Bleeding Disorders

    .

    Source: MKSAP

    Coagulation Cascade

    • Primary Hemostasis
      • Symptoms: MUCOSAL BLEEDING
      • Injured blood vessel releases tissue factor, causes platelet to "activate" -->  secrete granular contents --> further hemostasis
      • GpIIBIIIA in plt surface undergoes conformational change --> binds fibrinogen, crosslinking platelets
      • Platelet surface --> makes phospholipid scaffold to facilitate secondary hemostasis.
    • Secondary Hemostasis
      • Symptoms: Hemarthrosis/Hematomas
      • Coagulation factors
      • Begins when Tissue Factor (TF) --> activates Factor VII
        • activated Factor VII --> common pathway to convert Factor X --> Xa 
        • Thrombin (II) generated, activating Factor XI --> also feeds in to common coag pathway (through factors IX and VIII cofactors)
        • Eventually crosslinked fibrin
      • Burst of thrombin --> generating insoluble fibrin meshwork

    CoagulationCascadeC.png

    (Image Source: Wikipedia)

    Approach to Bleeding Disorders

    • Types:
      • Congenital:
        • Hemophilia A: Factor VIII Deficiency
        • Hemophilia B: Factor IX Deficiency
        • von Willebrand's Disease (Types I, II, III)
      • Acquired:
        • Acquired Hemophilia A
        • DIC
        • Liver Disease Coagulopathy
        • Vitmain K Deficiency

    History/Physical

    • History
      • History of Bleeding:
        • Bleeding during infancy/childhood (umbilical stump, circumcision)
        • Bleeding during loss of teeth, trauma, surgeries.
        • Easy bruising (poor sensitivity/specificity)
        • Surgical Bleeding: ask about timing!
          • Immediate
          • Delayed
          • Need for transfusion
        • Gynecological
        • Secondary Hemostasis Disorders:  Bleeding into muscles and joints.
        • Primary Hemostasis (Platelet Dysfunction, thrombocytopenia)
          • Superficial bleeding: (Mucosal/Gums, menorrhagia)
      • Family History
      • Medications/ Herbals
    • Exam Findings:
      • Petechiae - Thrombocytopenia / Platelet Defect
      • Ecchymosis
      • Scurvy - Perifollicular Hemorrhage
      • HHS - Telangectasias (lips/fingertips) (hereditary hemophilic telangiectasias)
      • Amyloidosis - Enlarged tongue, carpal tunnel, periorbital purpura (acquired clotting protein deficiency, esp FX)
      • Ehlers-Danlos Syndrome - Joint hypermobility, skin elasticity (Bleed b/c cannot constrict arterioles)
      • Severe AS - Harsh systolic murmur (acquired Type II vWF disease)
      • Thrombocytopenia - Splenomegaly.
      • Liver Disease - coagulopathy

     

    Lab Tests

    • PT - Prothrombin Time
      • Prolonged PT:
        • MOST common: Acquired deficiency of factor VII (Vitamin K, Liver disease, DIC, warfarin)
    • aPTT - activated Partial Thromboplastin time
      • MOST common: Lupus inhibitor
      • Abnormalities in FVIII and IX
    • (Adds nothing to preoperative evaluation of pt with no hx of abnormal bleeding)
    • How they are done:
      • Lab tests performed on citrated plasma, tests thrombin generation on phospholipid surface.
        • Tubes MUST be adequately filled (otherwise too much or too little citrate that comes with the tube).
      • Careful to draw from heparin line
    • TT - Thrombin Time
      • Time for clot formation after thrombin added to citrated plasma. 
      • Indicated if PT or PTT prolonged or heparin contamination suspected.
      • Prolonged in any thrombin inhibitor (heparin, leparudin, argatroban). 
      • Abnormal fibrinogen or dysfibrinogenemia = prolonged TT.
    • Isolated 

      PT Elevation

      Isolated

      PTT Elevation

      PTT & PT Elevation

      -Vitamin K Deficiency

      -Liver Disease

      -Warfarin Therapy

      -Factor VII Deficiency/Inhibitor

      -Heparin

      -Factor Deficiency/Inhibitor:

