Background
TTP-like syndrome
Hereditary TTP (GA-VMTD) Acquired TTP (AA-VMTD) | TTP-like syndrome (EA-VMTD) | |
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Primary causes/events | Hereditary ADAMTS13 gene mutation Acquired ADAMTS13 antibody formation ↓ | Pathogen (e.g., viruses; bacteria; fungi; rickettsia; parasites) Polytrauma (e.g., chest/lung; bone; skull/brain injury) Pregnancy (e.g., preeclampsia; abruptio placenta; amniotic fluid embolism) Cancer (e.g., disseminated stomach/breast/lung cancer) Transplant (e.g., liver; kidney; bone marrow) Drug and toxin (e.g., cyclosporine; mitomycin C; Shiga toxin) ↓ |
Secondary event | Excessive circulating mULVWF ↓ | Complement activation (C5b-9) and endothelial injury → endotheliopathy ↓ |
Tertiary event | Microthrombogenesis → platelet-ULVWF complexes ↓ Microthrombi lodged in arteriolar and capillary lumens ↓ | Cytokine release → inflammation → SIRS Platelet activation and endothelial exocytosis of eULVWF ↓ Microthrombogenesis → platelet-ULVWF complex strings ↓ |
Final event | Microvascular microthrombosis ↓ DIT/VMTD ↓ TTP | Vascular microthrombosis ↓ DIT/VMTD ↓ TTP-like syndrome |
Hematologic features | ||
Platelet | Consumptive thrombocytopenia | Consumptive thrombocytopenia |
Red blood cell | MAHA | MAHA/aMAHA |
Clinical syndromes | ||
Inflammation | Uncommon | Very common |
Cytokine storm | Absent | Often present in sepsis and MODS |
SIRS | Absent | Often present in sepsis and MODS |
Encephalopathy | Very common | Common, especially in HUS |
ARDS | Probably absent | Common |
AFHF | Probably absent | Common, sometimes with hepatic coagulopathy |
ARF/HUS | Very common | Common |
“DIC” (see text) | Doesn’t occur | Identical to TTP-like syndrome |
Laboratory features | ||
ADAMTS13 activity | Markedly decreased (< 5% of normal) | Mild to moderately decreased (20–70% of normal) |
ADAMTS13 antibody | Positive in acquired TTP | Negative |
Haptoglobin | Markedly decreased | Markedly decreased |
Schistocytes | ++ to ++++ | None to +++ |
Therapeutic response to | ||
TPE | Very good response | Excellent and fast response if treated in early stage |
Platelet transfusion | Contraindicated | Contraindicated |
rADAMTS13 | Unknown; expected to be effective in GA-VMTD | Unknown; expected to be very effective |
TTP vs. TTP-like syndrome
Pathogenesis of TTP-like syndrome
Thrombocytopenia in critically ill patients (TCIP)
Role of complement activation on the endothelium
TTP-like syndrome in the critical illness
“Two-activation theory of the endothelium”
Microthrombogenesis in VMTD
Megakaryocytic ULVWF(mULVWF) and endothelial ULVWF(eULVWF)
mULVWF multimers | eULVWF multimers | |
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Synthesized in | Megakaryocytes | Endothelial cells |
Stored in | α granules of platelets | Weibel-Palade bodies of ECs |
Primary distribution at release | In circulation | On the membrane of ECs |
Availability | In microcirculation | At ECs following endothelial exocytosis |
Exposure to ADAMTS13 | As platelet-adherent form | As ECs-adherent form |
Interaction with platelets causing | Platelet aggregation and adhesion | Platelet-ULVWF strings |
Localization of platelet-ULVWF complexes | Arteriolar and capillary lumens lodged as microthrombi in situ | Endothelial membrane-anchored as microthrombi strings |
Example of leading its activity | ADAMTS13 autoantibody | Sepsis-induced endotheliopathy |
Endotheliopathic lesion | Microthrombotic microangiopathy | Microthrombotic angiopathy |
Hematologic manifestation | Thrombocytopenia and MAHA | Thrombocytopenia and MAHA/aMAHA |
Associated inflammation | None to minimal (?) | Mild to severe |
Associated clinical syndrome | TTP | TTP-like syndrome |
Dissimilarity between TTP and TTP-like syndrome
Reinterpretation of “DIC”
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No clearly defined clinical and pathological diagnostic criteria are available.
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Not a single test or set of the tests can confirm and establish the diagnosis.
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Unexplained bleeding disorders such as viral hemorrhagic fevers are often blamed to it without foundation.
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Establishing the diagnostic application has been very subjective among investigators.
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The scoring system for the diagnosis is imprecise, confusing and subjective.
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The pathogenesis (i.e., tissue factor [TF]-FVIIa activated coagulopathy) has never been proven.
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Not a single treatment has been clearly proven to be effective.
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No therapeutic benefit has occurred even after numerous clinical trials.
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It occurs in critical illnesses (e.g., sepsis) and APL, but with different phenotypes.
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Clinical features are VMTD (i.e., DIT).
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Pathologic features are arteriolar and capillary hyaline microthrombi.
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Hematologic features are thrombocytopenia and MAHA.
