Hemostasis and Related Disorders

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jknell
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Hemostasis and Related Disorders
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2013-04-02 20:52:55
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Hemostasis and related disorders
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  1. Coagulation Cascade
  2. Extrinsic Pathway
    • "lucky pathway"
    • -only have to remember one factor

    • -factor VII ("lucky number 7")
    • -PT Pathway

    -Activated by TT: Tissue thromboplastin

    • -"less numbers, less letters: PT, TT"
  3. Intrinsic Pathway
    "unlucky pathway"

    • Need to remember multiple numbers
    • XII, XI, IX, VIII

    • -PTT Pathway
    • -activated by SEC (subendothelial collagen)
    • -"more numbers, more letters: PTT, SEC"
  4. Common Pathway
    • "Small Bills:
    • FI (Fibrinogen)
    • FII (Prothrombin)
    • FV (interacts with FX: FII --> FIIa)
    • FX

    • Deficiency: increase in PT and PTT
    • "V x II x I = X"
  5. Vitamin K
    -Reduced in the LV by epoxide reductase

    -Needed to activated factors: II, VII, IX, X and Protein C and S

    *** Warfarin inhibits epoxide reductase
  6. Anticoagulation
    -Protein C: inactivates V and VIII

    -Protein S: helps protein C inactivate V and VIII

    • -ATIII (antithrombin III): inhibitis activation of II, VII, IX, X, XI, XII
    • -ATIII is activated by heparin

    -tPA: used to activate plasminogen to plasmin --> cleavage of fibrin mesh
  7. Platelet Plug Formation
    • 1. Injury:
    • -(endothelial damage): vWF binds exposed collagen

    • 2. Adhesion:
    • -platelet GP11b binds vWF
    • -platelets release ADP and Ca (necessary for coagulation cascade)

    • 3. Activation:
    • -ADP induces GPIIb/IIIa

    • 4. Aggregation:
    • -Fibrinogen binds GpIIb/IIIa --> links platelets

    Temporary Platelet plug

    • PRO-AGGREGATION
    • -TXA2 (platelets)
    • -decreased blood flow

    • ANTI-AGGREGATION
    • -PGI2 and NO (endothelial cells)
    • -increased blood flow
  8. Erythrocyte Sedimentation Rate
    -acute phase reactants in plasma (eg: fibrinogen) cause RBC aggregation --> increased ESR

    Increased ESR: infections, autoimmunity, malignancy, GI disease, pregnancy

    Decreased ESR: polycythemia, SCA, CHF, microcytosis, hypofibrinogenemia
  9. Hemostasis
    • 1. Primary
    • -weak platelet plug
    • -platelets interacting with vessel wall

    • 2. Secondary
    • -stabilized platelet plug
    • -coagulation cascade
  10. Primary Hemostasis
    1. Transient vasoconstriction (neural stim, endothelin release)

    • 2. Platelet adhesion (vWF binds GPIb)
    •      ***wVW from Weibel-Palade bodies of endothelium and aplha granules of plt

    • 3. Platelet degranulation (change in shape and degranulation)
    •      -ADP (promotes GPIIb/IIIa)
    •      -TXA2 (plt aggregation)

    4. Platelet aggregation (fibrinogen links plts by GpIIb/IIIa)
  11. Disorders of Primary Hemostasis
    • 1. Immune Thrombocytopenia Purpura (ITP)
    • 2. Microangiopathic Hemolytic Anemia (TTP, HUS)
    • 3. Bernard-Soulier Syndrome
    • 4. Glanzmann thrombasthenia
    • 5. Aspirin
    • 6. Uremia

    -quantitative and qualitative abnormalities of platelets

    -mucosal and skin bleeding: epistaxis, hemoptysis, GI bleeding, hematuria, menorrhage

    -intracranial hemorrhage with severe thrombocytopenia

    • Labs:
    • -increased bleeding time
    • -possible decreased platelet count

    • Symptoms:
    • -petechiae, ecchymoses, purpura, easy bruising

    ***petechiae not usually seen with qualitative disorders
  12. Immune Thrombocytopenia Purpura (ITP)
    FA: "Idiopathic Thrombocytopenia Purpura