          Factor VIII

          Factor IX

          Factor XI

          Factor XII

      -vWF Disease

      -Lupus Anticoagulant

      -High Dose Heparin/Warfarin

      -Dilutional Coagulopathy

      -DIC

      -Vitamin K Deficiency

      -Mod-To-Sev Liver Disease

      -Common Pathway Deficiency/Inhibitor

          Factor II

          Factor V

          Factor X

      -Paraproteinemia

      -A/Hypo/Dysfibrinogenemia

    • Mixing Studies
      • Used when evaluating PT or PTT prolongation (and less commonly TT)
      • Distinguishes clotting factor deficiency vs. inhibitor
      • Mix normal plasma with patient's:
        • Corrects = deficiency of clotting factor (even 50% of clotting factor is enough, 20-30% needed for normal PT/PTT
        • If NOT correct = inhibitor (antibody produced that inhibits clotting factor). Tx w/ immunosuppression.
      • Most common inhibitors: Factor VIII (acquired hemophilia), Lupus anticoagulant etc.. 
    • Bethesda Assay
      • Strength and titre of inhibitor directed against Factor VIII or IX
    • Factor Studies:
      • Factor VIII - Hemophilia A
      • Factor IX - Hemophilia B
      • Factor XI - Hemophilia C (Ashkenazi Jews, not associated with bleeding problems)
      • Factor V - "Para-hemophilia"
      • D-Dimer - fibrin breakdown products
        • Deciding if stopping anticoagulation in pts with DVT

    Congenital Hemophilias

     

    Hemophilia A & B

    • Hemophilia A: Factor VIII Deficiency (more common)
    • Hemophilia B: Factor IX Deficiency
    • NOTE: Hemophilia C (Factor XII deficiency) is not associated with bleeding problems.
    • X-linked recessive disorders (Practically indistinguishable)
      • Devited into: Mild, Moderate, Severe (depends on activity level of the factor)
        • Mild: >5% of factor activity
        • Severe: <1% of factor activity
    • Clinical Features:
      • Recurrent Hemarthrosis --> eventually chronic crippling degenerative joint disease.
        • MUST treat with factor replacement
      • CNS hemorrhage possible and fatal
      • Presentation based on type:
        • MILD: Presents in adulthood, post-traumatic or surgical bleeding.
    • Treatment:
      • Factor VIII or IX replacement with recombinant or plasma-derived.
        • Can be taught to administer by IV at home.
      • Desmopressin - helps treat mild hemophilia A
        • (release of vWF and Factor VIII from endothelium)
      • ASA and NSAID use --> CONTRAINDICATED

     

    Von Willebrands Disease (vWD)

    • Function of von Willebrand's Factor:
      • Tethers platelets
      • Protects Factor VIII from circulation
        • Therefore, many vWD patients have low Factor VIII levels enough to raise aPTT.
    • Von Willebrands Disease (vWD)  - 1% of population.
      • Type I - MILD - Normal multimers of vWF, but lower levels of all.
      • Type II - mutations in vWB factor. (absence of high molelcular weight vWF multimers).
      • Type III - SEVERE - Undetectable vWF levels. (Autosomal Recessive)
    • Autosomal Disorder
      • Named after Von Willebrand who described it in patients on Olive Islands off Sweden.
      • DIFFERENT from hemophilia (because seen in women & men)
    • Clinical Features:
      • Mucocutaneous bleeding (hemarthrosis rare)
      • Women: Menorrhagia, endometriosis, post-partum hemorrhage.
      • MILD vWD: may not be detected (Platelet function analyzer assay - PFA)
    • Workup:
      • Platelet Function Analyzer (measure clotting time)
        • May be normal in Type I MILD disease.
      • To diagnose:
        • vWF antigen level
          AND  
        • vWF activity
      • Caution: vWF levels fluctuate with stress, estrogen, exercise, bleeding etc..
        • May need repeated assays. (Type O can have lower levels)
    • Treatment:
      • Desmopressin causes release of vWF from endothelial cells.
        • use when they have symptoms of bleeding.
        • Once use DDAVP, all vWF released, so can't use continuously
      • vWF + Factor VIII concentrates (i.e.
        • If more severe bleeding or Type II and III vWD

     

     

    • Thromabasthenia (Glanzman's Syndrome) - plts > 400,000/cc with malfunction.

