Chapter 2: Hematology Flashcards
Three initial responses to vascular injury
Vascular vasoconstriction, platelet adhesion, thrombin generation
Intrinsic coagulation cascade
Exposed collagen + prekallikrein + HMW kininogen + Factor 12 -> activate factor 11 -> activate 9, then 8 -> activate 10, then add 5 -> Convert prothrombin (factor II) to thrombin -> thrombin then converts fibrinogen to fibrin
Extrinsic coagulation cascade
Tissue factor (injured cells) + factor 7 -> activate 10, then add 5 -> convert prothrombin to thrombin -> thrombin then converts fibrinogen to fibrin
Prothrombin complex (for intrinsic and extrinsic pathways)
- 10, 5, Ca, platelet factor 3, prothrombin.
- Forms on platelets - Catalyzes the formation of thrombin
Convergence point for intrinsic and extrinsic pathway
Factor 10
Inhibits factor 10
Tissue factor pathway inhibitor
Links platelets together (binds GpIIb /IIIa molecules) to form platelet plug -> hemostasis
Fibrin
Factor XIII: function
Helps crosslink fibrin
Key to coagulation
- Converts fibrinogen to fibrin and fibrin split products
- Activates factors 5 and 13
- Activates platelets
Thrombin
Key to anticoagulation
- Binds and inhibits thrombin
- Inhibits factors 9, 10, and 11
Antithrombin III (AT-III)
Heparin activates AT-III (up to 1000x normal activity)
Protein C: function
degrades factors 5 and 8; degrades fibrinogen
Protein S: function
Protein C cofactor
Tissue plasminogen activator: origin and function
Released from endothelium and converts plasminogen to plasmin
Plasmin: function
Degrades factors 5 and 9, fibrinogen, and fibrin -> lost platelet plug
Alpha-2 antiplasmin: origin and function
Released from endothelium, natural inhibitor of plasmin
Factor: shortest half life
Factor 7
Factors: labile, activity lost in stored blood; activity not lost in FFP
Factors 5 and 8
Factors: only factor not synthesized in the liver
Factor 8, synthesized in the endothelium
Vitamin K: onset of action
6 hours
FFP: onset and duration of action
Works immediately, lasts 6 hours
Prothrombin is also known as…
Factor II
Half life: RBCs
120 days
Half-life: platelets
7 days
Half life: PMNs
1-2 days
Prostacyclin (PGI2) - origin and action
From endothelium - decreases platelet aggregation and promotes vasodilation (antagonistic to TXA2)
Thromboxane (TXA2) - origin and action
From platelets
- Increases platelet aggregation and promotes vasoconstriction
- Triggers release of calcium in platelets -> exposes Gp2b/3a receptor and causes platelet-to-platelet binding; platelet-to-collagen binding also occurs (Gp1b receptor)
Cryoprecipitate contains…
highest concentration of vWF-VIII; high levels of fibrinogen
Used in von Willebrand’s disease and hemophilia A (factor 8 deficiency)
FFP contains…
high levels of all coagulation factors, protein C, protein S, and AT-III
DDAVP and conjugated estrogens: function
Causes release of VIII and vWF from endothelium
Lab: PT measures…
factor 2, 5, 7, and 10; fibrinogen; best for liver synthetic function
Lab: PTT measures…
most factors except 7 and 13 (thus does not pick up factor 7 deficiency); also measures fibrinogen
What do you want PTT for routine anticoagulation?
60 - 90 sec
What do you want ACT (activated clotting time) for routine anticoagulation?
150 - 200 sec for routine anticoagulation, > 460 sec for cardiopulmonary bypass
Most common congenital bleeding disorder
Von Willebrand’s disease
Type 1 von Willebrand’s disease: description and Tx
Reduced quantity of vWF
Tx: recombinant VIII:vWF, DDAVP, cryoprecipitate
Type 2 von Willebrand’s disease: description and Tx
Defect in vWF molecule itself, vWF does not work well
Tx: recombinant VIII:vWF, cryoprecipitate
Type 3 von Willebrand’s disease: description and Tx
Complete vWF deficiency (rare)
Tx: recombinant VIII:vWF, cryoprecipitate; (DDAVP will not work)
Lab findings: von Willebrand’s disease
PT normal; PTT can be normal or abnormal. Prolonged bleeding time (ristocetin test).
