Thrombotic Microangiopathy

Etiology (NEJM, 2014) [MEDLINE]

Primary Thrombotic Microangiopathy

Hereditary Thrombotic Microangiopathy

  • Hereditary Thrombotic Thrombocytopenic Purpura (Hereditary TTP) (Upshaw–Schulman Syndrome) (see Thrombotic Thrombocytopenic Purpura-Hereditary, [[Thrombotic Thrombocytopenic Purpura-Hereditary]])
    • Epidemiology: typically presents in childhood (occasionally in adults)
    • Etiology: ADAMTS13 deficiency due to homozygous/compound ADAMTS13 mutations
    • Diagnosis: severely deficient ADAMTS13 (activity level <10%)
    • Clinical
      • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]]): uncommon
      • Ischemic Organ Injury
    • Initial Treatment: fresh frozen plasma (FFP) (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]])
  • Complement-Mediated Hemolytic-Uremic Syndrome (see Complement-Mediated Hemolytic-Uremic Syndrome, [[Complement-Mediated Hemolytic-Uremic Syndrome]])
    • Epidemiology: typically presents in childhood (occasionally in adults)
    • Etiology: mutations in CFH, CFI, CFB, C3, CD46, and other complement genes, resulting in uncontrolled activation of alternative complement pathway
    • Clinical: heterozygous mutations may be symptomatic
    • Initial Treatment: fresh frozen plasma (FFP) (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]]), plasma exchange, anti-complement agent
  • Metabolism-Mediated Hemolytic-Uremic Syndrome
    • Epidemiology: typically presents in child <1 y/o (one case report in young adult with acute kidney injury and hypertension)
    • Etiology: homozygous mutations in MMACHC (encoding methylmalonic aciduria and homocystinuria type C protein)
    • Clinical: xxx
    • Initial Treatment
      • Vitamin B12 (see Vitamin B12, [[Vitamin B12]])
      • Betaine
      • Folinic Acid
  • Coagulation-Mediated Hemolytic-Uremic Syndrome
    • Epidemiology: typically presents in child <1 y/o (with DGKE mutations)
    • Etiology: homozygous mutations in diacylglycerol kinase ε (DGKE) (mutations in plasminogen and thrombomodulin have also been implicated)
    • Clinical
    • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
    • Initial Treatment: fresh frozen plasma (FFP) (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]])

Acquired Thrombotic Microangiopathy

  • Acquired Thrombotic Thrombocytopenic Purpura (Acquired TTP) (see Thrombotic Thrombocytopenic Purpura-Acquired, [[Thrombotic Thrombocytopenic Purpura-Acquired]])
    • Epidemiology: initial presentation usually in adults
    • Etiology: autoantibody inhibition of ADAMTS13 activity
    • Diagnosis: detectable (Autoantibody) ADAMTS13 Inhibitor
    • Clinical
      • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]]): uncommon
      • Ischemic Organ Injury
    • Initial Treatment: plasma exchange, immunosuppression
  • Shiga Toxin-Producing Escherichia Coli Hemolytic-Uremic Syndrome (see Shiga Toxin-Producing Escherichia Coli Hemolytic-Uremic Syndrome, [[Shiga Toxin-Producing Escherichia Coli Hemolytic-Uremic Syndrome]])
    • Epidemiology: initial presentation more common in young children
      • Most cases are sporadic (although large outbreaks may occur)
    • Etiology: enteric infection with a Shiga toxin–secreting strain of Escherichia Coli or Shigella Dysenteriae
    • Clinical
    • Initial Treatment: supportive care only
  • Drug-Induced Thrombotic Microangiopathy (see Drug-Induced Thrombotic Microangiopathy, [[Drug-Induced Thrombotic Microangiopathy]])
    • Immune Reaction Type: due to drug-dependent antibodies
      • Associated Drugs
        • Quinine (see Quinine, [[Quinine]])
      • Clinical: sudden onset of severe systemic symptoms with with anuric acute kidney injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
      • Initial Treatment: withdraw drug with supportive care
    • Toxic Dose-Related Reaction Type: multiple potential mechanisms
      • Associated Drugs
        • Bevacizumab (Avastin) (see Bevacizumab, [[Bevacizumab]]): VEGF inhibitor
      • Clinical: gradual onset of acute kidney injury (AKI) over weeks-months (see Acute Kidney Injury, [[Acute Kidney Injury]])
      • Initial Treatment: withdraw drug with supportive care
  • Complement-Mediated Hemolytic-Uremic Syndrome (see Complement-Mediated Hemolytic-Uremic Syndrome, [[Complement-Mediated Hemolytic-Uremic Syndrome]])
    • Epidemiology: initial presentation in children and adults
    • Etiology: antibody inhibition of complement factor H activity
    • Clinical
    • Initial Treatment: plasma exchange, immunosuppression, anti-complement agent

