Thrombotic Thrombocytopenic Purpura-Acquired (Acquired TTP)

Epidemiology

  • Incidence: 3 cases/1 million adults (Oklahoma TTP-HUS Registry Data) [MEDLINE]
  • Median Age at Time of Diagnosis: 41 y/o (range: 9-78 y/o)
    • Very Rare in Children: 30x less common than in adults
  • Risk Factors
    • Black Race: blacks (Oklahoma TTP-HUS Registry Data) [MEDLINE]: 36% of cases were black
    • Female Sex (Oklahoma TTP-HUS Registry Data) [MEDLINE]: 76% of cases were female

Physiology

Background-Von Willebrand Factor (vWF)

  • Von Willebrand Factor (vWF) is a Long Stringlike Molecule Synthesized by Vascular Endothelial Cells and Megakaryocytes
    • vWF is Synthesized as a Single VWF Precursor: cleavage and assembly into disulfide-linked multimers occurs in plasma
    • VWF Activity is Distributed Among a Series of Plasma Multimers: ranging in size from MW 400k-20 million
    • Modest Reduction in Plasma VWF Concentration OR Selective Loss of One of the High Molecular Weight Multimers Results in Decreased Platelet Adhesion and Clinical Bleeding
  • Locations of Von Willebrand Factor
    • VWF Circulates as a Series of Multimers Formed from a Basic Dimer Subunit
    • Ultralarge Von Willebrand Factor Multimers Attach to the Endothelial Surface
  • Von Willebrand Factor Binds to the Platelet GP1b Receptor
    • Platelet Shape Change (with Increased Platelet Surface Area)
    • Platelet Granule Release of Procoagulant Molecules (from Alpha Granules) and Cofactors (from Dense Granules)
    • Receptor Activation and Expression
  • Functions of Von Willebrand Factor in Primary Hemostasis
    • VWF Forms an Adhesive Bridge Between Platelets and Exposed Vascular Subendothelial Basement Membrane
    • VWF Forms an Adhesive Bridge Between Adjacent Platelets at Sites of Endothelial Injury
    • VWF is the Plasma Carrier Protein for Factor VIII While it is Inactive in the Circulation: factor VIII degrades rapidly when not bound to vWF

Background-ADAMTS13 (see ADAMTS13 Activity, [[ADAMTS13 Activity]])

  • ADAMTS13 (A Disintegrin And Metalloprotease with a Thrombospondin Type 1 Motif, Member 13) is a Von Willebrand Factor-Cleaving Plasma Protease
    • Cleavage by ADAMTS13 is a Normal Function Which Prevents Ultralarge Von Willebrand Factor Multimers from Accumulating, Especially in Areas of High Shear Stress (Such as Small Arterioles and Capillaries)
    • Shear Stress Results in a Conformational Change in Von Willebrand Factor Multimers, Exposing the ADAMTS13 Cleavage Site
    • Physiologic Sites of ADAMTS13 Synthesis
      • Hepatic Stellate Cells: primary site of synthesis
      • Endothelial Cells: lesser site of synthesis
      • Megakaryocytes: lesser site of synthesis

Acquired Thrombotic Thrombocytopenic Purpura is a Thrombotic Microangiopathy Caused by Decreased Activity of ADAMTS13 (Due to an Acquired Autoantibody Inhibitor of ADAMTS13) (see Thrombotic Microangiopathy, [[Thrombotic Microangiopathy]])

  • Decreased ADAMTS13 Levels (<10% Activity) Result in Ultralarge Von Willebrand Factor Multimer Accumulation on the Endothelial Surface, Where Platelets Then Subsequently Accumulate
    • Microangiopathic Hemolytic Anemia (MAHA): predominantly intravascular hemolysis
    • Small Vessel Platelet-Rich Thrombi
    • Thrombocytopenia
    • Organ Damage
  • Relationship of Disease to ADAMTS13 Activity
    • Severe Reduction in ADAMTS13 Activity is Required for Clinical Manifestations of TTP
      • Lesser decreases in ADAMTS13 may be observed in sepsis, liver disease, cardiac surgery, pancreatitis, and last two trimesters of pregnancy (lowest levels occur at 36-40 weeks of gestation and during early puerperium): these conditions are extremely unlikely to cause disease by themselves
    • However, Reduction in ADAMTS13 Activity Alone is Not Sufficient to Cause Disease: other factors such as acute inflammation or a prothrombotic stimulus may be required to trigger the onset of disease
      • In addition, plasmin may substitute for ADAMTS13 in cleaving ultralarge Von Willebrand factor multimers

Diagnosis

Complete Blood Count (CBC) (see Complete Blood Count, [[Complete Blood Count]])

  • Anemia (see Anemia, [[Anemia]])
  • Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])
    • May Be Severe: median platelet count 17k (Blood, 2010) [MEDLINE]

