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2. hemotology > intro to hemostasis > Flashcards

intro to hemostasis Flashcards

1
Q

Its all about balance!

A

Primary and secondary hemostasis and fibrinolysis need to occur tightly regulated, coordinated fashion to ensure appropriate clot formation and dissolution (clotting vs bleeding)

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2
Q

normal hemostasis: clotting

A

divided into 2 categories:
Primary: vasculature, blood flow, platelet count and function, extracellular matrix proteins–> PLATELET PLUG

Secondary: coagulation factors–> FIBRIN CLOT

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3
Q

Initial steps to vasculature injury

A

Arteriolar vasoconstiction: reduces blood flow, mediated by endothelin

Exposure of subendothelial von Willebrand factor (vWf) and collagen

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4
Q

Primary hemostasis

A
  1. platelet adhesion (binding of platelet glycoprotein 1b (Gp1b), to vWF and exposed collagen
  2. Platelet activation (shape change, granule release). Shape change- increases their surface area, move negatively charged phospholipids to the surface (for binding Ca++), conformationa gange in Gp2b/3a. Granule release- alpha granules (fibrinogin, clotting factors), Dense granules (ADP, ATP, Ca++), Stimulate platelet activation–>
    recruitment
  3. Recruitment
  4. Aggregation-Gp2b/3a binds fibrinogen, forming bridges between platelets. Thrombin stimulates (irreversible platelet contraction, conversion of fibrinogen to insoluble fibrin)
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5
Q

Secondary hemostasis

A 
goal is to strengthen the fibrin glue via generation of THROMBIN (factor 2 a)
1. tissue factor release
2. phospholipid complex expression
3. Thrombin activation
4. Fibrin polymerization
REPEAT
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6
Q

Clotting in vivo

A

Vascular damage, exposes tissue factor, tissue factor Activates Factor 7 (7a)
Factor 7a stimulates Factor 9 (9a)
(9a) and Factor 8a Stimulates Factor 10

10 a and 5 a activate factor 2 (Prothrombin) to 2a (thrombin

2a catalyzes fibrinogen to fibrin

creating a Fibrin clot

Thrombin feeds back and creates positive feedback to keep the process going

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7
Q

Clotting factors

A

Produced in the liver hepatocytes (factor 8 is the exception, made by endothelial cells)

Clotting factors circulate in inactive forms, but are functional (Active forms are produced during the cascade)

Some are vitamin K dependent: 2, 7 9, 10, Protein C and Protein S (anticoagulants) carboxylated with a negative charge, Vit K is antagonized by warfarin

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8
Q

charge and secondary hemostasis

A

negatively charged clotting factors (2 7 9 10) also the vitamin k dependent clotting factors

Localized to the Ca which has been attracted to the negatively charged phospholipid surface of the platelets

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9
Q

Along with the clot hemostasis what else is happening concurrently

A

t-PA is being released- fibrinolysis (digest fibrinogen)
Thrombomodulin (blocks coagulation cascade)

Fibrinolysis is always occuring during hemostasis to keep the clot at bay

Limits the size of the thrombus and dissolution
tPA (endothelium) activates plasminogen into plasmin
Plasmin breaks up fibrin, producing fibrin degradation products (D dimers)
alpha antiplasmin inactivates free plasmin

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10
Q

Normal hemostasis: natural anticoagulants

A

Endothelial cell activation and release of mediators (PGi2, NO, ADP) which inhibits platelets

Activation of thrombomodulin, which leads to activation of protein C and S which inactivate F5a, F8a

Tissue factor pathway inhibitor (TFPI) released, inactivating F7a

Heparin-like molecules activated antithrombin 3, (AT3), which inactivates f2a, and others

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11
Q

Laboratory screening for primary hemostasis vs Secondary hemostasis

A

Primary hemostasis: platelet count and morphology, bleeding time, platelet function (PFA100, Platelet aggregation studies), vWillebrand studies (vW Ag, vW activity), fibrinolysin: D imer is free and means plasmin has occured

Secondary Hemostasis: Activated clotting time (ACT), Prothrombin time (PT), Activated partial thromboplastin time (aPTT), fibrinogen activity, thrombin time

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12
Q

Morphology of hemostasis

A

Normal platelets (variably sized, smaller than RBC, granulated)

Abnormal (hypogranular- MDS, grey platelet syndrome), Giant (MPNs, bernard soullier disorder, MHY9 disorders)