Systemic Disorders Associated with Microangiopathic Hemolytic Anemia (MAHA) and Thrombocytopenia (see Hemolytic Anemia, [[Hemolytic Anemia]] and Thrombocytopenia, [[Thrombocytopenia]])

Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation, [[Disseminated Intravascular Coagulation]])

  • Clinical: less severe than TTP usually
    • Hemolytic Anemia: variable
    • Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])

Infection

Malignant Hypertension (see Hypertension, [[Hypertension]])

  • Physiology: abnormal vessel wall -> damage to RBC
  • Clinical

Metastatic Carcinoma

  • Associated Malignancies
    • Multiple Pulmonary Metastases from Adenocarcinoma
    • Multiple Pulmonary Metastases from Lymphoma (see Lymphoma, [[Lymphoma]])
  • Physiology: due to activation of multifocal clotting -> hemolysis and thrombocytopenia

Pregnancy-Related Disorders

  • HELLP (Hemolysis, Elevated Liver Enzymes, and Low Platelets) Syndrome (see HELLP Syndrome, [[HELLP Syndrome]])
  • Severe Pre-Eclampsia/Eclampsia (see Pre-Eclampsia, Eclampsia, [[Pre-Eclampsia, Eclampsia]])

Rheumatologic Disease

  • Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome, [[Anti-Phospholipid Antibody Syndrome]])
    • Clinical: thrombocytopenia
  • Scleroderma (see Scleroderma, [[Scleroderma]])
    • Clinical: mild thrombocytopenia
  • Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus, [[Systemic Lupus Erythematosus]])
    • Physiology: severe vasculitis -> fibrin deposition in vessels with damage to platelets and RBC
    • Clinical: thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])

Transplant-Related Disease

  • Bone Marrow Transplant/Stem Cell Transplant (see Bone Marrow Transplant, [[Bone Marrow Transplant]])
  • Renal Allograft Rejection (see Renal Allograft Rejection, [[Renal Allograft Rejection]])
    • Physiology: abnormal vessel wall -> damage to RBC
    • Clinical: mild thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])

Other

  • Adult-Onset Still’s Disease (see Adult-Onset Still’s Disease, [[Adult-Onset Stills Disease]])
  • Giant Hemangioma (Kasabach-Merritt Syndrome) (see Kasabach-Merritt Syndrome, [[Kasabach-Merritt Syndrome]])
    • Physiology: abnormal vessel wall -> damage to RBC
    • Clinical: mild thrombocytopenia
  • Severe Vitamin B12 Deficiency (see Vitamin B12, [[Vitamin B12]])
  • Vasculitis (see Vasculitis, [[Vasculitis]])

Physiology

  • xxxx

Pathologic Features

  • Arteriolar and Capillary Thrombosis with Characteristic Endothelial and Vessel Wall Abnormalities

Clinical Manifestations of Thrombotic Microangiopathies

  • Microangiopathic Hemolytic Anemia (MAHA) (see Hemolytic Anemia, [[Hemolytic Anemia]])
  • Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])
  • Organ Injury

References

  • Syndromes of thrombotic microangiopathy. N Engl J Med. 2014 Aug 14;371(7):654-66. doi: 10.1056/NEJMra1312353 [MEDLINE]