EA-DIT/VMTD and “DIC” of McKay | True DIC | |
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Example | TTP-like syndrome | APL |
Nature of the clots | “Microthrombi strings” made of platelet-ULVWF complexes | “Fibrin clots” made of fibrin meshes |
Mechanism of the genesis | Intravascular microthrombogenesis | Intravascular fibrinogenesis |
Inciting causes/events | Infection; surgery; pregnancy; transplant; cancer; drug; toxin, leading to edotheliopathy | APL, leading to TF expression |
Hematological manifestation | Microthrombotic disorder | Hemorrhagic disorder |
Pathogenesis | ||
Mechanism | Activation of microthrombotic pathway | Activation of TF-initiated coagulation cascade |
Site of activation | Intravascular membrane of ECs | In circulation |
Thrombopathic result | Intravascular hemostasis of ULVWF path | Consumption of fibrinogen, FV and FVIII |
Effect on the involved organ | Hypoxic organ dysfunction | Generalized bleeding tendency |
Coagulation tests | ||
Fibrinogen | Normal | Decreased |
PT; aPTT; TT | Normal | Prolonged |
FVIII activity | Normal or markedly increased | Markedly decreased |
Thrombocytopenia | Mild to moderately severe | Not consumed but decreased due to APL |
Associated clinical syndrome | MODS; cytokine storm; SIRS | Hemorrhagic syndrome |
Associate hematologic features | ||
Schistocytes | Often present | Absent |
MAHA/aMAHA | Almost always present | Does not occur |
Hepatic coagulopathy | Common | Does not occur |
Incidence in clinical practice | Very common | Extremely rare |
Management | ||
Platelet transfusion | Contraindicated | May be used if needed for APL |
Treatment | TPE; rADAMTS13 (expected to be very effective) | Treat underlying pathology (e.g., ATRA in APL) |
Pathologic coagulation (DVT) vs. microthrombogenesis (DIT)
“DIC” perplexity discussed
Acute “DIC” is due to DIT-associated hepatic coagulopathy
Differential diagnosis of true DIC and TTP-like syndrome
TTP & TTP-like syndrome (DIT) | TTP-like syndrome (DIT) associated with HC (e.g., sepsis) equal to acute “DIC” | DIC (e.g., APL) | PF (e.g., amyloidosis) | |
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Thrombocytopenia | Always present | Always present | Present due to APL, but not due to consumption (?) | Not present |
MAHA/aMAHA | Always present | Always present | Do not occur | Not present |
Fibrinogen | Normal | Decreased | Always decreased | Always decreased |
Factor VIII | Normal | Normal or increased | Markedly decreased | Decreased |
Factor V | Normal | Decreased | Decreased | Normal or decreased |
Factor X | Normal | Decreased | Usually normal | Normal (?) |
Factor VII | Normal | Markedly decreased | Normal | Normal |
Factor IX | Normal | Decreased | Normal | Normal |
FDP | Normal | ? | Positive | Strongly positive |
Prothrombin time | Normal | Prolonged | Prolonged | Prolonged |
Activated partial thromboplastin time | Normal | Prolonged | Prolonged | Prolonged |
Thrombin time | Normal | Prolonged | Prolonged | Prolonged |
Thrombosis form | Microthrombi | Microthrombi | Friable fibrin clots (meshes) | Absent |
Bleeding: Character Treatment | Petechiae; Usually no need of treatment | May cause serious bleeding; Controllable with FFP & rFVIIa | Common, serious bleeding; Abrogated with ATRA & chemotherapy | Slow & persistent bleeding; Treatable with AFA |
Hypoxic organ dysfunction (MODS) | Present | Present | Not present | Not present |
Platelet transfusion | Contraindicated | Contraindicated | May be used for APL | Not needed |
Hope for the future in the treatment
Conclusion
1. Thrombocytopenia and MAHA/aMAHA. | |
2. Underling critical illness due to such conditions as. | |
√ Pathogen (bacterial; viral; fungal; rickettsial; parasitic) | |
√ Polytrauma (chest and lung; bone; skull/brain) | |
√ Pregnancy (preeclampsia; abruptio placenta; amniotic fluid embolism) | |
√ Cancer (breast; stomach; lung) | |
√ Surgery (heart; bowel; uterus; bone) | |
√ Transplant (liver; kidney; bone marrow) | |
√ Disease (autoimmune vascular disease; malignant hypertension) | |
√ Drug (cyclosporin; mitomycin C) | |
√ Toxin (venom; ricin; Shiga toxin) | |
3. Negative antibody against ADAMTS13. | |
4. Mild to moderately decreased activity of ADAMTS13 (20–70% of normal). | |
5. One or more organ phenotype dysfunction syndromes such as. | |
√ Pancreatitis. | |
√ Myocardial infarction. | |
√ ARDS. | |
√ Acute fulminant hepatic failure. | |
√ Acute adrenal insufficiency. | |
√ Rhabdomyolysis. | |
√ Non-occlusive mesenteric ischemia. | |
√ Hepato-renal syndrome. | |
√ Hepatic-encephalopathy. | |
√ Cardio-pulmonary syndrome. | |
√ Tissue gangrene. | |
√ Peripheral digit ischemic syndrome. |