    Anti-GpIIb/IIIa antibodes produced by plasma cells in spleen --> splenic macrophage consumption of platelets

    • Acute: children
    • -after viral infection or vaccination
    • -self limiting

    • Chronic: adults
    • -women of child-bearing age
    • -primary
    • -secondary (ie: SLE)
    • ***IgG can cross the placenta

    • Labs:
    • -decreased platelet count
    • -NORMAL PT/PTT
    • -increased megakaryocytes on BM bx

    • Treatment:
    • -corticosteroids: children respond well, adults relapse
    • -IVIg
    • -Splenetctomy
  13. Microangiopathic Hemolytic Anemia
    Form of extrinsic hemolytic normocytic anemia

    • Causes:
    • -TTP
    • -HUS
    • -DIC
    • -SLE
    • -Malignant HTN

    • Pathogenesis:
    • -formation of platelet microthrombi in small vessels
    • -platelets are consumed
    • -RBCs are sheared --> schistocytes (helmet cells)
  14. Thrombotic Thrombocytopenia Purpura (TTP)
    • Presentation:
    • 1. neurologic sx (more common in TTP)
    • 2. renal sx (more common in HUS)
    • 3. fever
    • 4. thrombocytopenia (skin and mucosal bleeding)
    • 5. microangiopathic hemolytic anemia

    • Pathophysiology:
    • -most commonly autoantibody to to ADAMTS13
    • -ADAMTS13 cleaves vWF multimers into monomers for degradation
    • -commonly seen in adult females

    • Labs:
    • -thrombocytopenia
    • -increased bleeding time
    • -increased megakaryocytes on BM bx
    • -schistocytes on blood smear
    • -increased LDH
    • **PT/PTT NORMAL!
    • Treatment:
    • -plasmapheresis
    • -corticosteroids
  15. Hemolytic Uremic Syndrome
    Damage to endothelial cells due to drugs or infection

    • Pathophysiology:
    • -commonly in children with E. coli O157:H7 (EHEC) dysentery (undercooked beef)
    • -verotoxing damages endothelial cells
    • -damages --> platelet microthrombi

    • Presentation:
    • 1. Anemia
    • 2. Acute renal failure
    • 3. Thrombocytopenia

    • Labs:
    • -thrombocytopenia
    • -increased bleeding time
    • -increased megakaryocytes on BM bx
    • -schistocytes on blood smear

    **PT/PTT normal!
  16. Bernard Soulier Syndrome
    • Pathophysiology:
    • -genetic deficiency in GPIb (defect in plt adherence to vWF)
    • -impaired platelet adhesion and platelet plug formation
    • -platelets don't live as long without GPIb

    • Labs:
    • -thrombocytopenia
    • -increased bleeding time
  17. Glanzmann Thrombasthenia
    • Pathophysiology:
    • -defect in GPIIb/IIIa (defect in plt-plt aggregation)

    • Labs:
    • -normal Plt count
    • -increased bleeding time
    • -blood smear shows no platelet clumping
  18. Other causes of platelet dysfunction
    -Aspirin: irreversibly inactivates COX --> lack of TXA2 --> impaired aggregation

    -Uremia: due to poor kidney function, disrupts platelet function --> impaired aggregation and adhesion
  19. Secondary Hemostasis
    • -stabilizes weak platelet plug via the coagulation cascade
    • -coag cascade generate thrombin
    • -thrombin converts fibrinogen to fibrin
    • -fibrin crosslinks and stabilizes platelet plug

    • Coagulation Factors:
    • -produced in liver in inactive form
    • -activation:
    •      -exposure to activating substance  
    •      -phospholipid surface of platelets
    •      -Ca from platelet dense granules
  20. Disorders of Secondary Hemostasis
    • 1. Hemophilia A
    • 2. Hemophilia B
    • 3. Coagulation Factor Inhibitor
    • 4. von Willebrand Disease
    • 5. Vitamin K therapy
    • 6. Liver Failure
    • 7. Large Volume Transfusion

