Hemostasis

Question 1

What produce endothelial cells to inhibit aggregation of platelets ?

Answer 1

Prostacyclin (prostaglandin I 2), nitric oxide (NO), adenosine diphosphatase (CD39)

Question 2

What does the endothelium do to carry out anticoagulant activity?

Answer 2

1. Increase activation of protein C, an anticoagulant, via surface glycoprotein thrombomodulin (TM) => activate protein C 1000 times faster.
2. Increase endothelial cell protein C receptor => activate protein C additional 20-fold.
3. Endothelial - bound glycosaminoglycans (heparin sulfate=> accelerate the protease activity of antithrombin (AT)=> degrades factors IXa, Xa and Trombin
4. Tissue factor pathway inhibitor (TEPI) =>inhibit procoagulant activity of factor Xa.
5. Tissue plasminogen activator (t-PA)=>activating fibrinolysis

Question 3

what happens when the endothelium is damaged?

Answer 3

1) Underlying extracellular matrix (ECM), which contains collagen, von Willebrand factor (vWF)=>platelets bind to and are activated by exposure to ECM complex.=> Activates plasma mediated coagulation pathway to generate thrombin and fibrin clot
2. Cytokines ( interleukin -1, tumor necrosis factor, gamma-interferon) and hormones (desmopressin acetate (DDAVP) or endotoxin) induce prothrombotic changes in endothelium=> increasing synthesis, expression vWF, tissue factor, plasminogen activator inhibitor -1 (PAI-1)
3. Thrombin, hypoxia and high fluid shear stress=> increase synthesis PAI-1.

Question 4

Lifespan of platelets

Answer 4

8-12 days

Question 5

How much formed platelets daily?

Answer 5

1,2-1,5*10в11

Question 6

Phases of forming platelets plug

Answer 6

1. Adhesion
2. Activation
3. Aggregation

Question 7

Second pathway for platelet activation

Answer 7

Generation of Trombin

Question 8

Specific types of storage granules of platelets

Answer 8

1. Alfa-granules contain fibrinogen, coagulation factor V and VIII, vWF, platelet-derived growth factor
2. Dense bodies contain adenine nucleotides ADP, ATF, calcium, serotonin, histamine, epinephrine

Question 9

What do glycoprotein IIb/IIIa receptors on the platelets

Answer 9

Bind fibrinogen, thereby promoting cross-linking and aggregation with adjacent platelets.

Question 10

What need to each stage of the coagulation cascade ?

Answer 10

1. Enzyme ( activated coagulation factor)
2. Substrate ( inactive precursor zymogen)
3. Cofactor (accelerator or catalyst)
4. Calcium

Question 11

Extrinsic pathway of coagulation

Answer 11

Vascular injury=>tissue factor+VIIa complex=>factor X->factor Xa; additionally also activated factor IX of the intrinsic pathway

Question 12

Intrinsic pathway of coagulation

Answer 12

Factor XII activation after contact with negatively charged surfaces (glass, dextran sulfate, kaolin)=> factor XIIa=>XI->XIa=>IX->IXa=>X->Xa

Question 13

Common pathway of coagulation

Answer 13

Activation of factor X by both intrinsic (FIXa, FVIIIa, Ca) and extrinsic (tissue factor, FVIIa, Ca) tenase complex=> formation prothrombinase complex (FXa, FII (protrombin) FVa (cofactor), Ca)=>thrombin generate=>proteolytically cleaves fibrinopeptides A and B from fibrinogen molecules to generate fibrin monomer=>polymerize into fibrin strands to form clot. => FVIIIA, transglutaminase activated by thrombin, covalenty crosslinks fibrin strands to produce an insoluble fibrin clot, resistant to fibrinolytic degradation

Question 14

What do thrombin

Answer 14

1) mediate conversion of fibrinogen to fibrin
2) activated platelets
3) Activated FXIII
4) converts inactive cofactor V andVIII to active conformation
5) activated factor XI and intrinsic pathway
6) up-regulates expression of tissue factor
7) stimulate vascular endothelial expression of PAI-I to down-regulate fibrinolytic activity
8) activation of protein C => suppresses uncontrolled thrombosis

Question 15

Major counter-regulatory pathway down -regulating hemostasis

Answer 15

1) fibrinolysis
2) TEPI
3) protein C system
4) serine protease inhibitors (SERPINs)

Question 16

Hemophilia A

Answer 16

Factor VIII deficiency

Question 17

Hemophilia B

Answer 17

Factor IX deficiency

Question 18

What procoagulant factors produce liver?

