HUS | Anatomy2Medicine

HUS

    • Thrombotic Microangiopathies
    • Include

 

  • Thrombotic Thrombocytopenic Purpura (TTP)
  • Hemolytic-Uremic Syndrome (HUS)

 

    • TTP was defined as the pentad of (MCQ)

 

  • Fever
  • Thrombocytopenia
  • microangiopathic hemolytic anemia
  • transient neurologic deficits

 

      • renal failure.
    • HUS is also associated with microangiopathic hemolytic anemia and thrombocytopenia but is distinguished by the (MCQ)
      • absence of neurologic symptoms
      • prominence of acute renal failure
      • frequent occurrence in children.
    • HUS and TTP are both caused by insults that lead to the excessive activation of platelets, which deposit as thrombi in microcirculatory beds. (MCQ)
    • These intravascular thrombi cause a microangiopathic hemolytic anemia and widespread organ dysfunction(MCQ)
    • the attendant consumption of platelets leads to thrombocytopenia

 

  • TTP (MCQ)

 

      • usually associated with a deficiency in a plasma enzyme called ADAMTS13

 

  • ADAMTS13 (MCQ)

 

        • designated as “vWF metalloprotease.”
        • deficiency of ADAMTS13 can be inherited or acquired.
        • normally degrades very high-molecular-weight multimers of von Willebrand factor (vWF)
        • In its absence, these multimers accumulate in plasma and tend to promote platelet activation and aggregation.
      • Superimposition of endothelial cell injury (caused by some other condition) may further promote the formation of platelet microaggregates, thus initiating or exacerbating clinically evident TTP(MCQ)
      • Plasma exchange
        • removes autoantibodies
        • provides functional ADAMTS13,

 

  • TTP

 

      • treated successfully in more than 80% of patients.
  • HUS 
        • In contrast, HUS is associated with normal levels of ADAMTS13
        • Epidemic, “typical” HUS (MCQ)
          • strongly associated with infectious gastroenteritis caused by Escherichia coli strain O157:H7, which elaborates a Shiga-like toxin(MCQ)
          • This toxin is absorbed from the inflamed gastrointestinal mucosa into the circulation
          • it alters endothelial cell function in some manner that results in platelet activation and aggregation. (MCQ)
          • Children and the elderly are at highest risk.
          • Those affected present with bloody diarrhea, and a few days later HUS makes its appearance.
          • With appropriate supportive care complete recovery is possible
          • irreversible renal damage and death can occur in more severe cases. (MCQ)
        • Nonepidemic, “atypical” HUS (MCQ)

     

  • often associated with defects in three proteins that normally act to prevent excessive activation of the alternative complement pathway
  • complement factor H
  • membrane cofactor protein (CD46)
            • factor I,
          • Deficiencies of these proteins can be caused by inherited defects or acquired inhibitory autoantibodies

     

  • It is associated with a remitting, relapsing course
  • DIC  vs thrombotic microangiopathies(MCQ)
          • In TTP and HUS (unlike in DIC), activation of the coagulation cascade is not of primary importance

     

  • hence laboratory tests of coagulation, such as the PT and PTT, are usually normal.
  • Thrombotic Microangiopathies: Causes and Associations
  • Thrombotic thrombocytopenic purpura
  • Deficiency of ADAMTS13
            • Inherited
            • Acquired (autoantibodies)

     

  • Hemolytic uremic syndrome
  • Epidemic:
            • Escherichia coli strain O157 : H7 infection(MCQ)
            • Endothelial damage by Shiga-like toxin(MCQ)

     

  • Nonepidemic:
            • alternative complement pathway inhibitor deficiencies (complement factor H, membrane cofactor protein (CD46), or factor I)

     

  • Inherited
  • Acquired (autoantibodies)
  • Miscellaneous associations
            • Drugs
              • Cyclosporine(MCQ)
              • chemotherapeutic agents
              • Radiation
              • bone marrow transplantation
            • Other infections

     

  • HIV(MCQ)
  • pneumococcal sepsis(MCQ)
          • Conditions associated with autoimmunity

     

  • systemic lupus erythematosus
  • HIV infection
  • lymphoid neoplasms

  • Topic – Hypercoaguable states

      • Coagulation Cascade

     