    -usually due to factor abnormalities

    • Labs:
    • -Prothrombin Time (PT): extrinsic and common pathways
    • -Partial Thromboplastin Time (PTT): measures intrinsic and common pathways


    • **PTT better for measuring effects of heparin
    • **PT better for measuring effects of coumadin

    • Symptoms:
    • -deep tissue bleeding into muscles and joints
    • -rebleeding after surgical procedures
  21. Hemophilia A
    • FVIII deficiency (defect in intrinsic pathway)
    • 1. X linked recessive
    • 2. de novo mutation

    • Presentation:
    • -deep tissue, joint and postsurgical bleeding
    • -easy bruising

    • Labs:
    • -increased PTT
    • -Normal PT
    • -platelet count and bleeding time normal

    • Treatment:
    • -recombinant FVIII
  22. Hemophilia B
    • "Christmas disease"
    • FIX deficiency (defect in intrinsic pathway)

    Same presentation and labs as Hemophilia A except FIX is decreased
  23. Coagulation Factor Inhibitor
    • Acquired antibody against coagulation factor
    • -most commonly FVIII

    Presents like hemophilia A

    *PTT does NOT correct upon mixing patient's plasma with normal plasma (antibodies inactivate normal FVIII) vs Hemophilia
  24. von Willebrand Disease
    • Epidemiology:
    • -mild
    • -most common inherited bleeding disorder

    • Pathophysiology:
    • -defect in vWF (autosomal dominant)
    • -leads to a defect in the intrinsic pathway and in platelet plug formation
    • -vWF acts to carry/protect FVIII from degradation

    • Presentation:
    • -varies depending on severity
    • -mild mucosal skin bleeding

    • Labs:
    • -normal platelet count
    • -increased bleeding time
    • -normal PT
    • -increased or normal PTT
    • -risotcetin test

    • Treatment:
    • -desmopressin (DDAVP) (releases vWF stored in endothelium)
  25. Vitamin K Deficiency
    • -disrupts multiple coagulation factors
    • -vitamin K is activated by epoxide reductase in liver
    • -activated vitamin K gamma carboxylates factors II, VII, IX, X, prot C and S

    • Causes:
    • 1. Newborns (lack GI colonization that generates vitamin K)
    • 2. Long term antibiotic therapy
    • 3. Malabsorption (deficiency in fat soluble vitamins)

    • Labs:
    • -elevated PT and PTT
  26. Liver Failure: abnormal secondary hemostasis
    • -decreased production of coagulation factors
    • -decreased activation of vitamin K
  27. Large volume transfusion: abnormal secondary hemostasis
    -dilutes coagulation factors
  28. Other Disorders of Hemostasis
    • 1. Heparin-Induced Thrombocytopenia (HIT)
    • 2. Disseminated Intravascular Coagulation (DIC)
    • 3. Disorders of Fibrinolysis
  29. Heparin Induced Thrombocytopenia
    • -platelet destruction secondary to heparin therapy
    • -heparin forms a complex with platelet factor 4 (PF4)
    • -Antibodies target heparin-PF4 complex

    -fragments of destroyed platelets may activate remaining platelets --> thrombosis

    *these patients are at high risk for coumadin skin necrosis
  30. Disseminated Intravascular Coagulation
    • Pathophysiology:
    • -widespread activation of clotting
    • -leads to a deficiency in clotting factors --> creates a bleeding state

    • -widespread microthrombi (ischemia and infarction)
    • -bleeding from IV sites and mucosal surfaces

    • Causes:
    • "STOP Making New Thrombi"
    • Sepsis (G-)
    • Trauma
    • Obstetric complications
    • Pancreatitis, acute
    • Malignancy
    • Nephrotic syndrome
    • Transfusion

    • Labs:
    • -schistocytes
    • -thrombocytopenia
    • -increased bleeding time
    • -increased PT
    • -increased PTT
    • -increased fibrin split products (D-dimers)
    • Treatment:
    • -tx underlying cause
    • -transfuse blood products and cryoprecipitate
  31. Fibrinolysis
    Normally removes thrombus after damaged vessel heals

    tPA converts plasminogen to plasmin

    • Plasmin
    • 1. cleaves fibrin and fibrinogen
    • 2. destroys coagulation factors
    • 3. blocks platelet aggregation
    • --> breaks down clot and prevents new clot formation

    a2-antiplasmin: inactivates plasmin
  32. Disorders of Fibrinolysis
    • Causes:
    • 1. Radical Prostatectomy
    • -release of urokinase activates plasmin
    • 2. Cirrhosis
    • -decreased production of a2-antiplasmin

    • Presentation:
    • -increased bleeding
    • **resembles DIC!!