Answer 18

Fibrinogen, protrombin (F II), FV, VII, IX,X,XI, XII

Question 19

What anticoagulant produce liver?

Answer 19

Protein C, S, AT

Question 20

What is laboratory findings will there be in a patient with liver disease coagulation test?

Answer 20

1) prolonged PT
2) possible prolongation of the aPTT
3) thrombocytopenia from splenic sequestration. Platelets dysfunction due increase production of endothelial NO
4) levels of plasma metalloprotease ADAMTS13 decreased=> increase circulating levels of vWB=> promote platelet aggregation

Question 21

Treatment of platelets disfunction related to chronic renal failure

Answer 21

1) infusion of cryoprecipitate (rich in vWB)
2) desmopressin (0,3 mcg/kg)
Conjugated estrogen (0.6 mg/kg intravenously for 5 days)=> shorten bleeding times, because decreased generation if NO

Question 22

Renal disease and platelet

Answer 22

1) platelet dysfunction associated with chronic renal failure: prolonged bleeding time. Mechanism: decreased platelet aggregation and adhesion to injured vessel walls. Adhesion impaired, 1) due to defects of the glycoprotein IIb/IIIa, wich facilitates platelet binding of fibrinogen and vWF. 2) Accumulation of guanidinosuccinic acid=>increase endothelial NO synthesis=>decrease platelet responsiveness
2) correction of anemia shortened bleeding time, dialysis shortened bleeding time.
3) treatment: transfusion of cryoprecipitate (rich in vWB); administration of desmopressin (0.3 mcg/kg), wich stimulates release og vWF from endothelial cell; conjugated estrogen (0.6 mg/kg intravenously for 5 days) decreased generation of NO=>shorten bleeding time

Question 23

High risk for perioperative thrombosis

Answer 23

1) heparin -induced thrombocytopenia
2) antithrombin deficiency
3) protein C deficiency
4) protein S deficiency
5) anti phospholipid antibody and syndrome

Question 24

Moderate risk for perioperative thrombosis

Answer 24

1) factor V Leiden genetic polymorphism
2) prothrombin G20210 genetic polymorphism
3) hyperhomocysteinemia
4) dysfibrinogenemia
5) postoperative prothrombotic state
6) malignancy
4) immobilisation

Question 25

Virchow’s triad

Answer 25

Blood stasis, endothelial injury and hypercoagulability

Question 26

Antiphospholipid syndrome

Answer 26

Prolongation of the aPTT, positive testing for lupus anticoagulant, anti cardiolipin, anti-beta2-glycoprotein I antibodies. Increase bleeding risk, risk of thrombosis

Question 27

Heparin -induced thrombocytopenia (HIT)

Answer 27

1) 5% patients receiving heparin therapy
2) HIT is mediated by immune complex: IgGAb+platelet factor 4(PF4) +heparin
3) manifests clinically as thrombocytopenia occuring 5 to 14 days after initiating heparin therapy
4) test: the enzyme -linked immunosorbent assay (ELISA) is sensitive, not specific. Serotonin release assay (SRA), sensitive+specific
5) stop heparin, starting thrombin inhibitor (bivalirudin, lepirudin, argotroban)
6) PF4/heparin complex cleared from the circulation within 3 months

Question 28

Protrombin time

Answer 28

1) integrity of the extrinsic and common pathways of hemostasis
2) It measures time required in seconds for clot formation to occur after mixing a sample of patient plasma with tissue factor (thromboplastin) and calcium.
3) sensitive to deficiencies in fibrinogen, factor II, V, VII or X.
4) II, VII, X vitamin K - dependent synthesis
5) INR patient PT/standard PT

Question 29

Activated partial thromboplastin time (aPTT)

Answer 29

1) assesses integrity of the intrinsic and common pathways of plasma -mediated hemostasis
2) time in seconds for clot formation to occur after mixing a sample of patient plasma with phospholipid, calcium and activator of the intrinsic pathway of coagulation (celite, kaolin, silica, ellagic acid)
3) more sensitive to deficiencies in factor VIII and IX.
4) patient -specific factors affecting response to heparin: age, weight, intravascular volume, concentration of AT, heparin cofactor II, PF4 and other heparin - binding proteins.

