count with thrombosis |
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DIC |
secondary to things like sepsis, cancer activation of coagulation system (by tissue factor), formation of fibrin and occlusion of small vessels (organ failure) with activation of fibrinolytic system Consumption of clotting factors Tx is underlying cause and supportive |
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Hemolytic Uremic Syndrome |
In infants and young children preceding colitis (E coli verotoxin) renal failure is primary manifestation tx: dialysis and supportive care plasmapharesis doesn't treat this |
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Thrombotic thrombocytopenic purpura (TTP) |
diagnostic pentad: microangiopathic hemolytic anemia, thrombocytopenia, neuro findings, renal manifestations, fever abrupt onset so treat quickly schistocytes elevated LDH and reticulocytes negative coombs renal not as severe as HUS reduced plasma levels of ADAMTS13 |
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ADAMTS13 |
in TTP usually cleaves large vWF without it then large vWF and more adhesions and aggregations leading to thrombosis |
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TTP tx |
80% mortality without therapy plasmapharesis to replace ADAMTS13 High relapse rate (20-30%) |
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Platelet sequestration occurs in |
hypersplenism (portal htn, hematologic disorders, infiltrative disease)- accumulate in spleen |
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Platelet loss/dilution |
massive transfusion exchange transfusion |
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Diminished/impaired platelet production |
marrow infiltration (leukemia) marrow injury/failure- aplastic anemia Ineffective thrombopoiesis (hereditary or megaloblastic state) |
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Qualitatitve disorders |
MB receptor: Glanzmann's thrombasthenia and Bernard Soulier syndrome Storage granule: alpha granule (gray platelet), dense granule Or in signal transduction |
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Glanzmann's thrombasthenia |
deficiency or absence of GP IIb/IIIa auto recessive severe mucocutaneous bleeding starting in infancy Absent platelet aggregation in response to ADP, epi, collagen normal aggregation with ristocetin GLOBAL |
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Bernard-Soulier Syndrome |
Abnormal or absent surface receptor for vWF (GF Iv/IX complex macrothrombocytopenia normal aggregation in response to ADP, epi, collagen absent aggregation to ristocetin |
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Secondary Hemostasis (factors leading to intrinsic vs extrinsic) |
Stable Fibrin clot formation forms on top of primary plug subendothelial Tissue factor exposed on injured endothelial cells leading to activation of procoagulant cascade (EXTRINSIC) Phospholipid complexes exposed on platelet surfaces -> INTRINSIC Requires platelet activation, and platelet phospholipid membrane surface and receptors Coagulation proteins which require activation Ca dependent complex consisting of activated cofactor and protease platelet lipid mb/mb receptors serve to localize the reactions to site of injury
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Clinical presentation of thrombocytopenia |
Hemorrhagic manifestations, purpura, petechiae, epistaxis, menorrhagia, bleeding gums and other mucosal surfaces |
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Evaluation of a Suspected platelet abnormality (These 5 categories/tests) |
CBC History (drug or viral illness) Physical Exam (splenomegaly) Bone Marrow (megakaryocytes, look to see it isn't replaced by cellular lymphoma/tumor) PFA-100 |
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Platelet clumping (Satelitosis) What other test is important? |
Machine will read it as lymphocytes Some ppl have Ab against the media (EDTA) that can cause clumping Importnat to look at peripheral smear to look for clumps and count platelets |
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Bleeding Time and PFA-100 |
Bleeding time not very accurate (in vivo) Now use PFA-100 (platelet function analyzer)- in vitro, run blood through aperture lined by Collagen/Epi and Collagen/ADP- tests the quality of platelets |
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Light Transmission Study |
Run light through plasma with platelets and light disperses Then add activator and platelets clump and light can better pass through Secondary Test for quality of platelets |
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Von Willebrand Disease (clinical manifestations, epidemiology,platelets)*** |