     

    Acquired Hemophilias

    Acquired Hemophilia A

    • Acquired antibody to Factor VIII
      • Often occurs in women (post-partum, but many idiopathic)
    • Clinical Features:
      • Bleeding with isolated PTT prolongation.
        • Can be severe and life-threatening
      • Bleeding is mucocutaneous & multifocal (hemarthrosis is rare) --> unlike Congenital Hemophilia!!!
    • Labs:
      • Isolated PTT prolongation
      • Factor VIII level are barely detectable
      • Mixing study: Uncorrectable PTT (inhibitor)
      • Lupus inhibitor is NEGATIVE.
      • Further Workup:
        • Measure titre of antibody in Bethesda Assay
    • Treatment
      • LOW Titre: Factor VIII high dose concentrates
      • HIGH Titre: Recombinant Factor VIIa or activated Prothrombin Complex Concentrates (aPCC)
        • (PCC: contain Factors II, VII, IX, X ---> all activate Factor X, secure hemostasis without VIII)
        • May require immunosuppression
      • NOTE: The only indication for Factor VIIa use is in treatment of inhibitors in Hemophilia patients.
        • Off-Label use of Factor VIIa ==> complications.

     

    Liver Disease Coagulopathy

    • Liver synthsizes all factors.
    • Liver Failure --> Hemorrhagic condition.
      • Coagulopathy of Liver Failure

              1.  High PT, PTT, and TT.

              2.  Hypofibrinogenemia

              3.  Dysfibrinogenemia

              4.  Thrombocytopenia due to: (can be refractory to transfusions)

        • Splenic sequestration
        • D-Dimers Poorly cleared --> Accelerate fibrinolysis --> Consume platelets
    • Clinical Features:
      • Present not anticoagulated with high INR.
      • Despite high INR, liver disease patients can be hypercoagulable (natural anticoagulants are deficient to)
    • Treatment:
      • INR correction with FFP almost impossible.  (short half-life of F VII of few hours).
        • Surgeons often ask for this, but very hard.
        • Can try with FFP, but also give Vitamin K to correct coagulopathy.

     

    Disseminated Intravascular Coagulation

     

    Vitamin K Deficiency

    • Acquired for active forms of Factors II, VII, IX, X (gamma-carboxyllation of these factors)
    • Vitamin K produced by GI flora, and present in green-leafy vegetables.
      • Deficiency common in:
        • Malnourished
        • Antibiotics
        • Fat Malabsorption (Vitmain K is fat soluble)
    • Treatment:
      • Vitamin K 5-10mg/day
      • Anticoagulation with warfarin is challenging, small amounts can cause very high INR
        • Partial repletion of Vitamin K is needed (removes labile quality to INR) - often 200-300mcg/day.

     

    Platelets

    Liver Failure Coagulopathy

    • Liver synthesizes all coagulation factors
    • Liver failure is a hemorrhagic condition
      • Elevates both PT and PTT
      • Nearly all clotting factors are usually low.
      • Thrombin time can be low too (not only from low fibrinogen, but low glycosylation of fibrinogen - causes functionally abnormal fibrinogen).
      • Splenomegaly in cirrhosis --> thrombocytopenia (platelet sequestration - can be refractory to transfused platelets).
      • D-Dimers (breakdown of fibrin) not cleared in liver disease --> can accelerate fibrinolysis and platelet consumption
        • D-Dimer can be anticoagulant and fibrinolytic.
    • Despite prolongued INR values, patients in liver disease can get VTE
      • Many of naturally occuring anticoagulants are also deficient.
      • Full correction of INR is difficult with FFP, almost impossible (short halflife of Factor VII - only few hours).
      • Surgeons often want correction of INR, which is hard.
    • Main Effects:
      • Coagulopathy
      • Hypofibrinogenemia
      • Dysfibrinogenemia (D-Dimer effect)
      • Thrombocytopenia.
    • Management:
      • FFP can be used to correct coagulopathy, but short half-life of Factor VII limits efficacy... 
        • If going to correct coagulopathy, should also also give Vitamin K