Serum Chemistry (see Serum Chemistry, [[Serum Chemistry]])

  • Indirect Hyperbilirubinemia

Prothrombin Time (PT)/International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT) (see Prothrombin Time, [[Prothrombin Time]] and Partial Thromboplastin Time, [[Partial Thromboplastin Time]])

  • Required to Exclude Disseminated Intravascular Coagulation (DIC)

Serum Lactate Dehydrogenase (LDH) (see Serum Lactate Dehydrogenase, [[Serum Lactate Dehydrogenase]])

  • Increased Lactate Dehydrogenase (LDH): usually extremely high, due to hemolysis and ischemic tissue damage [MEDLINE]

Serum Haptoglobin (see Serum Haptoglobin, [[Serum Haptoglobin]])

  • Decreased Serum Haptoglobin

Reticulocyte Count (see Reticulocyte Count, [[Reticulocyte Count]])

  • Technique
    • Reticulocytes are Newly-Released RBC’s: they are slightly larger than mature RBC’s and have some residual ribosomal RNA -> presence of RNA allows for staining, with detection and counting
    • Normal Reticulocyte Percentage: 1-2%
    • Reticulocyte Production Index (RPI) = Reticulocyte Percentage x (Patient’s Hct/Normal Hct) x (1/RMT): corrects reticulocyte percentage for the degree of anemia (normalized to Hct 45%) and reticulocyte maturation time (RMT)
      • Use Normal Hct = 45%
      • RMT
        • Hct 45% -> RMT = 1.0 days
        • Hct 15% -> RMT = 2.5 days
      • Reticulocyte Production Index > or = to 2.5%: indicates adequate bone marrow response to anemia [MEDLINE]
        • Acute/Subacute Hemorrhage: note that acute hemorrhage may not result in an increased RPI, due to the time that it takes to increase epo synthesis and increase bone marrow RBC production
        • Hemolytic Anemia
      • Reticulocyte Production Index <2.5%: indicates inadequate bone marrow response to anemia [MEDLINE]
        • Chronic Anemia
        • Hypoproliferative Anemia: such as iron deficiency, marrow hyporesponsiveness, aplasia, etc
        • Maturation Disorder: such as vitamin B2 deficiency, etc
  • Reticulocytosis: common

Direct Coombs Test (Direct Anti-Globulin Test) (see Direct Coombs Test, [[Direct Coombs Test]])

  • Negative: due to absence of immune hemolysis

Indirect Coombs Test (Indirect Anti-Globulin Test)

  • Negative: due to absence of immune hemolysis

Peripheral Blood Smear (see Peripheral Blood Smear, [[Peripheral Blood Smear]])

  • Findings
    • Polychromasia: due to reticulocytosis
    • Schistocytes/Helmet Cells/Triangular Cells: RBC fragments
      • Number is affected by the duration of disease and quality of peripheral blood smear
      • There is no threshold number of schistocytes below which TTP can be excluded
    • Microspherocytes: less commonly observed (larger numbers suggest a warm autoimmune hemolytic anemia)
    • Nucleated Red Blood Cells: less commonly observed (larger number suggest a myelophthisic process instead)

Urinalysis (see Urinalysis, [[Urinalysis]])

  • May Be Normal in Some Cases
  • Urine Dipstick
    • Mild Proteinuria (1-2 g/day)
    • Bilirubinuria: positive for bilirubin
    • Hemoglobinuria: positive for occult blood
  • Microscopy
    • Few Cells or Casts

Urine Hemosiderin (see Urine Hemosiderin)

  • Positive Urine Hemosiderin

ADAMTS13 Activity (see ADAMTS13 Activity)

  • Severely Decreased ADAMTS13 Activity (<10%): characteristic during an acute flare of the disease
    • However, if Disease is Suspected and ADAMTS13 Test Results are Not Available, Therapy Should Not be Delayed
    • Relationship of Disease to ADAMTS13 Activity
      • Severe Reduction in ADAMTS13 Activity is Required for Clinical Manifestations of TTP
      • However, Reduction in ADAMTS13 Activity Alone is Not Sufficient to Cause Disease: other factors such as acute inflammation or a prothrombotic stimulus may be required to trigger the onset of disease
    • Range of ADAMTS13 Levels in TTP in Harvard Thrombotic Microangiopathy Research Collaborative [MEDLINE]: bimodal distribution of ADAMTS13 activity was observed in suspected TTP cases
      • ADAMTS13 Activity <10%: found in 27% of cases -> this cohort was less likely to have an alternative explanation for MAHA and thrombocytopenia
      • ADAMTS13 Activity 56% (Range: 42-68%): found in 73% of cases -> this cohort was likely to have an alternative explanation for MAHA and thrombocytopenia
    • Decreased ADAMTS13 Activity Levels May Persist (Due to Presence of an Anti-ADAMTS13 Inhibitor Antibody) for Months-Years in Some Cases After Recovery: despite a lack of clinical symptoms
      • However, most cases demonstrate a recovery in ADAMTS13 activity levels with clinical recovery
  • Low ADAMTS13 Activity (10-50%): may be seen in hospitalized patients with sepsis/malignancies
    • In addition, activity levels of 10-20% may be seen in TTP patients who have received blood products (since blood products contain functional ADAMTS13)
  • Normal ADAMTS13 Activity (>50%): considered normal