Question 30

Aspirin

Answer 30

1) non- selective irreversible cox inhibitor. Reduce cox-1 ⇒ prevents the production THA2 in platelets⇒platelets are anuclear (unable to synthesize new Cox-1. Half-life 15-20 min. Inhibitory effect persists 7-10 days (platelets lifespan. Hemostasis is expected in 2 to 3 days after the last dose.
2) Cox_2 is 170 times less sensitive than Cox-1.
3) Neuraxial procedures: NO restrictions.
4) recommendations currently are to continue aspirin for patients with moderate , high risk for cardiovascular events noncardiac Surgery. Patients with low risk for cardiovascular events ⇒ stop aspirin use 7 to 10 days prior to surgery.
5) After baremetal stent placement surgery should be delayed if possible for at least 6 weeks. After drug-eluting Stent - 6 months. If surgery is required before this time⇒dual platet therapy should be continued. Unless the patient is undergoing intracranial procedures, transurethral prostatectomy, intraocular procedures or surgeries with extremely high bleeding risk. If there is very high risk of Stent thrombosis- bringing therapy with intravenous, reversible glycoprotein inhibitors or a reversible intravenous P2Y12 inhibitor.

Question 31

P2Y12 receptor antagonist

Answer 31

1) a. ticlopidin, clopidogrel, prasugrel-thienopyridines (pro-drugs requiring hepatic metabolism to generate the active metabolite ⇒irreversibly inactivares the ADP-binding site of the P2Y12 receptor.
b. ticagrelor and cangrelor-reversible inhibitor, causes a conformational change of the receptor .
2) inhibiting P2Y12 receptors ⇒inhibits platelet adhesion and aggregation by preventing the expression of GPIIb/IIIa on the surface of activated platelets. .
3) Clopidogrel - N platelets function 7 days.Genetic polymorphism 14%, Neuraxial procedures after 7 days stopped, next dose after 2h.N function Ticlopedine - 7 to 21 days, Neuraxial procedures after 14 days, next dose after 2h.
4) Cangrelor intravenous administration, fastest onset of action (sec.), platelets function N 60 min.

Question 32

Glycoprotein IIb/IIIa inhibitor

Answer 32

1) abciximab (Half-life 10 min, can producethrombocytopenia immediately in a smallproportionof patients).eptifibatide ,tirofiban
2) decreasing the binding of fibrinogen and vWF to glycoprotein IIb /IIIA receptors on the surface of activated platelets,
3) Given intravenously in order to: stop ongoing arterial thrombosis, eliminate excessive platelet reactivity in diseased vessels so that occlusive thrombi and restenosis do not occur.
4) high associated bleeding risk, use only for patients with high risk anfiographic features or those not loaded adequately with high dual antiplatelet agents.

Question 33

warfarin .

Answer 33

1) inhibits the vitamin K dependet carboxylation of coagulation factors II, VII, IX, X, protein C and S.
2) . Half-life 40 hours complete anticoagulant effect take 3to4 days (long_life preexisting Coagulation factors ( Prothrombin 60 hours, fVII, protein c 3-6 hours ⇒imbalance toward a hypercoagulable State if it started alone .⇒ thrombosis, warfarin -induced skin necrosis.
3) Stop 5 days prior to surgery, should be restarted 12 to 24 hours postoperative if there are adequate hemostasis.
4) neuraxial anesthesia : 5 days before and INR <1.5, next dose 2 hours
5) Reversal agent : pCC; FFP ; vitamin K.

Question 34

Unfractionated Heparin

Answer 34

1) Molecular weight 15000 daltons or 35 _45 polysaccharide units,.
2) UFN binds to AT and indirectly inhibits thrombin and fXa.
3) Half-life 60-90 min ; full reversibility with protamin
4) Full-dose heparin for cardiac surgery- 300-400 U/kg. ACT-400 to 480
sec for CBP (21% resistance during CBP - Often hereditary AT deficiency. Treatment - FFP ; AT concentrate.
5) should be stopped 4to6 hours / delayed 48-72 hours, if high postoperative risk.
6) Neuraxial procedures: stop 4 hours, start after procedures 2 h.

Question 35

Low molecular weight hepain ( LMWH ) and Fondaparinux.

