Hematology Flashcards
Damage outside of blood vessels triggers release of Thromboplastin (III) from damaged cells
Extrinsic Pathway
Trauma to the blood itself or exposure of the blood to collagen in a traumatized blood vessel wall activates factor XII (XIIa).
Intrinsic Pathway:
IXa when complexed on the platelet surface with activated factor VIII:C (VIII:Ca) and Ca++ activates factor X (Xa).
Common Pathway?
Activated factor X (Xa) when complexed on the platelet surface with activated factor V (Va) and calcium (factor IV) on the platelet surface, converts prothrombin (factor II) to thrombin (IIa).
IIa converts fibrinogen (I) to fibrin (Ia), and in the presence of factor XIII, cross-linking occurs.
What does Heparin do?
Accelerates Anti Thrombin III (ATIII) which neutalizes thrombin (IIa) and Factor Xa.
Essentially it only binds to newer baby unbound clotting factors.
Heparin MOA
Increase the rate of Thrombin - ATIII reaction at least 1000 fold.
Uses of Heparin
-prophylaxis VTE, DVT, PE Tx
-A-fib, new heart valves
-tx of peripheral artery embolism
-CV surgery
-complications in pregnancy
Heparin metabolism
Reticuloendothelial system of the LIVER. Does Not cross the placenta.
Heparin Dose for VTE
5,000 units bolus then 1200-1600 units/hr
Keep aPTT 1.5-2.5 times normal level
What does aPTT measure? (Heparin monitoring)
Measures activity of the INTRINSIC and COMMON pathways time to clot formation
has issues with results
Anti-Xa (IU/mL) measure?
(Heparin monitoring)
More direct measurement of Heparin concentrations
has less factors that can affect levels but results may vary between labs
ACT (seconds) (activated clotting time) measure?
(Heparin monitoring)
-Whole blood sample
-measures INTRINSIC pathway
-used in procedures with significant Heparin use
-has good linear dose response
Issues that may lead to a prolonged baseline aPTT
-Intrinsic clotting factor pathway deficiency (8,9,11,12)
-Leukemia
-Meds (warfarin, DOACs)
-DIC
-Liver disease
-recent pregnancy or miscarriage
-polycythemia
-lupus
What is Heparin resistance and how is it caused?
-Requires high doses: > 35,000 units/day
-Due to increase in Factor VIII (8), ATIII deficiency, massive PE
-Acquired AT III deficiency in patients with cirrhosis, nephrotic syndrome or DIC, ECMO tx
Treatment for Heparin resistance?
Administer 2 units FFP to provide AT III
Check both aPTT and Anti-Xa
Heparin Toxicity presentation/symptoms
-Bleeding (major bleeds in 1-11.5% of pts.)
-Thrombocytopenia (HIT)
-abnormal LFTs
-infrequent risk of osteoporosis
-rare hyperkalemia d/t aldosterone suppression and natriuresis
What is HIT and how is it caused?
-< 100,000 drop from baseline
-Heparin dependent antiplatelet IgG antibodies (Type II HIT)
Direct, non-immunogenic platelet effect
-5-15 days after start of treatment
Earlier with previous exposure
Risks of getting HIT?
-1-15% with heparin (any dose)
-5% with heparin flush
-10x lower risk with LMWH
HIT Treatment
-Stop heparin products
-Administer non-heparin anticoagulants to prevent thrombosis
-Add allergy to the chart
-PROTAMINE SULFATE (ANTEDOTE)
How is Protamine Sulfate dose determined?
Determined by the dose of heparin, route of heparin administration and time elapsed since the heparin was administered.
1 mg Protamine : 100 units heparin
Protamine hypersensitivity reaction to….
fish
pre-treat with corticosteroid and antihistamine
LMWH MOA
Inhibition of Factor Xa by antithrombin.
Do not use ______ in patients with HIT
LMWH
Synthetic indirect specific inhibitor of Factor Xa only
Fondaparinux (Arixtra)
DOAC drug names
Oral Xa Inhibitors
Rivaroxaban (Xarelto ®)
Apixaban (Eliquis ®)
Edoxaban (Savaysa ®)
Taking over warfarin
XA
How long to hold Oral Xa inhibitor before surgery w/ low-mod bleed risk and high bleed risk?
1 day- low/mod
2/day- high
Apixaban, Edoxaban, Rivaroxaban
Dabigatran preop monitoring?