Anti-ADAMTS13 Antibodies

  • May Be Detected: laboratories usually run this testing reflexively when ADAMTS13 activity levels are low

Tissue Biopsy

  • Pathologic Changes: small arteriolar/capillary platelet microthrombi with hyaline changes in/around the vessel walls
    • Changes are consistent with thrombotic microangiopathy -> there are no specific findings which TTP this from other thrombotic microangiopathies

Genetic Testing for ADAMTS13 Gene Mutations

  • May Be Used for Suspected Cases of Hereditary Thrombotic Thrombocytopenic Purpura (TTP) (see Thrombotic Thrombocytopenic Purpura-Hereditary, [[Thrombotic Thrombocytopenic Purpura-Hereditary]])
    • Testing Availability: through the Hereditary TTP (Upshaw-Schulman Syndrome) Registry (www.ttpregistry.net)

Clinical Differentiation of Hemolytic Syndromes


Clinical Differentiation of Intravascular Hemolysis Syndromes


Clinical Manifestations

General Comments

  • Course of Disease: may span days-weeks (but may continue for months in some cases)
  • Classic Pentad of Microangiopathic Hemolytic Anemia + Thrombocytopenia + Fever + Acute Kidney Injury + Neurologic Findings: rare (occurs in only 5% of cases)
  • Other Organ Involvement
    • Adrenal Involvement: may occur
    • Pulmonary Involvement: rare [MEDLINE]
      • Possibly due to presumptions that pulmonary microvasculature may be inherently resistant to the formation of platelet thrombi and pulmonary function can be maintained in spite of multiple microvascular thrombi
    • Thyroid Involvement: may occur

Cardiovascular Manifestations

Chest Pain with Elevated Serum Troponin (see Chest Pain, [[Chest Pain]] and Serum Troponin, [[Serum Troponin]])

  • Epidemiology: chest pain occurs in 22% of cases
    • However, Clinically-Significant Acute Myocardial Infarction/Arrhythmia is Rare

Other Less Common Cardiovascular Manifestations

  • Acute Myocardial Infarction (MI) (see xxxx, [[xxxx]])
  • Arrhythmias
  • Cardiogenic Shock (see xxxx, [[xxxx]])
  • Congestive Heart Failure (CHF) (see xxxx, [[xxxx]])
  • Sudden Cardiac Death

Dermatologic Manifestations

Petechiae (see Petechiae, [[Petechiae]])

  • Epidemiology: common

Purpura (see Purpura, [[Purpura]]): common

  • Epidemiology: common

Gastrointestinal Manifestations

General Comments

  • Prevalence of Gastrointestinal Involvement: occurs in 69% of Cases

Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]])

  • Epidemiology: may occur

Diarrhea (see Diarrhea, [[Diarrhea]])

  • Epidemiology: common
    • Note: the timing of diarrhea is crucial, as diarrhea that precedes the onset of symptoms by several days may instead be indicative of 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]])

Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]])

  • Clinical: liver is usually not palpable though

Nausea/Vomiting (see Nausea/Vomiting, [[Nausea/Vomiting]])

  • Epidemiology: common

Hematologic Manifestations

Microangiopathic Hemolytic Anemia (MAHA) (see Hemolytic Anemia, [[Hemolytic Anemia]])

  • Epidemiology: common
  • Physiology: due to (intravascular) mechanical shearing of red blood cells as they pass through platelet-rich microthrombi in the microvasculature
  • Diagnosis

Splenomegaly (see Splenomegaly, [[Splenomegaly]])

  • Clinical: spleen is not usually palpable though

Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]])

  • Epidemiology: common
  • Clinical: median platelet count 17k (Blood, 2010) [MEDLINE]
    • Hemorrhage: hemorrhage or purpura occur in 54% of cases (Blood, 2010) [MEDLINE]
    • Petechiae (see Petechiae, [[Petechiae]])
    • Purpura (see Purpura, [[Purpura]]): hemorrhage or purpura occur in 54% of cases (Blood, 2010) [MEDLINE]

Hemorrhage

  • Physiology: due to thrombocytopenia, tissue infarction, and vascular injury
  • Clinical: severe bleeding is rare
    • Petechiae (see Petechiae, [[Petechiae]]): common
    • Purpura (see Purpura, [[Purpura]]): common