Easy bruising (softball size) Epistaxis Bleeding after minimal trauma Menorrhagia (more bleeding with menstruation) Post-partum hemorrhage Most common hereditary coagulopathy** worldwide prevalence is 1% M=F 5-10% of menorrhagia associated hysterectomies due to vWD Spectrum: mild to severe (less than half with significant bleeding symptoms) Auto Dominant Normal platelet count Abnormal PFA Binds factor VIII (stabilizes it) so may have prolonged aPTT that corrects with mixing* |
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VWD (lab evaluation-3 tests) |
3 sepcific tests: VWF antigen (quantitative) VWF Ristocetin cofactor activity (functional/qualitative test to see how active VWF is) Test Factor VIII (VWF stabilizes factor VIII)
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Von Willebrand Multimers (VWD type 2A, TTP) |
VW is one of largest proteins in body Highest MW multimers interact with platelets VW type 2A deficiency- not many multimers and severe bleeding TTP- too many multimers, cause platelet clumping
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vWF functions |
released from endothelial cells as unusually large multimers that may diffuse into circulation or adhere to the endothelial cell surface Also binds to connective tissue at sites of vascular injury platelets adhere to vWF (GPIb), and vWF recruits other platelets to attach to already adhered platelets |
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Acquired vWD |
Ab against vWF that remove the high MW multimers (autoimmune) Cancer- too many platelets and too much binding with multimers creating abnormality Trauma (ie stenotic valve)- Bc its such a big protein the high MW ones get cleaved |
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PT |
Prothrombin Time- for extrinsic and common pathway Use Tissue factoror thromboplastin, phospholipid, heparin neutralizer, Ca at 37 degrees Normal is around 12-15 seconds Prolonged PT means factor deficiency or inhibitor of extrinsic or final common pathways USE INR (int'l ratio) to standardize number
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aPTT (and what disease it tests) |
For Intrinsic pathway and common Activator (ellagic acid or silica) phospholipid extracted from thromboplastin CaCl (first activates XII) around 23-35 seconds Test for hemophilia (VIII, IX, XI) |
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Intrinsic Pathway (Vit K dependent) |
XII -> XIIa (catalyzes conversion of XI to XIa) XI IX (Vit K dependent) and Ca VIII X (common) |
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Extrinsic Pathway (Vit K dependent) |
VII (vit K dependent) then X Activated by Tissue Factor
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Common Pathway (Vit K dependent) |
X (Vit K) and Ca to Xa V II (vit K) (prothrombin) to thrombin IIa I Fibrin clot |
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dRVVT |
from factor X down (common pathway) |
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Thrombin Time (TT)** |
from prothrombin (II) down measure thrombin induced conversion of fibrinogen to fibrin TT prolonged by: thrombin inhibitors (heparin), qualitative fibrinogen defects, decreased fibrinogen production (liver failure)* inhibitors of fibrin formation 12-14 sec |
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Reasons for prolonged aPTT |
Blood sampling/pre-analytical Heparin Congenital deficiencies (hemophilia, VWD) Acquired deficiencies (liver disease, DIC, Vit K def, warfarin) Autoantibodies (specific or non specific) |
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Vitamin K deficiency causes |
Vit K comes from intestinal flora so antibiotics can lead to deficiency |
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Mixing Study |
If corrected then Deficiency If not corrected then Inhibitor (Ab, drug) Mixed with normal plasma |
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Vit K involved with these factors |
II, VII, IX, X |
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Hemophilia A |
Factor VIII deficiency X linked recessive so more in males intron inversion |
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Hemophilia B |
Factor IX deficiency X linked recessive
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Hemophilia Manifestations |
Deep muscle and joint hemorrhage Hematomas easy bruising deep bleeding post surgical wound bleeding and oozing intracranial hemorrhage But huge range from moderate to severe |
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DVT/PE |
