Factor VII – shortest half-life

  Factors V and VIII – labile factors, activity lost in stored blood, activity not lost in FFP

  Factor VIII – only factor not synthesized in liver (synthesized in endothelium)

  Vitamin K–dependent factors – II, VII, IX, and X; proteins C and S

  Vitamin K – takes 6 hours to have effect

  FFP – effect is immediate and lasts 6 hours

  Factor II – prothrombin

  Normal half-life – RBCs: 120 days; platelets: 7 days; PMNs: 1–2 days

  Prostacyclin (PGI₂)

•  From endothelium

•  Decreases platelet aggregation and promotes vasodilation (antagonistic to TXA₂)

  Thromboxane (TXA₂)

•  From platelets

•  Increases platelet aggregation and promotes vasoconstriction

•  Triggers release of calcium in platelets → exposes GpIIb/IIIa receptor and causes platelet-to-platelet binding; platelet-to-collagen binding also occurs (GpIb receptor)

COAGULATION FACTORS

  Cryoprecipitate – contains highest concentration of vWF-VIII; used in von Willebrand’s disease and hemophilia A (factor VIII deficiency), also has high levels of fibrinogen

  FFP (fresh frozen plasma) – has high levels of all coagulation factors, protein C, protein S, and AT-III

  DDAVP and conjugated estrogens – cause release of VIII and vWF from endothelium

COAGULATION MEASUREMENTS

  PT – measures II, V, VII, and X; fibrinogen; best for liver synthetic function

  PTT – measures most factors except VII and XIII (thus does not pick up factor VII deficiency); also measures fibrinogen

•  Want PTT 60–90 sec for routine anticoagulation

  ACT = activated clotting time

•  Want ACT 150–200 sec for routine anticoagulation, > 460 sec for cardiopulmonary bypass

  INR > 1.5 – relative contraindication to performing surgical procedures

  INR > 1.3 – relative contraindication to central line placement, percutaneous needle biopsies, and eye surgery

BLEEDING DISORDERS

  Incomplete hemostasis – most common cause of surgical bleeding

  von Willebrand’s disease

•  Most common congenital bleeding disorder

•  Types I and II are autosomal dominant; type III is autosomal recessive

•  vWF links GpIb receptor on platelets to collagen

•  PT normal; PTT can be normal or abnormal

•  Have long bleeding time (ristocetin test)

•  Type I is most common (70% of cases) and often has only mild symptoms

•  Type III causes the most severe bleeding

•  Type I – reduced quantity of vWF

•  Tx: recombinant VIII:vWF, DDAVP, cryoprecipitate

•  Type II – defect in vWF molecule itself, vWF does not work well

•  Tx: recombinant VIII:vWF, cryoprecipitate

•  Type III – complete vWF deficiency (rare)

•  Tx: recombinant VIII:vWF; cryoprecipitate; (DDAVP will not work)

  Hemophilia A (VIII deficiency)

•  Sex-linked recessive

•  Need levels 100% pre-op; keep at 80%–100% for 10–14 days after surgery

•  Prolonged PTT and normal PT

•  Factor VIII crosses placenta → newborns may not bleed at circumcision

•  Hemophiliac joint bleeding – do not aspirate

•  Tx: ice, keep joint mobile with range of motion exercises, factor VIII concentrate or cryoprecipitate

•  Hemophiliac epistaxis, intracerebral hemorrhage, or hematuria

•  Tx: recombinant factor VIII or cryoprecipitate

  Hemophilia B (IX deficiency) – Christmas disease

•  Sex-linked recessive

•  Need level 100% pre-op; keep at 30%–40% for 2–3 days after surgery

•  Prolonged PTT and normal PT

•  Tx: recombinant factor IX or FFP

  Factor VII deficiency – prolonged PT and normal PTT, bleeding tendency. Tx: recombinant factor VII concentrate or FFP

  Platelet disorders – cause bruising, epistaxis, mucosal bleeding, petechiae, purpura

•  Acquired thrombocytopenia – can be caused by H₂ blockers, heparin

•  Glanzmann’s thrombocytopenia – GpIIb/IIIa receptor deficiency on platelets (cannot bind to each other)

•  Fibrin normally links the GpIIb/IIIa receptors together

•  Tx: platelets

•  Bernard Soulier – GpIb receptor deficiency on platelets (cannot bind to collagen)

•  vWF normally links GpIb to collagen

•  Tx: platelets

•  Uremia – inhibits platelet function

•  Tx: hemodialysis (1st), DDAVP, platelets

  Heparin-induced thrombocytopenia (HIT)

•  Thrombocytopenia due to antiplatelet antibodies (IgG PF4 antibody) results in platelet destruction

•  Can also cause platelet aggregation and thrombosis (HITT; T = thrombosis)

•  Forms a white clot

•  Can occur with low doses of heparin

•  Low-molecular-weight heparin has a decreased risk of causing HIT

•  Tx: stop heparin; start argatroban (direct thrombin inhibitor) to anticoagulate

  Disseminated intravascular coagulation (DIC)

•  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 (eg sepsis)

  ASA – stop 7 days before surgery; patients will have prolonged bleeding time

•  Inhibits cyclooxygenase in platelets and decreases TXA₂

•  Platelets lack DNA, so they cannot resynthesize cyclooxygenase

  Clopidogrel (Plavix) – stop 7 days before surgery; ADP receptor antagonist; Tx: platelets

  Coumadin – stop 7 days before surgery, consider starting heparin while Coumadin wears off

  Platelets – want them > 50,000 before surgery, > 20,000 after surgery

  Prostate surgery – can release urokinase, activates plasminogen → thrombolysis

•  Tx: ε-aminocaproic acid (Amicar)

