TTP and HUS, are thrombotic microangiopathies (TMAs) caused by platelet-vWF aggregates and platelet-fibrin aggregates, respectively.
TMAs result in thrombocytopenia, MAHA, and organ ischemia.
TMAs has an association with DIC, HIV inf, malignant HTN, vasculitis, organ and stem cell transplant-related toxicity, adverse drug reactions, and, during pregnancy, pre-eclampsia/eclampsia and HELLP syndrome.
Epidemiology: Sporadic TTP has an incidence of ~11.3 case per 106 persons and occurs more frequently in African Americans. HUS usually outbreaks in children. However, adults may also present with both typical and atypical variants of HUS.
TTP:
Definition:
Thrombotic microangiopathy.
Rare but life-threatening condition caused by immune-mediated platelet aggregation with widespread microvascular thrombosis.
Systemic d/o resulting from decreased circulating levels of vWF-cleaving protease, leading to high levels of HMW multimers of vWF seen in sporadic TTP. Occurs most often due to autoantibodies removing the plasma vWF-cleaving protease. (ADAMTS13), leading to high levels of multimeric vWF that stick to platelets and produce occlusions the microcirculation and subsequently microangiopathy. Second hit events may involve endothelial dysfunction or injury.
Severe ADAMTS13 deficiency does not cause HUS and other TMA, with the exception of some cases associated with HIV and pregnancy.
Clinical features:
Pentad (seen only in 30%): FAT RN. Fever, microangiopathic hemolytic anemia, thrombocytopenia, renal failure, fluctuating neurological abnormalities. All five clinical features are required for the diagnosis.
Preceding h/o: postpartum, pregnancy, HIV, drug induced (cyclosporine, ticlopidine, quinine).
Rare autosomal recessive inherited deficiencies of vWF-cleaving proteases (ADAMTS13) with chronic relapsing TTP (Upshaw-Shulman syndrome).
Pts. have fever, depressed level of consciousness > coma > sz.
Not associated with other coagulation abnormalities, which distinguishes TTP from DIC.
DDx: DIC, malignant HTN, pre-eclampsia, HELLP synd, and vasculitis.
Lab: anemia, low haptglobin, elevated LDH, thrombocytopenia, normal coagulation studies, and renal insufficiency. Presence of schistocytes and thrombocytopenia on peripheral blood smears. The findings of anemia, elevated reticulocytes, low or undetectable haptoglobin, and elevated LDH support the presence of hemolysis.
CBC, electrolytes, BUN, Cr, Sr. haptoglobin, LDH, PTT, PT/INR, UA
Sporadic TTP has TMA findings, normal PT, and aPTT, mild to moderate azotemia, very low or undetectable ADAMTS13 enzyme activity, and sometimes an ADAMTS13 inhibitory antibody.
Tx:
Critical, emergent, needs hospitalization.
Plasma exchange of 1 - 1.5 plasma volumes daily x 7 days is the main stay of therapy. Use of plamapheresis equipment.
Normal plasma volume is 40 mL/kg in adult men and 36 mL/kg in adult women
Remission is high if done promptly.
If plasma exchange is not available, give FFP immediately to replace ADAMTS13.
Do not give platelet transfusion in the absence of severe bleeding, as it may aggravate the underlying thrombosis.
Glucocorticoids: methyprednisolone, 1 gm IV daily, or prednisone, 1 mg/kg PO daily.
RBC transfusion as needed.
Do not give platelet if there is no bleeding, as it may cause worsening of condition.
PRBCs transfusion as needed.
C/w plasma exchanges daily for at least 7 days after platelets, and LDH are normal range, resolution of neurological signs, and improvement clinically.
Schistocytes may be seen for several weeks into remission.
Renal failure may be slow.
Pts who do not respond initially to plasma exchanges usually receive a trial of plasma exchange with cryosupernatant (depleted vWF), before going on for FFP.
Relapse is common <1 mo after d/c plasma exchange
Start intermittent plasma exchanges.
Splenectomy may help in refractory cases.
Immunosuppression with cyclophosphamide, azathioprine, or vincristine and splenectomy may be beneficial in refractory or relapsing TTP.
Rituximab, an anti-CD20 monoclonal antibody, has proved effective in achieving durable remission.
HUS triad: ART. autoimmune hemolysis (MAHA), renal failure, thrombocytopenia.
Platelet-fibrin aggregate
Typical HUS has preceding GI infection (E. coli O157:H7 production of Shiga-like toxins).
Diarrhea, often bloody, and abdominal pain often proceed typical HUS.
Associated with more severe renal dysfunction that seen in TTP.
In typical HUS, E. coli O157 stool cx has higher sensitivity than does Shiga toxin assays. Stool samples obtained after diarrhea has resolved reduce the sensitivity of both tests.
Atypical HUS is associated with transplantation, endothelial damaging drugs, and pregnancy.
Familial HUS is due to inherited defects in regulation of the alternative pathway of complement activation.
For sporadic or familial HUS molecular analysis or complement regulator factor H and I genes through reference lab.
Tx of typical HUS remains supportive. Does not improve with plasma exchanges. ABx Tx does not hasten recovery or minimize toxicity of HUS associated with infection. Atypical HUS associated with calcineurin inhibitors (cyclosporine, tacrolimus) usually responds to drug dose reduction or discontinuation. Eculizumab 1200 mg IV q2 week (start at 900 mg IV qweek x 4 weeks, then 1200 mg IV qwk x 1 wk, then 1200 mg IV q2week), give meningococcal vaccine >2 week before treatment if unvaccinated.