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13
Q

bleeding time

A

vascular integrity, platelet count and function. time when the pt stops bleeding, not really performed. 0-13 minutes

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14
Q

Platelet function assay

A

Gold standard=platelet aggregation study
You add agonist to platelets, measures PLT aggregation, manual, labor intensive (allows light to go through)

Screening: automated and fast, PFA100 test (screens for PLT functional defects and vonWillebrand disease, high sensitive for severe PLT function defect/ VWD, moderate sensitivity for mild to moderate disorders. False positives common, moderate sensitiveity to aspirin therapy

Antiplatelet medication monitoring: automated/fast, Verify Now, aspirin, clopidogredl responsiveness

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15
Q

Clotting/ secondary hemostasis in vivo vs in the lab differences

A

In the lab clotting is divided up in the extrinsic pathway, intrinsic pathway and the common pathway

Extrinsic pathway: TF activates 7, 7a activates 10

Intrinsic pathway: a reaggent stimulates 12, 12 activates 11, 11 activates 9, 9 along with 8a activates 10.

Common path:10 with 5a activates prothrombin into thrombin

Thrombin activates fibrinogen to fibrin

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16
Q

Prothrombin time (PT)

A

combine tissue factor, lots of phopholipid and calcium
Tests the extrinsic pathway and the common pathway
F7, F10, F2, F5, fibrinogen

Uses: screening for factor deficiencies, Warfarin monitoring

Reported in seconds and INR (normalizes across labs), not prolonged with heparin

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17
Q

Acitvated partial thromboplastin time (aPTT)

A

combines activator, low phospholipid, calcium
Tests the INTRINSIC and common pathway (F12, 11, 10, 9, 8, 2, 5, fibrinogen

Uses: screen for factor deficiencies, lupus anticoagulant, heparin monitoring

variably sensitive to warfarin

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18
Q

mixing studies

A

can be done with PT or aPTT,
Mix 1 part of the patient sample with one part of normal plasma

then run the PT or aPTT
Corrects with factor deficiencies
Fails to correct with inhibitors (drugs, lupus anticoagulant)

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19
Q

labs for fibrinolysis

A

D- dimers

Measurable breakdown product of plasmin-induced fibrinolysis
Immunoassay

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20
Q

thrombin time (TT)

A

add thrombin, measure time to form clot, abnormal/prolonged

Fibrinogen –> fibrn formation yes or no

Heparin will elongate, direct thrombin inhibitors

A/hypofibrinogenemia
Dysfibrinogenemia

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21
Q

Fibrinogen activity

A

Reflects fibrinogen activity and concentration, reported in mg/dL, abnormal (low: ahypofibrinogenemia, high: inflammatory state- acute phase reactant)

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22
Q

Bleeding disorders: defects in primary hemostasis

A

Skin, mucosal membrane hemorrhages (petechiae, epistaxis, menorrhagia) are common

Vascular abnormalities (ehlers- danlos)

thrombocytopenia

Platelet function disorders

Von willebrand disease

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23
Q

bleeding disorders:Defects in secondary Hemostasis

A

Defects in secondary Hemostasis
bleed into soft tissues or joints
Clotting factor deficiencies (hemophilia, liver disease)
Exogenous (anticoagulants)

24
Q

Thrombocytopenia

A

<100k/uL
differential: decreased bone marrow production, increased destruction (immune mediated, non immune mediated), dilutional, sequestration

Mostly small vessel bleeds but risk of intracranial hemorrgage when platelets <10k

Causes of thrombocytopenia: Decreased PLT production due to decreased Megakaryocytes (aplastic anemia, vit B12/folate deficiency, leukemia/lymphoma, MDS, metastatic carcinoma, alcohol, toxins, drugs, infection

Increased destruction: immune mediated (immune thrombocytopenia purpura, heparin induced thrombocytopenia, transfusion/pregnancy allo immune thrombocytopenia), drugs (quinine, vancomycin)

Non immune mediated: Disseminated intravascular coaulation (DIC), Thrombotic thrombocytopenia purpura, hemopytic uremic syndrome, drugs

25
Q

immune thrombocytopenia pupura (ITP)

A

Caused by auto antibodies made against PLT Ags (Gp2b/3A, Gp1B)

Destruction of PLTs occurs by phagocytosis
FC receptor mediated
Site is the spleen

Primary : etiology unknown
Secondary: associated with: lupus, leukemia (CLL/SLL), Drugs, Viruses (HIV hepatitis)