valvular surface is where clots form in veins valves become damaged (incompetent) so blood pools in leg leading to ulcers/gangrene or PE Half a million DVT cases in US/year 50K pulm embolism/year 20-30% of patients with first VTE have primary relative with history of thrombosis |
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Thrombosis: two models |
Virchows and two hit hypothesis (hereditary abnormaility and acquired)
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Padua Prediction |
Score risk assessment model- tells risk of venous thrombotic event Patients bed ridden so need to decide to give blood thinner (but don't risk them bleeding to death) Cancer, previous VTE and low mobility are high scores; or defects in antithrombin, protein C or S, V leiden |
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What regulates Thrombin |
Protein C or S, APC(activated Protein C) antithrombin These are anticoagulants |
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Antithrombin Deficiency |
Most Severe Age of presentation is 24 Very rare |
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Protein C or S deficiency |
Protein S shows up earlier in life Spontaneous events very common so keep on anticoagulants |
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Activated protein C resistance (APC-R) Factor V Leiden |
Normally protein C and S aren't doing anything unless active thrombin generated Protein S is cofactor for protein C (makes it more active) Protein C/S complex inactivate factor V and VIII Point mutation in factor V is resistant to degradation by APC so get more thrombin They do not spontaneously clot |
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Inherited Thrombophilia (types) |
APC resistance antithrombin deficiency protein C or S deficiency Prothrombin mutation |
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Antiphospholipid Antibody Syndrome |
Clinical event- venous thrombosis, arterial thrombosis, recurrent abortion lab: IgG or IgM Ab or lupus anticoagulant criteria: 1 clinical and 1 laborator finding with PERSISTANCE (retest in 12 weeks or more) bc Ab can come and go with infections |
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Lupus Anticoagulant |
Immunoglobulins (IgG, IgM mixtures) which interfere with one or more of the in vitro phospholipid dependent steps of coagulation resulting in prolonged coagulation tests Causes Blood blots
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DIC |
When lose balance between thrombin and plasmin ie in septicemia |
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D-Dimer (degradation of... and 3 uses) |
Forms when plasmin breaks down fibrin clot 3 Important uses: Test for DIC NPV for exclusion of VTE (If D- dimer is negative then don't have to do imaging study to see if had a venous thrombotic event) Test for risk factor for recurrent VTE (If patient wants to go off coumadin, then if no D dimer present then less risk of VTE) |
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Hemostatic bleeding disorders (primary vs secondary defects) |
Primary- disorders of connective tissue, platelet function, or vWF associated with microhemorrhages, mucocutaneous bleeding, petechiae, purpura Secondary- coagulation factor deficiencies or inhibitors (acquired or congenital) macrohemorrhages bleeding into joints/muscles easy bruising (hematomas, ecchymoses) |
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Platelet Disorders (2 categories) **** |
Quantitative- Abnormal distribution, dilution effect, decreased production, increased destruction (lab errors) Qualitatitve- Inherited disorders (rare), Acquired disorders (medications, chronic renal failure, cardiopulmonary bypass) |
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Thrombocytopenia (cell count, 3 mechanisms) |
under 150 Underproduction (marrow infiltration, BM failure syndromes, acquired aplastic anemia) Decreased survival (autoimmune destruction ie ITP, SLE, DIC, TTP/HUS) Blood loss/platelet use: bleeding, extravascular consumption, hyperspleen |
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Platelet Clumping**** |
Falsely decreased platelet count related to EDTA Try using citrullinated tube instead Always want to look at peripheral smear
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Shortened platelet survival |
Due to bleeding (ITP, drug induced) Or due to increased use of platelet ie associated with thrombosis (TTP, DIC) |
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Vessel Defects **** |
Nutritional deficiencies (vit C, zinc) Connective tissue disorders (acquired or hereditary) Vasculitis (infection related, immune related, hypersensitivity) Vessels are the foundation |
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Testing for qualitative platelet dysfunction** |
