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Flashcards in Acquired Coagulopathies Deck (23):

What are the causes of acquired coagulopathy associated with bleeding?

  • Vitamin K deficiency
  • Liver disease
  • Disseminated intravascular coagulation (DIC)
  • Drug induced (e.g., anticoagulants)
  • Inhibitors of coagulation factors (acquired hemophilia)
  • Abnormal fibrinolysis
  • Amyloidosis: factor X binding
  • Essential thrombocytosis


What are the acquired coagulopathies associated with clotting?

  • Antiphospholipid syndrome: associated with Lupus anticoagulant and/or Anticardiolipin antibodies
  • Nephrotic syndrome (loss of antithrombin III)
  • Liver disease
  • Disseminated intravascular coagulation
  • Polycythemia
  • Essential thrombocytosis
  • Drug induced (heparin induced thrombocytopenia)


What are the sources of vitamin K and what role does it play in coagulation?

  • Vitamin K sources
    • Diet 1° source
      • Leafy green vegetables
      • Requirements: ~100-200 μg/day
      • Stores depleted in ~1 week in absence of adequate dietary intake
    • Intestinal bacteria: produce Vitamin K2
    • Fat soluble
  • Vitamin K in Coagulation
    • Cofactor in enzymatic reaction involving post-translational modification of Factors II, VII, IX, X, Protein C & S
    • Turns N-termini glutamic acid residues of these proteins into γ-carboxyglutamic acids (G1a)
    • This then allows binding to phospholipids/cell membranes (Ca++ dependent)


What are the sequellae of deficiencies in vitamin K?

  • Hemorrhagic disease of the newborn
    • 2° Vit K poor nutritional state in the mother during the 3rd trimester of pregnancy
    • This leads to lack of bacterial colonization of newborn GI tract, and with this low vitamin K production in the newborn
    • Breast feeding: provides only 15 μg/L Vit K
    • This usually develops between 2-7 days of life
      • Symptoms: skin, mucosal bleeding (circumcision), rarely internal (intracranial hemorrhage, retroperitoneal bleeding)
      • With labs, see prolonged PT & PTT
    • Treatment/prevention
      • Prophylaxis: 100 μg-1mg given to all in-hospital births for the past 40+ years
      • Treatment: Vit K 100 μg corrects (no repeat doses usually necessary)
  • Acquired vitamin K deficiency
    • Inadequate intake of Vit K is rare, and causes mild deficiency
      • Usually no clinical manifestations, since GI production intact
      • Colonic bacteria produce functional forms Vit K
      • Malnutrition plus antibiotics (latter causing destruction of GI flora) can cause a deficiencey
    • Malabsorption syndromes (like cystic fibrosis)
    • Antagonists (warfarin)
  • Treatment
    • Oral, subcutaneous, or IV Vitamin K
    • Plasma products: fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC)
      • This is a poor treatment usually, since it wears off quickly


What is the normal physiology of the liver in regards to its role in hemostasis and thrombosis?

  • Synthesis of all coagulation factors
  • Factor VIII:
    • Also synthesized in vascular endothelial cells, parenchymal cells in the kidney, spleen, lungs, brain
    • FVIII is unstable; it requires von Willebrand’s factor for circulation
  • Synthesis of inhibitors of coagulation factors
    • Antithrombin (AT), Protein C, Protein S
    • Tissue factor pathway inhibitor (TFPI)
    • Plasminogen
  • The liver clears activated hemostatic proteins & protein inhibitor complexes from circulation
  • Synthesizes thrombopoieten (TPO) to help with platelet production


What is the impact of liver disease on clotting factors?