Bleed risk and CrCl (kidney function)
Oral Xa reversal?
(cannot measure INR)
D/C medication, mechanical compression, surgical hemostasis, transfusion support (blood products, activated charcoal)
Oral Xa Reversal?
Andexanet alpha (Andexxa)
Ciraparantag- pending since 2016
How does Andexxa work?
Reverses Factor Xa inhibitors- recombinant human Factor Xa
Binds competitively to Factor Xa inhibitors for complete reversal
Andexxa dosing
(Xa inhibitor reversal agent)
Low Dose
Initial IV bolus: 400 mg at 30 mg/min
Follow Infusion: 4 mg/min for up to 120 min
High Dose
IV Bolus: 800 mg at 30 mg/min
Infusion: 8 mg/min for up to 120 min
Andexxa Chart
Name Direct Thrombin Inhibitors
Argatroban, Hirudin Analogs (Bivalirudin, Lepirudin), Dabigatran
Argatroban MOA and Use
Small molecule.
Highly selective and reversible direct thrombin inhibitor (Factor IIa).
Used for the prevention and treatment of thrombosis in patients with HIT or HITTS (no reversal agent)
Hirudin Analogs indicated for?
Indicated for thrombosis associated with HIT
How do Hirudin analogs work?
Binds irreversibly to the active catalytic and substrate-recognition sites of both circulating and clot-bound thrombin (Factor IIa).
No Reversal agent.
Dabigatran reversal?
(Direct Thrombin inhibitor)
Idarucizumab (Praxbind )
MOA of Warfarin
Indirect anticoagulant that alters the synthesis of blood coagulation factors II, VII, IX, and X by interfering with the action of vitamin K
Warfarin characteristics. How long does it take to work?
No effect on normal factors already in the blood when the drug is started.
Slowing down the future, not immediate effect
Can take up to 5 days to build up
Warfarin Toxicity antidote and treatment?
Antidote is Vitamin K1, but takes up to 24 hours for the synthesis of new fully carboxylated
For immediate hemostatic competence: FFP 10-20ml/kg
Vitamin K recommendation
Oral Vit. K recommended for most situations.
I.V. for serious or life-threatening bleeds.
NEVER S.Q.
Warfarin toxicity plan?
Look at INR and look at condition, pick intervention
Warfarin preoperative management?
Goal INR is < 1.5
Begin holding at least 5 days prior to procedure
Restart based on bleeding risk within 24 hours at pre-op dose unless
Bridge Therapy recs DOAC and Warfarin?
Most DOAC DO NOT require bridge therapy as they are only held 24-48 H prior to procedure.
Warfarin has several different recommendations based on bleeding risk and thromboembolism risk.
A-fib guidelines for bridging?
Afib 2019 guidelines only support bridging if the patient is VERY high risk of stoke (mech valve, recent stroke,etc)
CHEST 2022 bridging rec
If Warfarin is used for mechanical heart values, atrial fibrillation, or VTE, no bridge therapy is recommended for most patients.
What is CHA2DS2-Vasc
CLOT RISK SCORING, FOR A-FIB PATIENTS WITH STROKE RISK
How long to hold bridge therapy if using a LMWH?
24 hours pre-procedure if using LMWH
At least 4 hours pre-procedure if using UFH
Name the Thrombolytic Agents
”ASEs”
Alteplase
Reteplase
Tenecteplase
Streptokinase
Urokinase
How do Thrombolytic Agents work?
t-PA binds to fibrin and plasminogen and converts bound plasminogen to plasmin WHICH BREAKS CLOTS
Thrombolytic Agent Uses
-Lysing thrombi during treatment of acute MI.
-Treatment of P.E.
-Treatment of venous thrombosis.
-Open occluded I.V. catheters.
What happens with Thrombolytic Agent Toxicity
Major toxicity is hemorrhage due to:
Lysis of fibrin in “physiological thrombi” at sites of vascular injury.
Do Thrombolytics have reversal agent?
No. Fibrinolytic activity can last for 7-24 hours after discontinuation of the drug
What does Sodium Citrate do?
Binds free Calcium(FACTOR IV) in blood
Dextran Use?
Water-soluble glucose polymer (polysaccharide).
Expansion of intravascular volume.
Prevent thromboembolism by decreasing blood viscosity.
Epsilon Aminocaproic Acid (Amicar®): Pro-coagulant
Inhibitor of fibrinolysis by indirect inhibition of plasmin’s anti-platelet effects.