  • Thrombin
        • converts the soluble plasma protein fibrinogen into fibrin monomers that polymerize into an insoluble gel. (MCQ)
        • The fibrin gel encases platelets and other circulating cells in the definitive secondary hemostatic plug

     

  • fibrin polymers are covalently cross-linked and stabilized by factor XIIIa (which itself is activated by thrombin). (MCQ)
        • Coagulation factors are typically assembled on a phospholipid surface and held together by calcium ions
      • vitamin K dependent coagulation factors
        • the binding of coagulation factors II, VII, IX, and X to calcium depends on the addition of γ-carboxyl groups to certain glutamic acid residues on these proteins. (MCQ)
        • This reaction uses vitamin K as a cofactor

     

  • antagonized by drugs such as Coumadin
  • PT assay
        • assesses the function of the proteins in the extrinsic pathway (factors VII, X, II, V, and fibrinogen). (MCQ)
      • Partial thromboplastin time (PTT)
        • screens for the function of the proteins in the intrinsic pathway (factors XII, XI, IX, VIII, X, V, II, and fibrinogen). I(MCQ)
        • in this assay, clotting is initiated through the addition of negative charged particles (e.g., ground glass), which activates factor XII (Hageman factor), phospholipids, and calcium, and the time to fibrin clot formation is recorded.

     

  • Antithrombin III
        • inhibit the activity of thrombin and other serine proteases, including factors IXa, Xa, XIa, and XIIa. (MCQ)
        • activated by binding to heparin-like molecules on endothelial cells
        • Proteins C and S (MCQ)

     

  • vitamin K–dependent proteins
        • act in a complex that proteolytically inactivates factors Va and VIIIa. (MCQ)
        • Protein C activation  is done by thrombomodulin (MCQ)
      • TFPI (MCQ)
        • protein produced by endothelium (and other cell types)
        • inactivates tissue factor–factor VIIa complexes

     

  • Fibrinolytic
        • largely accomplished through the enzymatic activity of plasmin
        • breaks down fibrin and interferes with its polymerization
        • fibrin split products (FSPs or fibrin degradation products) can also act as weak anticoagulants
        • Elevated levels of FSPs (most notably fibrin-derived D-dimers) can be used in diagnosing abnormal thrombotic states including disseminated intravascular coagulation (DIC), deep venous thrombosis, or pulmonary embolism

     

  • Plasmin
          • generated by enzymatic catabolism of the inactive circulating precursor plasminogen, either by a (MCQ)

     

  • factor XII–dependent pathway
            • plasminogen activators (PAs).
        • t-PA
          • most important plasminogen activators

     

  • synthesized principally by endothelium (MCQ)
          • most active when bound to fibrin.
          • The affinity for fibrin makes t-PA a useful therapeutic agent, since it largely confines fibrinolytic activity to sites of recent thrombosis. (MCQ)
        • Urokinase-like PA (u-PA)
          • another PA present in plasma and in various tissues
          • can activate plasmin in the fluid phase(MCQ)
        • streptokinase,
          • PA
          • bacterial enzyme

     

  • free plasmin is rapidly inactivated by α2-plasmin inhibitor
      • Thrombosis
        • Three primary abnormalities that lead to thrombus formation (called Virchow’s triad): (MCQ)
          • endothelial injury
          • stasis or turbulent blood flow
          • hypercoagulability of the blood

     

  • Hypercoagulability.
          • Of the inherited causes of hypercoagulability, point mutations in the factor V gene and prothrombin gene are the most common (MCQ)
          • factor V Leiden mutation
            • single-nucleotide mutation
            • results in a glutamine to arginine substitution at position 506 (MCQ)
            • factor V resistant to cleavage by protein C.
            • heterozygotes have a five-fold increased relative risk of venous thrombosis, homozygotes have a 50-fold increase

     

  • Elevated levels of homocysteine
            • contribute to arterial and venous thrombosis
            • contribute to the development of atherosclerosis

     

  • prothrombotic effects of homocysteine may be due to thioester linkages formed between homocysteine metabolites and a variety of proteins, including fibrinogen. (MCQ)
            • Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione β synthetase. (MCQ)
              • a variant form of the enzyme 5,10-methylenetetrahydrofolate reductase causes mild homocysteinemia
              • common in Asian population(MCQ)
              • as common as factor V Leiden
              • folic acid, pyridoxine, and/or vitamin B12 supplements can reduce plasma homocysteine concentrations (by stimulating its metabolism), they fail to lower the risk of thrombosis(MCQ)
          • inherited causes of hypercoagulability must be considered in patients under the age of 50 who present with thrombosis—even when acquired risk factors are present.