Answer 35

1) LMWH 4000 daltons, ~ 15 Saccharide units. Fondaparinux 1700 daltons half-life 17-21 hours, synthetic pentasaccharide of the AT binding region of heparin ⇒more specifically via AT to inhibit factor Xa.
2) Don’t affect the aPTT assay.
3) excreted by the kidney.
4) Should be administered 24 hours before surgery / dosing should be resumed 24 h - low bleeding risk, 24-48 high bleeding risk. Fondaparinux stop 3 days.
5) reversal agent - Partially protamine

Question 36

Direct thrombin inhibitor

Answer 36

1) inhibit thrombin in its free (soluble) and fibrin - bound (insoluble) states.
2) Argatroban, Half-life of 45 min, eliminated by the liver, treatment HIT. Dosing goals -aPTT 1.5 to 3 times baseline. PT and INR prolongs ( thrombin dependent coagulation )
2) Bivalirudin metabolized by proteolytic cleavage and hepatic metabolism- drug of choice for patients with Both renal and hepatic dysfunction
3) argatroban stop before procedures 4-6 hours, bivalirudin 3 hours

Question 37

Direct Oral Anticoagulants

Answer 37

1) Dabigatran: Neuraxial procedures Stop 5 days - start after 6h, surgery procedures 2-4 days, reverse agent Idarucizumab.
2) Rivaroxaban, Apixaban: Neuraxial procedures Stop 3 days - staret after 6h .. Surgery procedures Stop 2 -3 days, reversal agent Andexanet alfa,
-
.

Question 38

Thrombolytics

Answer 38

1) Most thrombolytic agents are serine proteases ( converting plansminogen to plasmin⇒ loses the clot by breaking down fibrinogen and fibrin.
2) fibrin specific agent: Alteplase (tPa), reteplase, tenecteplase. Non fibrin specific agent: streptokinase.
3) tPa - thrombolytics and anticoagulant (products of degradation fibrin, which inhibit platelet aggregation) Surgery or puncture of non -compressible vessels is contraindicated within a 10 -day period after the use of thrombolytic drugs.
4) Early thrombolysis was associated with a lower mortality rate: 2 hours-30 day mortality 5.5%, >4 hours -9%.
5) acute Ischemic stroke treatment can be initiated within 4.5 hours of symptom onset.

Question 39

Absolute contraindications for Thrombolytics

Answer 39

1) vascular lesions
2) severe, uncontrolled hypertension ( SBP > 185 or DBP >110)
3) Recent cranial surgery or trauma
4) Brain tumor
5) Ischemic stroke < 3 months prior
6) Active bleeding

Question 40

Relative contraindications for thrombolytics

Answer 40

1) Ischemic stroke >3 month prior
2) Active peptic ulcer
3) Current use of anticoagelant drugs
4) Pregnancy
5) Prolonged / traumatic CPR < 3 weeks prior
6) Major surgery < 3 weeks prior

Question 41

Antifibrinolytics

Answer 41

1) lysine analogs: epsilon - aminocapronic acid ( EACA ) and TXA: inhibiting the binding site on peasminogen ⇒ inhibition plasmilogen activation ⇒ preventing plasminegen binding of fibrin ⇒ impairing fibrinolysis
2) use this drugs associated with reduce in all cause mortality, reduced blood transfusion by 39%
3) TXA : dose -response relationship of high -dose TxA and seizures
( mechanism - TXA binding to GABAa receptors ⇒ blocking GABAa - mediated inhibition in the CNS.

Question 42

Factor Replacements

Answer 42

1) Recombinant Factor VII a (rFVIIa): increases the generation of thrombin via the intrinsic and extrinsic pathways. Half-life 2 to 2.5 hours. Successful use of rFVIIa in hemophilia. Reduced progress of the hematoma following intracranial hemorrhage and reduced the risk ARDS, mortality or functional outcomes were not improved, can increase arterial and venous thrombosis.
2) prothrombin complex concentrate ( PCCs)-concentrates containing K- depended coagulation factors. 4-factor pcc-II, VII,IX,X; 3-Factor PCC ~II, IX, X. from human plasma Reduced to the risk of transfusion -transmitted infections, viral reduction process, transfusion -Associated circulatory overload (TACO)
3) Fibrinogen concentrate-correct hypofibrinogenemia . Low infusion volume and faster time to administration.
.
.

Question 43

Perioperative risk of Thromboembolism

Answer 43

1) High: Mechanical heart valve , Rheumatic valvulare heart disease, CHADs score > 5 , VTE < 3month / when VKA disconnected
2) Moderate: CHADs 3-4, VTE 3-12 month, active cancer
3) Low : CHADs 0-2, VTE > 12 month with no other risk factors

Question 44

Dominant sources of heat loss

Answer 44

Evaporation, radiation, convection, conduction