  • Decrease synthesis clotting factors
  • Decrease absorption Vitamin K (due to ↓ bile salt production)
  • With acute liver failure, you have:
    • High circulating inflammatory proteins/cytokines causing ↑ tissue factor (TF), which in turn causes activation of FII, V, VII, & X
    • The thrombin generated should be inhibited by Antithrombin III (AT III)
      • Prevents activation of FVIII, XI
      • Preserves their levels
  • Von Willebrand Factor: see elevated levels in liver failure
  • Fibrinogen
    • With severe liver failure, there is ↓ fibrinogen synthesis, causing ↓ levels
    • Dysfibrinogenemia: different from simple decreased fibrinogen production
      • The liver produces normal levels, but it is a qualitatively abnormal protein with a ↓ ability to clot
      • It is 2° increased activity of sialyltransferase by immature hepatocytes
      • With labs, you see a prolonged Thrombin Time (TT)
      • Usually, there is almost normal PT/PTT
      • Normal fibrinogen level, but decreased activity (qualitative defect)


What is the impact of liver disease on anticoagulants and clotting factors?

  • Anticoagulants: see decreased levels of AT III, protein C & Protein S, as these are normally produced in the liver
  • Platelet abnormalities in liver disease
    • Quantitative platelet problems in liver disease
      • Hypersplenism causes platelet sequestration (covered in Thrombocytopenia lecture as well)
      • Myelosuppression: liver disease often can cause decreased bone marrow production for various reasons
      • Consumptive coagulopathy: disseminated intravascular coagulation (DIC) can be seen in liver disease
      • Immune-mediated mechanisms: patients with liver disease due to Hepatitis C are at higher risk for an autoimmune/ITP like process
      • Decreased production of thrombopoieten
    • Qualitative platelet problems in liver disease
      • Decreased platelet aggregation
      • Intrinsic platelet defects
      • Multiple plasma factors present in liver disease interfere with normal platelet function


What are some abnormalities of the fibrinolytic system in liver disease?

  • Decreased levels of:
    • Plasminogen
    • α2-plasmin inhibitor
    • histidine rich glycoprotein
    • Factor XIII
    • Thrombin activatable fibrinolytic inhibitor (TAFI)
  • There is heightened fibrinolysis in chronic liver disease
    • Tissue Plasminogen Activator (tPA) levels are increased (2° decreased clearance)
    • Plasminogen Activator Inhibitor (PAI-1, which is a tPA inhibitor) is often normal or only slightly increased
      • This imbalance of tPA and PAI-1 leads to heightened fibrinolysis as well
    • Reflected in labs: you see a high  D-Dimer, as well as Prothrombin fragments 1+2, Fibrin degradation products
      • these are all breakdown products of a thrombin clot, released with clot breakdown through fibrinolysis


What is the impact of acute liver disease or acute cholestatic liver disease on coagulation?

  • Can have normal coagulation, or a hypercoagulable state
  • Increased PAI-1 levels since it is an acute phase reactant
  • Hypofibrinolysis can be seen depending on the PAI-1 levels


What are the ways of assessing risk for bleeding and clotting?

  • Risk Assessment: Clotting
    • Should not view patients as being “autoanticoagulated” due to the hemostatic abnormalities in liver disease
    • The above is demonstrated by the fact that there are high rates of portal vein thrombosis & hepatic vein thrombosis
      • the latter known as Budd-chiari syndrome
    • With liver disease, even with labs that look like the patient should be at high risk for bleeding: low platelets, elevated PT/PTT
  • Risk Assessment: Bleeding
    • Link between hemostatic abnormalities and the bleeding risk is unclear
    • Worsening coagulation studies may indicate decreased liver function, but this does not necessarily mean an increased bleed risk


In liver disease, what are the changes in hemostasis that favors bleeding?

  • Decreased clotting factor synthesis
    • FII, V, VII, IX, X, & XI
  • Decreased fibrinolytic inhibitors: TAFI, α-2 plasmin inhibitor, histidine-rich glycoprotein
  • Qualitative and quantitative fibrinogen defects
  • Imbalanced increase in tissue plasminogen activator (tPA) relative to smaller increase in plasminogen activator inhibitor (PAI-1)
  • Thrombocytopenia
  • Abnormalities in platelet aggregation
  • Nitrous oxide (NO) and prostacyclin mediated platelet inhibition


In liver disease, what are the changes to hemostasis that favors thrombosis?