Neurologic Manifestations

General Comments

  • Absence of Neurologic Findings: 34% of cases
  • Neurologic Findings Preceding Clinical Onset of MAHA + Thrombocytopenia: may occur in some cases

Major Neurologic Findings

  • General Comments: occur in 35% of cases (Blood, 2010) [MEDLINE]
  • Clinical
    • Coma (see Obtundation-Coma, [[Obtundation-Coma]])
    • Ischemic Cerebrovascular Accident (CVA) (see Ischemic Cerebrovascular Accident, [[Ischemic Cerebrovascular Accident]])
    • Seizures (see Seizures, [[Seizures]])
    • Transient Focal Neurologic Deficits: aphasia, hemiparesis, visual field deficits, etc

Minor Neurologic Findings

  • General Comments occur in 31% of cases (Blood, 2010) [MEDLINE]
  • Clinical
    • Confusion/Delirium (see Delirium, [[Delirium]])
    • Headache (see Headache, [[Headache]])
  • Weakness: occurs in 63% of cases (Blood, 2010) [MEDLINE]

Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome, [[Posterior Reversible Encephalopathy Syndrome]]) [MEDLINE]

Renal Manifestations

Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])

  • Epidemiology: anuria and acute kidney injury are rare in TTP
    • Mean Serum Creatinine was 1.1 mg/dL (Oklahoma TTP-HUS Registry Data) [MEDLINE]
  • Diagnosis
    • Normal or Mild Proteinuria (1-2 g/day)
    • Few Cells or Casts

Other Manifestations

  • Arthralgias (see Arthralgias, [[Arthralgias]])
  • Fever/Chills (see Fever, [[Fever]]): occurs in <33% of cases (Blood, 2010) [MEDLINE]

Treatment

Plasma Exchange (see Plasmapheresis, [[Plasmapheresis]])

  • Required Urgently
    • Although fresh frozen plasma (FFP) infusion may be used as a temporizing measure, it is not a substitute for plasma exchange since it does not remove the ADAMTS13 inhibitor autoantibody and the volume of plasma that can be infused is far less than with plasma exchange (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]]) [MEDLINE]

Glucocorticoids (see Corticosteroids, [[Corticosteroids]])

  • Used in Addition to Plasma Exchange
  • Prednisone or Methylprednisolone (Solumedrol) (see Prednisone, [[Prednisone]] or Methylprednisolone, [[Methylprednisolone]]))
    • Less Severe Disease with No Neurologic Abnormalities: prednisone 1 mg/kg/day PO
    • More Severe Disease: methylprednisolone 125 mg q6-12hrs IV

Rituximab (Rituxan) (see Rituximab, [[Rituximab]])

  • Indications
    • Refractory Disease

Investigational Therapies

  • Anti-VWF (Caplacizumab)
  • Recombinant ADAMTS13

References

  • Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991;325(6):393 [MEDLINE]
  • Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Ann Intern Med. 1995 Apr 15;122(8):569-72 [MEDLINE]
  • Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. J Clin Apher. 1998;13(1):16 [MEDLINE]
  • Thrombotic microangiopathy associated with reactivation of human herpesvirus-6 following high-dose chemotherapy with autologous bone marrow transplantation in young children. Bone Marrow Transplant 1999; 254: 919–923 [MEDLINE]
  • Hemolytic uremic syndrome in a child with leukemia and cytomegalovirus infection. Pediatr Nephrol 2000; 14: 1118–1120 [MEDLINE]
  • Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 2001; 98: 1765–1771 [MEDLINE]
  • A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int. 2006 Aug;70(3):423-31 [MEDLINE]
  • Current management of thrombotic thrombocytopenic purpura. Curr Opin Hematol. 2008 Sep;15(5):445-50 [MEDLINE]
  • Brain lesions are most often reversible in acute thrombotic thrombocytopenic purpura. Neurology. 2009;73(1):66 [MEDLINE]
  • How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood. 2010;116(20):4060 [MEDLINE]
  • Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features. Pediatr Blood Cancer. 2013 Oct;60(10):1676-82. Epub 2013 Jun 1 [MEDLINE]
  • Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015 Jan 22;125(4):616-8. doi: 10.1182/blood-2014-11-611335. Epub 2014 Nov 20 [MEDLINE]
  • Syndromes of thrombotic microangiopathy. N Engl J Med. 2014 Aug 14;371(7):654-66. doi: 10.1056/NEJMra1312353 [MEDLINE]
  • Pulmonary involvement in patients with thrombotic thrombocytopenic purpura. Eur J Haematol. 2014 Feb;92(2):156-63. Epub 2013 Nov 26 [MEDLINE]
  • Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative. Br J Haematol. 2015;171(5):836 [MEDLINE]