  H and P – best way to predict bleeding risk

  Normal circumcision – does not rule out bleeding disorders; can still have clotting factors from mother

  Abnormal bleeding with tooth extraction or tonsillectomy – picks up 99% patients with bleeding disorder

  Epistaxis – common with vWF deficiency and platelet disorders

  Menorrhagia – common with bleeding disorders

HYPERCOAGULABILITY DISORDERS

  Present as venous or arterial thrombosis/emboli (eg DVT, PE, stroke)

  Factor V Leiden mutation – 30% of spontaneous venous thromboses

•  Most common congenital hypercoagulability disorder

•  Causes resistance to activated protein C; the defect is on factor V

•  Tx: heparin, warfarin

  Hyperhomocysteinemia – Tx: folic acid and B₁₂

  Prothrombin gene defect G20210 A – Tx: heparin, warfarin

  Protein C or S deficiency – Tx: heparin, warfarin

  Antithrombin III deficiency

•  Heparin does not work in these patients

•  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 – Tx: heparin, warfarin

  Polycythemia vera – defect in platelet function; can get thrombosis

•  Keep Hct < 48 and platelets < 400 before surgery

•  Tx: phlebotomy, ASA

  Anti-phospholipid antibody syndrome

•  Not all of these patients have SLE

•  Procoagulant (get prolonged PTT but are hypercoagulable)

•  Caused by antibodies to cardiolipin and lupus anticoagulant (phospholipids)

•  Dx: prolonged PTT (not corrected with FFP), positive Russell viper venom time, false-positive RPR test for syphilis

•  Tx: heparin, warfarin

  Acquired hypercoagulability – tobacco (most common factor causing acquired hypercoagulability), malignancy, inflammatory states, inflammatory bowel disease, infections, oral contraceptives, pregnancy, rheumatoid arthritis, post-op patients, myeloproliferative disorders

  Cardiopulmonary bypass – factor XII (Hageman factor) activated; results in hypercoagulable state

•  Tx: heparin to prevent

  Warfarin-induced skin necrosis

•  Occurs when placed on Coumadin without being heparinized first

•  Due to short half-life of proteins C and S, which are first to decrease in levels compared with the procoagulation factors; results in relative hyperthrombotic state

•  Patients with relative protein C deficiency are especially susceptible

•  Tx: heparin if it occurs; prevent by placing patient on heparin before starting warfarin

  Key elements in the development of venous thromboses (Virchow’s triad) – stasis, endothelial injury, and hypercoagulability

  Key element in the development of arterial thrombosis – endothelial injury

DEEP VENOUS THROMBOSIS (DVT)

  Stasis, venous injury, and hypercoagulability are risk factors

  Post-op DVT Tx:

•  1st – warfarin for 6 months

•  2nd – warfarin for 1 year

•  3rd or significant PE – warfarin for lifetime

  Greenfield filters – indicated for patients with either:

•  Contraindications to anticoagulation

•  Documented PE while on anticoagulation

•  Free-floating IVC, ilio-femoral, or deep femoral DVT

•  Recent pulmonary embolectomy

  Temporary IVC filters can be inserted in patients at high risk for DVT (eg head injury patients on prolonged bed rest)

PULMONARY EMBOLISM (PE)

  If the patient is in shock despite massive inotropes and pressors, go to OR; otherwise give heparin (thrombolytics have not shown an improvement in survival) or suction catheter–based intervention

  Most commonly from the ilio-femoral region

HEMATOLOGIC DRUGS

  Procoagulant agents (anti-fibrinolytics)

•  ε-Aminocaproic acid (Amicar)

•  Inhibits fibrinolysis by inhibiting plasmin

•  Used in DIC, persistent bleeding following cardiopulmonary bypass, thrombolytic overdoses

  Anticoagulation agents

•  Warfarin – prevents vitamin K–dependent decarboxylation of glutamic residues on vitamin K–dependent factors

•  Sequential compression devices – improve venous return but also induce fibrinolysis with compression (release of tPA [tissue plasminogen activator] from endothelium)

•  Heparin

•  Binds and activates anti-thrombin III (1000× more activity)

•  Reversed with protamine (binds heparin)

•  Half-life of heparin is 60–90 minutes (want PTT 60–90 seconds)

•  Is cleared by the reticuloendothelial system

•  Long-term heparin – osteoporosis, alopecia

•  Heparin does not cross placental barrier (can be used in pregnancy) → warfarin does cross the placental barrier (not used in pregnancy)

•  Protamine – cross-reacts with NPH insulin or previous protamine exposure; 1% get protamine reaction (hypotension, bradycardia, and decreased heart function)

•  Low molecular weight heparin (eg enoxaparin, fondaparinux) – lower risk of HIT compared to unfractionated heparin; binds and activates antithrombin III but increases neutralization of just Xa and thrombin; not reversed with protamine

•  Argatroban – reversible direct thrombin inhibitor; metabolized in the liver, half-life is 50 minutes, often used in patients w/ HITT

•  Bivalirudin (Angiomax) – reversible direct thrombin inhibitor, metabolized by proteinase enzymes in the blood; half-life is 25 minutes

•  Hirudin (Hirulog; from leeches) – irreversible direct thrombin inhibitor; also the most potent direct inhibitor of thrombin; high risk for bleeding complications

•  Ancrod – Malayan pit viper venom; stimulates tPA release

  Thrombolytics

•  Streptokinase (has high antigenicity), urokinase, and tPA (tissue plasminogen activator)

•  All activate plasminogen

•  Need to follow fibrinogen levels – fibrinogen < 100 associated with increased risk and severity of bleeding

•  Tx for thrombolytic overdose – ε-aminocaproic acid (Amicar)

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