    • Labs:
    • -increased PT
    • -increased PTT
    • -increased bleeding time
    • -normal platelet count
    • -no D-dimers!
  33. Thrombosis
    -lines of Zahn (alternating RBCs and fibrin/platelets)

    • Virchow's Triad
    • 1. Stasis
    • 2. Endothelial damage
    • 3. Hypercoagulable state
  34. Thrombosis: Stasis
    • -immobilization
    • -cardiac wall dysfunction (MI, arrhythmia)
    • -aneurysm
  35. Thrombosis: Endothelial cell damage
    • Endothelial cells are protective:
    • 1. block exposure to collagen and TF
    • 2. produce PGI2 and NO (vasodilation and inhibit platelet aggregation)
    • 3. heparin like molecules (activate ATIII)
    • 4. secrete tPA
    • 5. secrete TM

    • Causes:
    • -atherosclerosis
    • -vasculitis
    • -high levels of homocysteine (B12/Folate deficiency, CBS deficiency)
  36. Thrombosis: Hypercoagulable State
    • Classic Presentation:
    • -recurrent DVTs
    • -DVTs at young age

    • 1. Protein C or S deficiency
    • 2. Factor V Leiden
    • 3. Prothrombin 20210A
    • 3. ATIII deficiency
    • 4. OCPs
  37. Protein C and S Deficiency
    • -autosomal dominant
    • -Prot C and S normally inactivate FV and VIII

    • **increased risk of warfarin skin necrosis
    • -prot C and S (anticoagulation) have a shorter half life and are depleted first compared to II, VII, IX and X (procoagulation)
    • -this increases risk for thrombosis esp in skin in patients who already have a deficiency

    *why you bridge warfarin therapy with heparin
  38. Factor V Leiden
    -mutated FV that is resistant to degradation by Prot C

    -most common cause of hypercoagulable state in whites
  39. Prothrombin 20210A mutation
    -activating mutation that increases gene expression

    -results in increased thrombin

    -increased venous clots
  40. ATIII deficiency
    -inherited

    • -Normally heparin like molecules produced by endothelium normally inactivate ATIII
    • -ATIII inactivates thrombin and coagulation factors

    PTT does NOT rise with standard heparin dosing
  41. Oral Contraceptives
    • -hypercoagulable state
    • -estrogen induces production of coagulation factors
  42. Embolism
    -intravascular mass that travels and occludes downstream vessels

    1. Thromboembolism (>95%)

    2. Atherosclerotic embolus (XOL clefts)

    3. Fat embolus (bone fractures: --> pulmonary vessels, dyspnea, petechiae)

    4. Gas embolus (the bends, caisson disease, laparoscopic surgery)

    5. Amniotic fluid embolus (SOB, neuro sx, DIC, squamous cells)
  43. Pulmonary Embolism
    -usually thromboembolus from DVT

    -usually clinically silent: dual blood supply, small embolus

    Pulmonary infarction if large vessel is obstructed and the patient has pre-existing cardiopulmonary compromise (only 10%)

    • Presentation:
    • -SOB
    • -hemoptysis
    • -pleuritic chest pain
    • -pleural effusion

    • Labs:
    • -V/Q lung scan (abnormal perfusion)
    • -Spiral CT (lung filling defect)
    • -lower ext doppler ultrasound
    • -D-dimer elevated (DVT)

    • Complications:
    • -Sudden death with large saddle embolism (blocks L and R PAs)
    • -Pulmonary HTN with chronic emboli
  44. Systemic Embolism
    • -usually due to thromboembolus
    • -most commonly arise in L heart
    • -occlude flow to organs (usually lower extremities)

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