  • Increased levels of von Willebrands factor (vWF) & FVIII
  • Decreased plasminogen
  • Decreased anticoagulant levels: ATIII, Protein C, Prot S, α2 macroglobulin
  • Decreased heparin cofactor II (heparin cofactor II inhibits thrombin)


What are some general features of pathologic inhibitors of coagulation (acquired hemophilia)?

  • In this disorder, circulating macromolecules (most are antibodies) directly inhibit clotting proteins or reactions leading to clot formation
  • This can arise in patients with a hereditary bleeding disorder (Hemophilia A or B) following use of plasma products, but it can also arise de novo


What are the usual settings that acquired FVIII inhibitors are seen?

  • Alloantibody inhibitors in Hemophilia
  • Post partum (approximately 13% of cases of acquired FVIII inhibitor)
    • Usually after birth of 1st or 2nd child
    • Cause unknown
    • ~2-5 month delay in diagnosis
    • Variable course: most disappear by 12-18 months
  • Related to various immunologic disorders
  • Malignancies
  • No associated disorder is found in approximately 50% of cases (ie, “idiopathic”)


What are some important characteristics of acquired Factor VIII inhibitors (acquired hemophilia A)? What are the properties of the inhibitor?

  • Characteristics:
    • Rare disorder, more common in elderly (~60% of cases occur in age >60)
    • ♀ ≈ ♂
    • Spontaneous disappearance of the inhibitor occurs in approximately 38% of cases
  • Inhibitor properties
    • IgG Antibody (Ab), frequent mixture of heavy chain subclasses
    • Directed to specific epitopes on the clotting factor
    • Specific for FVIII activity (most do not interfere with von Willebrand’s factor)
    • Can be completely neutralized with excess FVIII if the amount/titer of the Ab is low enough
    • Low titers: may be time and/or temperature dependent
    • Usually interferes w/ FIX, FX, vWF, or phospholipid interactions with FVIII


What is the presentation and diagnosis of acquired factor VIII inhibitors?

  • Symptoms:
    • Spontaneous, massive bruising
    • Hematomas: large joints or muscles
    • Gastrointestinal or Genitourinary bleeding
  • Lab
    • Prolonged PTT, normal PT & TT
    • No correction with incubated mixing study
      • Incubate at 37 C for 1-2° (some Ab time & temperature dependent)
    • Quantitative measurement: Bethesda unit (BU)
      • 1 BU = amount of Ab that inhibits 50% of FVIII present in normal plasma sample after incubation with equal volume of the patient’s plasma for 2 hours at 37 C
      • Low titer inhibitors defined as being <5 BU


What are the steps taken to treat acute bleeds in acquired FVIII inhibitors?

  • Conservative measures (Immobilization, compression of sites of bleeding)
  • Anti-fibrinolytics (Consideration of ε aminocaproic acid)
  • DDAVP (Desmopressin): 0.3 mcg/kg trial can be used initially if very low level inhibitor is present (<3 BU)
  • Factor VIII products: dose & efficacy depend on level of inhibitor
    • More effective with lower level inhibitors (BU <5)
    • Need to give enough to neutralize inhibitor, as well as additional excess to give FVIII activity ≥ 30% (0.3 U/mL)
  • Activated prothrombin complex concentrates
    • Contain prothrombin, factors VIIa, IXa, and Xa
    • Risk of thrombosis (including MI)
  • Recombinant Factor VIIa: bypasses the inhibitor action
    • Acts with Tissue Factor (TF) to activate FX to active Xa form
    • Currently only FDA approved for inhibitors to coagulation proteins
  • Plasmapharesis: attempted if patient not responding to other treatments
    • Plasmapharesis circulates the patient’s blood through a large centrifuge, and the abnormal antibody/inhibitor is removed in the machine


What are the drugs to decrease inhibitor titer in acquired Factor VIII inhibitors?

  • Rituximab
  • Steroids
  • Cyclophosphamide
  • Azathioprine (usually reserved when above measures fail)
  • Intravenous immunoglobulin


What is the course and prognosis of acquired Factor VIII inhibitors?