Amicar: USE?
PRO-COAGULANT
-Treatment of excessive bleeding
-Systemic hyperfibrinolysis is associated with surgical complications
-Allows completion of surgery after stopping oozing in patients with cirrhosis
-Reduces bleeding and transfusion requirements after CPB
Tranexamic Acid (TXA) MOA
PRO-COAGULANT
Competitive inhibitor of several plasminogen binding sites leading to inhibition of fibrinolysis, also reduced plasmin activity.
Uses: Bleeding prophylaxis for surgery, trauma, etc
What is RAPLIXA
Spray dried fibrin sealant to control bleeding during surgery when standard surgical techniques, such as suture, ligature, or cautery are ineffective or impractical.
MOA: Purified human plasma-derived fibrinogen and thrombin.
NovoSeven RT(Coagulation factor VIIa (Recombinant) USE
Hemophilia A or B.
Patients with congenital factor VII deficency.
Works in the extrinsic pathway.
NovoSeven RT off-label uses….
Warfarin-induced bleeding that cannot wait reversal with FFP or Vit. K.
Spontaneous intracranial hemorrhage.
Massive bleeding:
NovoSeven RT complications
Most significant are thromboembolic:
Myocardial ischemia or infarction.
Cerebral ischemia or infarction.
Platelet Function (1,2,3)
- Adhesion
- Activation
- Aggregation
What happens with Adhesion?
vonWillebrand’s factor (Factor VIII:vWF) is manufactured and released from endothelial cells
-Factor VIII:vWF promotes platelet adhesion to damaged vascular walls
Most common inherited coagulation defect?
vonWillebrand’s disease
Activation:
Thrombin (factor IIa) combines with the thrombin receptor on the platelet surface to activate the platelet
-Changes the shape of the platelet
Thromboxane A-2 and ADP do what?
promote platelet aggregation
Aggregation:
Thromboxane-A2 and ADP uncover fibrinogen receptors. Fibrinogen (factor I) attaches to the receptors linking the platelets to each other
How does Aspirin inhibit platelet aggregation?
-Cyclo-oxygenase (COX) is rendered non-functional (
-Persists for the life of the platelet (8-12 days).
How long does NSAIDs block thromboxane-A2 production?
temporary (approx. 24-48 hours).
Hold about 2 days prior to surgery
Thienopyridine ADP-receptor Antagonists
Clopidogrel (Plavix®)
Prasugrel (Effient®)
Ticagrelor (Brilinta®) - reversible
Cangrelor (Kengreal®)
Platelet Glycoprotein (GP IIb/IIIa) Receptor Inhibitors
Abciximab (ReoPro®)
Eptifibatide (Integrilin ®)
Tirofiban (Aggrastat ®)
How early should you hold Clopidogrel (Plavix ®): P2Y12 inhibitor before surgery?
-Stop 5 days prior to surgery
Platelet aggregation and bleeding time return to baseline values within 5 days.
Reversible P2Y12 inhibitors end in -
“-treglor”
How long hold Ticagrelor (Brilinta)
before surgery?
3-5 days
Cangrelor (Kengreal)
IV P2Y12 inhibitor
Reversible- platelet function returns to normal 1 hour after stopping infusion
ADRs of P2Y12 Inhibitors
Bleeding
N/V
Rash and diarrhea
Thrombotic Thrombocytopenia Purpura
Severe neutropenia (low risk)
Do P2Y12 inhibitors have reversal agents?
No!
-VerifyNow P2Y12:
Measures the percentage of platelet inhibition
Aspirin perioperative recommendation?
Do not hold for non-cardiac surgery unless high bleeding risk. If held- </= 7 days
Noncardiac Surgery P2Y12 (perioperative)
Clopidogrel: 5 days
Prasugrel: 7 days
Ticagrelor: 3-5 days
Resume </= 24 hours post op
GIIb/IIIa Inhibitors Uses
Acute ischemic complications of percutaneous coronary intervention (PCI)
Unstable angina and non-Q wave MI
DDVAP uses
-Hemostatic activity due to the increased release of vonWillebrand factor in patients with uremia, chronic liver disease and certain types of hemophilia
-Promotes platelet adhesiveness to the vascular endothelium
DDAVP for DI?
Intranasally for the treatment of DI due to inadequate production of ADH by the posterior pituitary
Clotting Cascade