    Immune Thrombocytopenic Purpura

    • Autoimmune condition.
      • Autoantibodies directed towards platelet surface proteins --> platelet destruction.
      • ALSO: Have decreased platelet production. (NEW!! was ignored in the past, but now can treat).
    • ITP is common, more often in children.
      • Children: often self-limited in children from viral infections
      • Adults: seldom self-limited
    • Clinical findings:
      • Often very asymptomatic (don't always bleed)
    • Diagnosis:
      • Diagnosis of ITP

         

        • Diagnosis of exclusion

                   1. Otherwise normal CBC (or concominant bleeding anemia)

                   2. Absence of organ dysfunction

                   3. Normal peripheral blood smear

    • Various forms:
      • Drug-induced
      • Abnormal Immune Regulation (SLE, HIV, Lymphoproliferative malignancies like CLL)
    • Pathology:
      • Platelets may be large (suggesting recently released from bone marrow)
        • They have advanced hemostatic function (accounts for less severe bleeding seen)
    • Management:
      • Not all require therapy, monitor for further platelet declines or signs of bleeding.
      • 30,000-40,000 have less than 15% chance of further thrombocytopenia.. follow CBC qFew-Weeks.
      • If <30,000 or bleeding, sometimes need treatment
        • Sometimes need treatment.
        • 1st line: prednisone or methylprednisolone (1-2 mg/kg/day)
          • Some hematologists use higher dose dexamethasone for higher response rate. (never been compared).
          • Response in 75-80% of pts, but relapse is common.
        • 2nd line (if don't respond to steroids, continue to bleed)
          • IVIG (if actively bleeding or anti-D (pregnant women to prevent hemolytic disease of newborn)
          • IVIG or anti-D also indicated for rapid increase in platelets (i.e. going to OR)
          • Also used: rituximab (not studied but used, anti-CD20) and mycophenolate mofetil.
        • In the past, splenectomy done for ITP, but post-splenectomy complications common.  Now 2nd line b/c now have excellent drugs (rituximab), but 3/4 effective.
        • Also have agents for platelet production: (BOTH NEW!)
          • Stimulate thrombopoeitin receptor, induce platelet production.
            • Romiplostim (IV)
            • Eltrombopag (oral)
          • Both new agents approved for refractory ITP, work well.

     

     

    Thrombophilic Syndromes

    • Cannot be done on warfarin (Protein C and Protein S levels are low) or during acute VTE.
    • Screening:
      • Prothrombin 22:10 mutation
      • Activated Protein C resistance (including Factor V Leiden testing)
      • APLA
      • Lupus inhibitor
      • Antithrobin Level
      • Protein C
      • Protein S
    • Syndromes:
      • Factor V Leiden
      • Prothrombin gene mutation
      • Antithrombin III Deficiency
      • Protein C Deficiency
      • Protein S Deficiency
    • Antiphospholipid Syndrome
    • Order lupus anticoagulant, Anti-Cardiolipin Antibody, and Anti-B2-glycoprotein I Antibody
    • Not covered by OHIP: aPTT is a "poor-mans" test.
    • Lupus Anticoagulant (LAC)
      • IgG, IgM or both that interfers with phopholipid-depdent tests of in-vitro coagulation.  Misnomer because it increases thrombosis (not anticoagulates), and not usually associated with SLE. 
      • To diagnose: aPTT (common, insensitive, cannot be used in pregnancy), Kaolin clot time, dilute russel viper venom time (dRVVT) and plasma clot time (PCT).
    • Antiphopholipid Antibodies (APA)
      • Acquired IgG, IgA, or IgM that are targeted against a phospholipids in cell membranes.  These often cause placental thrombosis and infarction (unknown how). Prostacyclin normally vasodilates and inhibits platelet aggregation.  Removal causes vasoconstriction and platelet aggregation occur causing thrombosis. Also inhibits protein C. 
    • Cardiolipin (ACA)
      • phospholipid in inner mitochondrial membrane.  ACL (aka aCL, cardiolipin), IgG and IgM are important (IgA less important)  (Fun fact: VDRL uses beef cardiolipin, and pts with ACA cause false positives).