  • High mortality rate: 22% in one series
  • Adverse factors for course/prognosis:
    • advanced age
    • concomitant malignancy
    • and poor therapy response
  • Favorable risk factors:
    • pregnancy
    • underlying autoimmune disease
  • Spontaneous remission common (~1/3; spontaneous remission is more common if the disease is pregnancy-associated)
  • Relapses: ~20% after first remission


What is role of phospholipids in normal coagulation? What is the nature of the antibodies that target these phospholipids in antiphospholipid syndrome?

  • Normal physiology: phospholipids participate in coagulation at several steps
    • Component of prothrombinase complex
    • Tenase complex: cofactor for factor VIIIa and factor IXa
    • Cofactor for activation of FX by FVIIa
  • Anti-phospholipid antibodies (Ab): heterogeneous family of autoAb directed against anionic phospholipids and plasma proteins
    • They include the lupus anticoagulant, anticardiolipin Ab, and beta 2 glycoprotein Ab
    • Originally felt to be anticoagulants due to their ability to prolong phospholipid dependent coagulation test in vitro (eg, presence of the lupus anticoagulant causes prolongation of the PTT test, seemingly indicating “thinner blood”)
      • In fact, these antibodies do just the opposite: they increase the risk for thrombosis
    • β2 glycoprotein 1 (B2GP1) believed to be major target
    • In vivo/clinically, these Ab are associated with thrombosis and recurrent fetal loss
    • Thrombosis can be either arterial or venous, or both
  • Ab be found in isolation or in association with autoimmune diseases


Describe the different types of antibodies found in antiphospholipid syndrome.

  • Transient Ab can be detected under certain conditions & are of unclear signifigance:
    • Viral/bacterial infections
    • Cancer
    • Medications: Procainamide, Quinidine, chlorpromazine
  • Anticardiolipin Ab
    • Can be IgG, IgM, or both
    • Low affinity monovalent Ab to β2GP1
    • Monovalent complexes bind weakly to anionic phospholipids
    • If antigen (Ag) density is high, this can lead to bivalent complexes to form, further resulting in high affinity for phospholipid surfaces
  • Lupus Anticoagulant (LAC)
    • Reacts in coagulation assay systems containing anionic phospholipids
    • β2-GPI and prothrombin bind phopholipids tightly
    • It is possible that Ab directed against these targets also interferes with phospholipid-dependent clotting reactions
    • These cause in vitro “anticoagulant” effect, as mentioned above
    • Tests to determine presence of the antiphospholipid Ab:
      • Dilute activated PTT
      • Kaolin clotting time
      • Dilute Russell’s viper venom time
      • Adding phospholipid markedly shortens the prolonged PTT


What is the diagnosis of antiphospholipid syndrome?

  • Requires presence of at least one clinical criteria and at least one laboratory criteria
  • Clinical criteria
    • Vascular thrombosis: one or more clinical episodes of arterial, venous, or small vessel thrombosis occurring in any tissue or organ
    • Complications of pregnancy
      • One or more unexplained death of morphologically normal fetus after the 10th gestational week OR
      • Three or more premature births of morphologically normal neonates at or before the 34th gestational week OR
      • Three or more unexplained consecutive spontaneous abortions prior to the 10th gestational week
  • Laboratory criteria
    • Anticardiolipin Ab: Presence of Anticardiolipin IgG or IgM at moderate-high levels on two or more occasions as measured by standard ELISA assay
    • Lupus anticoagulant: Presence of LAC Ab on two or more occasions ≥6 weeks apart
  • Catastrophic Antiphospholipid syndrome: thrombosis of multiple small blood vessels
    • Dysfunction in ≥3 organs
    • High antibody titers
    • Life threatening


What is the treatment of antiphospholipid syndrome?

  • Venous thrombosis: anticoagulation
  • Arterial thrombosis: antiplatelet agents
  • No history of thrombosis: low-dose aspirin may be helpful
  • Catastrophic antiphospholipid Ab syndrome can be treated with plasma exchange/plasmapharesis, using the same principles discussed in the pathologic inhibitors of coagulation