Hemophilia A: inheritance, description, lab findings, Tx
Sex linked recessive
VIII deficiency
Prolonged PTT, normal PT
Tx - for hemophiliac epistaxis, intracerebral hemorrhage, or hematuria: rFactor 8 or cryoprecipitate
Tx - for joint bleeding: Do not aspirate - Ice, keep joint mobile with ROM exercises - Factor 8 concentrate or cryoprecipitate
Why do hemophilia A newborns not bleed at circumcision?
Factor 8 crosses the placenta
Goals for hemophilia A pre and post op
Need levels 100% pre-op, keep at 80-100% for 10-14 days after surgery
Hemophilia B: inheritance, description, lab findings, Tx
Sex-linked recessive
Factor 9 deficiency
Prolonged PTT and normal PT
Tx: rFactor9 or FFP
AKA Christmas Disease
Goals for Hemophilia B pre and post op
Need levels 100% pre-op, keep at 30-40% for 2-3 days after surgery
Factor 7 deficiency: lab findings, Tx
Prolonged PT. Normal PTT.
Tx: rFactor7 or FFP
S&S: Platelet disorders
Bruising, epistaxis, mucosal bleeding, petechiae, purpura.
Acquired thrombocytopenia
Platelet disorder: caused by H2 blockers, heparin
Glanzmann’s thrombocytopenia: description and Tx
Platelet disorder: Gp2b/3a receptor deficiency on platelets (cannot bind to each other). - Fibrin normally links the Gp1b/3a receptors together
Tx: Platelets
Bernard Soulier: description and Tx
Gp1b receptor deficiency on platelets (cannot bind to collagen) - vWF normally links Gp1b collagen
Tx: Platelets
Uremia inhibited platelet function: treatment
hemodialysis (1st), DDAVP, platelets
Heparin-induced thrombocytopenia (HIT): description, Tx
Thrombocytopenia due to antiplatelet antibodies (IgG PF4 antibody) results in platelet destruction. - Can also cause platelet aggregation and thrombosis. - Forms a white clot. - Can occur with low doses of heparin.
Tx: stop heparin, start argatroban (direct thrombin inhibitor) to anticoagulate
Disseminated intravascular coagulation (DIC): description and Tx
Decreased platelets, low fibrinogen, high fibrin split products, and high d-dimer - Prolonged PT and prolonged PTT - Often initiated by tissue factor
Tx: need to treat the underlying cause
Aspirin: mechanism of action
Inhibits cyclooxygenase in platelets and decreases TXA2
Blood thinners: pre-op recommendations
Aspirin: stop 7 days before surgery; patients will have prolonged bleeding time
Plavix: stop 7 days before surgery; ADP receptor antagonist. Tx: platelets
Coumadin: stop 7 days before surgery; consider starting heparin
Platelet pre-op recommendations
Want them > 50,000 before surgery, > 20,000 after surgery
Bleeding after prostate surgery…
Can release urokinase, activates plasminogen -> thrombolysis
Tx: e-aminocapropic acid (Amicar)
Most sensitive history finding (99% of patients with bleeding disorder)
Abnormal bleeding with tooth extraction or tonsillectomy
Common with vWF deficiency and platelet disorders
Epistaxis
Factor V Leiden: description and Tx
MC congenital hypercoaguability disorder - 30% of spontaneous venous thromboses
Causes resistance to activated protein C; the defect is on factor 5.
Tx: heparin, warfarin
Hyperhomocysteinemia: treatment
Folic Acid. B12
prothrombin gene defect G20210A: treatment
Heparin, warfarin
protein C or S deficiency: treatment
Heparin, warfarin
Heparin does not work in these patients…
Antithrombin H1 deficiency. Can develop after previous heparin exposure
Tx: recombinant AT-III concentrate or FFP (highest concentration of AT-III) followed by heparin, then warfarin
dysfibrinogenemia, dysplasminogenemia: treatment
Heparin, warfarin
Polycythemia vera: description ,causes, treatment
Defect in platelet function; can get thrombosis
Primary: JAK2 mutation Secondary: low oxygen tension (e.g.: living at high altitudes, smoking, carbon monoxide exposure)
Tx:
Anti-phospholipid antibody syndrome: description, cause
Hypercoagulabe with prolonged PTT (not corrected with FFP). Positive Russell viper venom time, false-positive RPR test for syphillis.