Clinical features: Skin, mucosal bleeds, normal spleen size
Variants: Acute (self limited, < 6 months, post viral, children, most common), Chronic (adults, usually females) persisten, >6 months

26
Q

PAthologic and diagnisis of immune thrombocytopenia purpura (ITP) and treatment

A

Pathologic findings: thrombocytopenia (low), large platelets, normal to increased megakaryocytes in the marrow, white pulp expansion

Diagnosis: presumptive, diagnosis of exclusion, no diagnostic tests, normal clotting tests bone marrow

Treatment might not need: esp in kids where its a self limited disease, immunosuppressent to stop the antibody attack of platelets (steroids, IVIG, AntiCD20 Ab), thrombopoietin agonist, splenectomy

27
Q

other causes of thrombocytopenia

A

Dilutional (massive transfusion of trauma patients)

Sequestration (seen with hypersplenism, increased storage of PLTs)

28
Q

Platelet functional disorders

A

Heterogeneous group of inherited and acquired, qualitative disorders with variable clinical presentation

Bernard soullier (Gp1b deficient, inherited, severe), Glanzmanns thrombasthenia (Gp2b/3a deficiency, inherited, severe), Storage pool disease (granule/transient defects, inherited, variable clinical), Aspirin (COX inhibition, ascquired, variable), Uremia (acquired, variable)

29
Q

vonWillebrand disease

A

Most common inherited bleeding disorder

Usually autosomal dominant
Incidence may be underestimated given the mild presentation, rarely can be acquired

Clinically heterogeneous: Mild, revealed with surgery, dental work, trauma
Moderate to severe: menorrhagia, spontaneous bleeding, dependent on clinincal type

30
Q

What is vonWillebrand factor ?

A

A protein produced by endothelial cells, megakaryocytes, PLTs

Function: in the circulating Form, it stabilizes F8
in the fixed form: it adheres to collagen and PLTs through Gp1b

31
Q

Von Willebrand disease types and treatments

A

Types: (LOW, Weird, NO- 1,2 ,3)
1- quantitative (most common 80%), Autosomal dominant, clincally heterogenous, usually mild
2- qualitative (2A- 10-15%), 2B (<5%), 2N, and 2M (rare). Moderate to severe bleeding, 2N is Autosomal recessive other are usually A/D

3- Complete absence of vWF, rare A/R, severe bleeding disorder, mimicking hemophilia

Treatment:
Desmopressin- stimulates vWF release, factor concentrates, Anti-fibrinolytics, oral contraception

32
Q

vWD lab evaluation

A

Screen: CBC (normal Plt coount), PT (normal), aPTT (normal or prolonged), vWF levels, vWf activity (ristocetin), Factor 8 activity

Confirmatory studies: multimer electrophoresis, specific binding assayas, platelet aggregation

33
Q

Defects in secondary hemostasis, Single clotting factors vs multiple clotting factors

A

Single clotting factors- hemophilia

Multiple clotting factors- liver disease, vitamin K deficiency, exogenous anticoagulants

34
Q

hemophilia

A

Inherited factor deficiencies:
X linked recessive for hemophilia A, B
Mostly males are affected, females most often are only carriers, 30% are sporatic new mutations

Types:
Hemophila A-F8 deficiency, most common inherited disease, associated with life threatening bleeds

Hemophilia B- F9 deficiency
Hemophilia C- F11 deficiency Ar inheritance, not predictable bleeding

35
Q

Clinical presentation of hemophilia and lab evals (A and B)

A

Spontaneous bleeds, hemarthrosis–> progressive deformity, deep muscle bleeds, easy bruising with trauma, bleeding tracts with factor levels

Lab evaluation:
APTT prolonged, PT normal
aPTT mixing shows corrections

Factor levels/Activities severe to mild depending on F8 /F9 (<1%, <5%, 50%)

36
Q

Single factor deficiencies

A

Defects in factor 12 is asymptomatic (factor 12 is only in lab, not in vivo coag cascade)
Factor 5- topical bovine thrombin, 10 amyloid, 13- poor wound healing and infertility in men

Inhibitors (auto Abs against any clotting factor can develop and cause a deficiency in the setting of Auto immune disorders, medications, and malignancies

37
Q

Coagulopathy of liver disease

A

Deficiency of multiple coagulation factors: Procoagulants (factors 2, 5, 7, 9, 10), Anticoagulants (antithrombin 3, protein C and protein S)

Thrombocytopenia: Hypersplenism (in pts with cirrhosis associated splenomegaly), decreased thrombopoietin production