     

  • Heparin-induced thrombocytopenia (HIT) syndrome.
          • occurs following the administration of unfractionated heparin(MCQ)

     

  • induce the appearance of antibodies that recognize
            • complexes of heparin and platelet factor 4 on the surface of platelets
            • complexes of heparin-like molecules and platelet factor 4-like proteins on endothelial cells.
          • Binding of these antibodies to platelets results in their activation, aggregation, and consumption (hence the thrombocytopenia in the syndrome name).

     

  • This effect on platelets and endothelial damage combine to produce a prothrombotic state, even in the face of heparin administration and low platelet counts. (MCQ)
  • Antiphospholipid antibody syndrome
  • manifestations(MCQ)
  • recurrent thrombosis
  • repeated miscarriages
  • cardiac valve vegetations
  • thrombocytopenia.
        • clinical presentations can include (MCQ)
          • pulmonary embolism (following lower extremity venous thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary emboli),

     

  • stroke, bowel infarction
          • renovascular hypertension.
          • renal microangiopathy
            • renal failure associated with multiple capillary and arterial thromboses
        • autoantibodies interfere with phospholipids and thus inhibit coagulation prolonging APTT
        • frequently give a false-positive serologic test for syphilis because the antigen in the standard assay is embedded in cardiolipin.
        • Antiphospholipid antibody syndrome has
        • Primary form
            • only the manifestations of a hypercoagulable state
            • lack evidence of other autoimmune disorders
        • Secondary form(MCQ)
            • seen in systemic lupus erythematosus
        • catastrophic antiphospholipid syndrome
        • characterized by widespread small-vessel thrombi and multi-organ failure h

     

  • has a 50% mortality
  • Antemortem clots
          • Lines of Zahn(MCQ)
            • Thrombi often have grossly and microscopically apparent laminations called lines of Zahn
            • represent pale platelet and fibrin deposits alternating with darker red cell–rich layers.
            • Such laminations signify that a thrombus has formed in flowing blood
            • their presence can therefore distinguish antemortem thrombosis from the bland nonlaminated clots that occur postmortem (MCQ)

     

  • Postmortem clots
        • gelatinous with a
          • dark red dependent portion where red cells have settled by gravity
          • a yellow “chicken fat” upper portion(MCQ)
        • usually not attached to the underlying wall.
    • Hypercoagulable States
      • PRIMARY (GENETIC)
        • Common
          • Factor V mutation (G1691A mutation; factor V Leiden)
          • Prothrombin mutation (G20210A variant)
          • 5,10-Methylenetetrahydrofolate reductase (homozygous C677T mutation)
          • Increased levels of factors VIII, IX, XI, or fibrinogen
        • Rare
          • Antithrombin III deficiency
          • Protein C deficiency
          • Protein S deficiency
        • Very Rare
          • Fibrinolysis defects
          • Homozygous homocystinuria (deficiency of cystathione β-synthetase)
      • SECONDARY (ACQUIRED)
      • High Risk for Thrombosis
        • Prolonged bedrest or immobilization
        • Myocardial infarction
        • Atrial fibrillation
        • Tissue injury (surgery, fracture, burn)
        • Cancer
        • Prosthetic cardiac valves
        • Disseminated intravascular coagulation
        • Heparin-induced thrombocytopenia
        • Antiphospholipid antibody syndrome
      • Lower Risk for Thrombosis
        • Cardiomyopathy
        • Nephrotic syndrome
        • Hyperestrogenic states (pregnancy and postpartum)
        • Oral contraceptive use
        • Sickle cell anemia
        • Smoking