     

    Approach to Abnormal PT/PTT

     

    Patients with Bleeding

    Coagulation Test Result

    Inherited or Acquired

    Underlying Cause/Disorder

    Treatment

    ↑PT, normal aPTT

    Congenital

    Factor VII deficiency

    FFP, recombinant factor VIIa

     

    Acquired

    DIC

    Treat underlying cause, supportive transfusions (FFP, cryoprecipitate, platelets)

     

    Acquired

    Liver disease

    FFP

     

    Acquired

    Vitamin K deficiency

    Vitamin K

     

    Acquired

    Vitamin K antagonists

    Vitamin K, FFP, PCCs

     

    Acquired

    Certain paraproteins

    No specific treatment for hemostasis. Treatment for paraproteinemia as otherwise indicated

     

    Acquired

    Certain dysfibrinogenemias

    Cryoprecipitate

    Normal PT, ↑aPTT

    Congenital

    Hemophilia A (factor VIII deficiency)

    Factor VIII concentrates, desmopressin for mild cases

     

    Congenital

    Hemophilia B (factor IX deficiency)

    Factor IX concentrates

     

    Congenital

    Factor XI deficiency

    FFP

     

    Congenital

    vWD

    Desmopressin or vWF-containing factor VIII concentrates

     

    Acquired

    Acquired hemophilia

    Bypassing agents to treat bleeding

    Immunosuppressants to eradicate inhibitor

     

    Acquired

    Acquired vWD

     

    Acquired

    Heparin

    Protamine sulfate

     

    Acquired

    Direct thrombin inhibitors

    No antidote available

    ↑PT, ↑aPTT

    Congenital

    Factor V deficiency

    FFP

     

    Congenital

    Factor X, factor II deficiency

    PCCs

     

    Congenital

    Hypofibrinogenemia or afibrinogenemia

    Cryoprecipitate or fibrinogen concentrates

     

    Congenital

    Combined deficiency of factor V and factor VIII

    Factor VIII concentrates and FFP

     

    Congenital

    Combined deficiency of factors II, VII, IX, and X

    High-dose vitamin K, FFP, PCCs

     

    Acquired

    Fibrinolysis (tPA, urokinase, etc.)

    Cryoprecipitate

     

    Acquired

    Factor V inhibitors

    FFP, platelets, immunosuppression

     

    Acquired

    Lupus inhibitor-associated hypoprothrombinemia

    FFP, PCCs

     

    Acquired

    Factor X deficiency from amyloidosis

    PCCs, FFP

     

    Acquired

    Vitamin K deficiency

    Vitamin K

     

    Acquired

    Vitamin K antagonists

    Vitamin K, FFP, PCCs

     

    Acquired

    Heparin

    Protamine sulfate

     

    Acquired

    Direct thrombin inhibitors

    No antidote available

     

    Acquired

    DIC

    Treat underlying cause, supportive transfusions (FFP, cryoprecipitate, platelets)

     

    Acquired

    Liver disease

    Supportive transfusions (FFP, cryoprecipitate)

    Normal PT and aPTT

    Congenital

    vWD

    Desmopressin or vWF-containing factor VIII concentrates

     

    Congenital

    Factor XIII deficiency

    Cryoprecipitate

     

    Congenital

    Platelet deficiency or dysfunction

    Platelets

     

    Congenital

    Deficiencies of fibrinolytic inhibitors (PAI-1 or α2-antiplasmin)

    ε-Aminocaproic acid

     

    Congenital

    Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

    ε-Aminocaproic acid

     

    Congenital

    Ehlers-Danlos syndrome

     

    Acquired

    Low-molecular-weight heparin and fondaparinux

    No antidote. Protamine reverses ≤50% of enoxaparin activity at most

     

    Acquired

    Drugs and herbs causing platelet dysfunction

    Desmopressin, platelet transfusion

     

    Acquired

    Uremia

    Desmopressin, cryoprecipitate

     

    Acquired

    Scurvy

    Vitamin C

     

    Acquired

    Myeloproliferative disorders

     

    Acquired

    Factor XIII inhibitors

    Patients without Bleeding

    Coagulation Test Result

    Inherited or Acquired

    Disorder

    Treatment

    Normal PT, ↑aPTT

    Congenital

    Deficiency of contact factors (HMWK, PK, factor XII)

     

    Acquired

    Lupus inhibitor

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