Vitamin K deficiency

Fibrinogen abnormalities- low fibrinogen dysfibrogenemia- dysfunctional protein

Therapy of coagulation disorder- treatment not required if patient not bleeding, if bleeding Vit K replacement, rarely corrects PT, replacement of plasma, cryoprecipitate, platelets, therapy specific for bleed site

Can be seen in acute liver injury (hepatitis, toxins tylenol and alcohol), or can be seen in chronic like cirrhosis

PT, aPTT, TT are going to be prolonged
Low fibrinogen activity, Normalish platelets, low factor activities (except F8 and vwF - made by endothelial cells)

38
Q

Vitamin K deficiency

A

Dependent factors 2 7 9 10, Protein C and S
Cofactor fo gamma carboxylation (gamma carboxylation and Ca is required for factor binding to phospholipid), provided by diet and bacterial flora

Vitamin K deficienct Drugs (oral anticoagulant warfarin inhibits clotting factors, antibiotics decrease bowel flora and therefore there is less vitamin K synthesis)
Malabsorpption of dietary deficiency, liver disease, newborns

Treatment: vit K replacement, fresh frozen plasma for emergencies, newborns recieve an injection at birth

39
Q

Anticoagulants

A

multiple clotting factors inhibited (Warfarin- fs 2 7 9 10 c and S)
Heparin inhibits 2 9 10, accelerates antithrombin 3 activity

Single clotting factor inhibited (direct thrombin inhibitors (2)
Factor X inhibitors (10)

anticoagulant activity- INR (warfarin), PTT/antiXa assay for heparin, and Ptt (some direct thrombin inhibitors)

40
Q

virchows triad of thrombosis formation

A

Endothelial injury, abnormal blood flow, hypercoagulability

41
Q

Thrombophilia risk factors

A

a couple of risk factors can be either inherited or acquired (more commonly acquired)
Protein C, S , anti Thrombin 3 deficiencies
Hyperhomocysteinemia
Dysfibrinogenemia

42
Q

sources of thrombi

A

Venous- develop at sites of stasis, travel in direction of blood flow, DVT occuring in leg veins, may travel through heart to pulmonary veins (pulmonary embolism), unusual locations (splenic v, cerebral vein, branhial v)

Heart: atrial or ventricular walls or valve leaflets. Right heart (embolus may detach and travel into lung),

Arterial - develop at sites of endothelial injury and turbulence, travel retrograde, atherosclerotiic plaque

43
Q

Site of thrombi by disease

A

Factor 5 leiden, prothrombin 20210a mutation and AT 3, protein C and S deficiency will cause a venous thrombosis

Antiphohpholipid antibody syndrom and homocystein will cause either venous or arterial

44
Q

Factor 5 leiden

A

essentially a messed up factor 5 disease

Most common inherited predisposition to thrombosis (venous)
Single point mutation in F5 gene G-> cleavage site for protein C (anticoagulant degrades factor 5 and 8),
2-15 % of caucasians are heteros, most patients will not have thrombosis unless coupled with other risk facots

Activated ptotein C resistance=mutated F5 is resistant to protein C inactivation, F5 is active for longer and promotes clotting

So protein C cant degrade factor 5 (because of the messed up cleavage site)

45
Q

Factor 5 leiden testing

A

diagnosis: molecular analysis (PCR, microarray) for mutation (cheap and automated

Who should be tested- younger adults whove ever had a venous thrombosis (VT). recurrent VTs, VT famHx, VT in pregnancy or while on OCs, MI in fem smokers under 50

46
Q

Prothrombin 20210a mutation

A

2nd most common inherited predisposition for thrombosis (venous), single base pair mutation in prothrombin (F2) gene
Heterozygotes vs homozygotes

Unclear mechonism of hypercoagulability (could be due to elevated ptothrombin levele

Diagnosis: molecular analysis for gene mutation

47
Q

double heterozygotes

A

heterozygotes for factor 5 leiden and prothrombin gene mutation
Greater risk of thrombosis

48
Q

AT3, protein C and Protein S deficiencies

A

May be inherited or acquired
Associated with venous thrombsis
inherited forms: account for 5- 15% of familial thrombosis risk higher after puberty

Acquired forms (consumptive (recent clot, DIC), decreased synthesis (liver failure or vit K deficiency)

Lab eval: AT3, C and S activities, S free Ag, do not evaluate during active thrombolytic event because these will be abnormally high