Platelet function screen; PFA Is reproducible (unlike bleeding time) Time for blood to block mb coated with Col/epi or Col/ADP If epi abnormal but ADP normal then "aspirin effect" Both abnormal: then abnormal platelet function |
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Other tests for coagulation Profile: fibrinogen, reptilase, test for specific factors |
Fibrinogen: quantitative measurement (not for quality) reptilase: enzyme promotes fibrinogen -> fibrin polymer, not inhibited by thrombin inhibitors Tests for specific factors: ie factor VIII, IX, XI |
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Prolonged PT could be...** |
deficiency/inhibitor of extrinsic or final pathway Factors II, V, VII, X and fibrinogen (I) If aPTT WNL then mostly influenced by VII Deficiency: congenital vs acquired? acquired: often Vit K deficiency (causes are VKAs, malnutrition, alcoholic, antiobiotics, gut malabsorption) Inhibitor: PT inhibitors RARELY prolong the PT without also prolonging the aPTT (unlike aPTT inhibitors); often inhibitors are from medication, |
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Prolonged aPTT could be...** |
Could be an indicator or could be a bleeding disorder, thrombotic disorder or neither! (lupus is thrombotic, factor 8 is bleeding, factor 12 is neither) Implies deficiency in factors SPECIFIC for intrinsic pathway (if PT is normal) Def of some of these factors associated with bleeding disorders Family history and duration of bleeding history can help determine if congenital or acquired Inhibitor: always acquired!, medications (heparin), antiphospholipid antibodies (lupus anticoag) |
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XII Deficiency ** |
High molecular weight kininogen (HMWK), prekallikrien prolongs the aPTT but NOT associated with significant bleeding |
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Prolonged PT and aPTT* |
Excessive vit K antagonist combined factor deficiencies (rare) common final pathway deficiency/inhibitor Potent lupus anticoagulant nonspecific Inhibitors Too much warfarin LIVER DISEASE |
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Hemophilia A, B, C *** |
Factor VIII, IX, XI normal PT prolonged aPTT congenital deficiencies |
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Warfarin |
acquired deficiency of Vitamin K dependent factors (II, VII, IX, X) Really increases PT/INR |
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Liver Disease*** (whats the important factor) |
factors II, V, VII, IX and X all made in liver only V is not vit K dependent (of these) Increases PT Deficiency in V implies liver disorder; normal V levels with other K dependent factors defeciencies suggests vit K deficiency Decreased fibrinogen levels, increased TT, increased aPTT |
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DIC *** |
excessive stimulation of coag system caused by underlying process (cancer, infection, trauma) Consumption of coagulation factors pathologic levels of thrombin and plasmin in circulation -> microangiopathic hemolysis can result in thrombosis or bleeding tx: underlying disease |
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DIC lab valeus (PT, aPTT, TT, Hb, platelet, fibrinogen, mixing study) |
PT: higher aPTT: higher TT: higher Hb: lower platelet: lower fibrinogen: much lower mixing; variable: depends on degree of deficiency |
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acquired autoimmune hemophilia |
Inhibitor of intrinsic pathway factors (not deficiency) originally lab values similar to hereditary hemophilia but after mixed studies can differentiate |
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Anticoagulants*** |
Heparins vitamin K antagonists Direct thrombin inhibitors antiplatelet agents |
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Heparins*** |
unfractionated heparin (UFH): binds antithrombin, stimulating antithrombin mediated inhibtion of factor Xa; UFH-AT inhibits parts of intrinsic cascade so prolongs aPTT low MW heparin (LMWH)- directly targets f. Xa without interacting with AT |
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Vit K antagonists |
Warfarin, Coumadin factors II, VII, IX, X prevents carboxylations
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INR |
international Normalized ratio vit K antagonists so PT can vary from lab to lab in identical people INR standardizes PT measurement to minimize lab variability |
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Medications can cause? (unintentional) |
BM suppression nutritional malabsorption immune medicated thrombocytopenia (ITP) activation of coag cascade (TTP) |