Caused by antibodies to cardiolipin and lupus anticoagulant (phospholipids)
Tx: heparin, warfarin
Causes of acquired hypercoagulability
Tobacco. Malignancy. Inflammatory states. IBD. Infections. OCPs. Pregnancy. Rheumatoid arthritis. Post-op patients. Myeloproliferative disorders.
How does cardiopulmonary bypass result in hypercoagulability?
Activates Factor 12 (Hageman factor).
Tx: heparin to prevent.
Why does warfarin-induced skin necrosis occur?
Short half-life of proteins C and S, which are first to decrease in levels compared with the pro coagulation factors; results in relative hyperthrombotic state. - Occurs when placed on coumadin without being heparinized first.
Who is at risk for warfarin-induced skin necrosis?
Patients with relative protein C deficiency are especially susceptible.
Key elements in the development of venous thromboses
Virchow’s triad (stasis, endothelial injury, hypercoagulability)
Key element in the development of arterial thrombosis
Endothelial injury
Post-op DVT Tx: 1st: 2nd: 3rd:
1st: Warfarin for 6 mo. 2nd: Warfarin for 1 yr. 3rd or significant PE: Warfarin for life.
Indications for Greenfield filter
- Contraindications to anticoagulation
- Documented PE while on anticoagulation
- Free-floating IVC, ilio-femoral, or deep femoral DVT
- Recent pulmonary embolectomy
Pulmonary embolism: treatment
Shock (despite massive interpose, pressors) -> OR. No shock -> Heparin (thrombolytics have not shown an improvement in survival) or suction catheter-based intervention.
Aminocaproic acid (Amicar): mechanism
Inhibits fibrinolysis by inhibiting plasmin. Used in DIC, persistent bleeding following cardiopulmonary bypass, thrombolytic overdoses
Warfarin: mechanism
Prevents vitamin-K dependent decarboxylation of glutamic residues on vitamin K dependent factors
What is the mechanism behind SCDs?
Improve venous return but also induce fibrinolysis with compression (release of tPA (tissue plasminogen activator) from endothelium.
Heparin: mechanism
Binds and activates anti-thrombin III.
Reverse with protamine. Cleared by the reticuloendothelial system.
Does not cross placenta.
Risks of long-term heparin
Osteoporosis. Alopecia.
Half-life / goal PTT of heparin
Half-life: 60-90 minutes. Goal PTT: 60-90 seconds
protamine reaction
Cross reacts with NPH insulin or previous protamine exposure
1% get protamine reaction (hypotension, bradycardia, and decreased heart function).
Low molecular weight heparin (ex, enoxaparin, fondaparinux)
Binds and activates antithrombin III but increases neutralization of just 10a and thrombin
Lower risk of HIT compared to unfractionated heparin. Not reversed with protamine
Argatroban: mechanism
Reversible direct thrombin inhibitor - Metabolized in the liver - Half life: 50 minutes - Often used in patients with HITT
Bivalirudin (Angiomax): mechanism
Reversible direct thrombin inhibitor - Metabolized by proteinase enzymes in the blood - Half life: 25 minutes
Hirudin (Hirulog; form leeches)
Irreversible direct thrombin inhibitor - most potent direct inhibitor or thrombin
High risk for bleeding complications
Ancrod: mechanism
Malayan pit viper venom; stimulates tPA release
Thrombolytics: Streptokinase, urokinase, tPA
Activate plasminogen - need to follow fibrinogen levels
Treatment for thrombolytic overdose
e-aminocaproic acid (Amicar)
Minor contraindications to TPA.
Minor surgery. Recent CPR. A fib with MV disease. Bacterial endocarditis. Hemostatic defects (i.e. renal or liver disease). Diabetic hemorrhage retinopathy. Pregnancy.