49
Q

Antiphospholipid antibody syndrome

A

1-5% of gen pop, acquired autoantibodies against various phospholipid complexes

Associated with arterial AND venous thromboses with high recurrence rates and repeat miscarriages (DVTs and chronic pulmonary emboli, stroke, renal failure, interference with placenta growth and devolopment

Primary/unknown, secondary associated with lupus

Inhibits clotting in vitro, promotes clotting in vivo, looks like a blleding disorder in a tube, but in body is a clotting disorder

50
Q

Antiphospholipid antibody syndrome diagnostic and lab eval

A

Diagnosis 2 criteria:
Positive lab test (only need 1): lupus anticoagulant test, antiphospholipid antibody ELISA

Postitive clinical findind: thrombosis, recurrent miscarriage

Lab eval: Lupu s anticoagulant: functional assessment, prolongation of clotting based tests

Anti-cariolipin, antiB2 glycoprotein ELISA (anti phospholipid), could be prolonged PTT

51
Q

Diagnosis of lupus anticoagulant (LA) for antiphospholipid antibodies

A

Prolongation of 1 clotting assay, sensitive to lupus anticoagulants (dRVVT, aPTT) NOT NOT NOT PT

correction fo clotting time with excess phospholipid

Failure to correct on mixing study

Persistently present (>12 weeks)

52
Q

Thrombotic states associated with thrombocytopenia

A

Heparin induced thrombocytopenia (HIT)
Thrombotic microangiopathies: thrombotic thrombocytopenia purpura (TTP), Hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC)

Disseminated intravascular coagulation (DIC)

53
Q

Heparin induced thrombocytopenia (HIT)

A

Definition: thrombocytopenia (<150k/ul) or >50 % drop in platelet count during heparin therapy

1-5% of pts on heparin devlop HIT (5-10 days after initiation of heparin, uncommonly seen within 24 hrs)

Most common in unfractionated heparin, CARDAIC>SURGICAL>MEDICAL

Major clinical manifestation: thrombosis!- venous or arterial

Drug antibody production: Abs made against heparin-PF4 complex (IgGs), immune complexes bind to platelets through Fc receptor, Platelets activate and initiate clot formation

Diagnosis: Screen ELISA for PF4-heparin IgG, 95% senstivitve, 80% spec, Confirm - seraotonin release as, 88% 100%

Treatment stop the fucking heparin, non heparinoid anticoagulants (direct thrombin inhibitors, warfarin)

54
Q

Thrombotic microangiopathies

A

disease charachterized by wide spread thrombi deposition in microvasculature, hemolytic anemia (MAHA, organ dysfunction, thrombocytopenia due to consumption

Thrombotic thrombocytopenic purpura- the classic thrombotic microangiopathy

Clinical emergency
Classic penta: feverm renal and neurologic impairment, thrombocytopenia, MAHA (micro angiopathic hemolytci anemia)

Acquired»»>congential
30-50 females> males
Deficiency of metalloproteinase ADAMTS (usually autoimmune-anti ADAMTS13 anti bodies), leads to large vWF multimers
Platelet activation and thrombi formation

Diagnosis: look for red cell fragments- schistocytes, decreased platelts, decreased ADAMTS13 levels

Treatment- rapid, plasma exchange- remove antibodies resupply ADAMTS 13

55
Q

Typical Hemolytic UREMIC syndrome

A

Associated with shiga toxin producing E coli
Local toxic effects on clonic cells-> pain and bloody diarrhea
Systemic toxin on endothelial cells–> systemic disease
Renal dysfunction, CNS dysfunction may occur

look for the ecoli in the stool, no decrease in ADAMTS 213

56
Q

Disseminated intravascular coagulation

A

characterized initially by clotting in the microvasculature, organ ischemia, followed by bleeding tendencies

Consuptive coagulopathy (widespread excessive clotting–> consumption of factors and platelets, clotting factors are consumed–> bleeding, platelets are consumes–> bleeding, activation of fibrinolusis –> bleeding

Associated with sever illnesses: sepsis, trauma, OBGYn, fat embolis, cancer (AML), burns ischemia

Acute or chronic (acute will be bleeding), chronic thrombotic,

end organ ischemia (kidney disease, brain mircoinfarct, hyaline membranes/ARDS, adrenal necrosis and hemorrhage, MI damage

MAHA: red cells lyse as they go through occlusiosn

Prolonged clotting, elevated D dimers, treat the unerlying cause

2. hemotology (11 decks)

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