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TTP (Thrombotic thrombocytopenic purpura)      REF:  TTP 2008.pdf

The thrombotic microangiopathies are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes.
In thrombotic thrombocytopenic purpura (TTP), systemic microvascular aggregation of platelets causes ischemia in the brain and other organs.
In the hemolytic–uremic syndrome, platelet–fibrin thrombi occlude predominantly the renal circulation.
Thrombotic microangiopathies are characterized by

• Thrombocytopenia (with increased numbers of marrow megakaryocytes),
• Fragmented erythrocytes (schistocytes, or helmet cells)
  - probably produced as blood flows through turbulent areas of the microcirculation that are partially occluded by platelet aggregates.
  This process causes microangiopathic hemolytic anemia., and
• extremely elevated serum levels of lactate dehydrogenase.

TTP is characterized by:

1. Severe hemolytic anemia with microangiopathic hemolysis smear (schistocytes, helmet cells)
2. Moderate to severe thromobocytopenia with increased marrow megakaryocytes
3. Fever, occasionally quite high
4. Prominent CNS Sx with transient agitation, headache, disorientation, then progress explosively to hemiparesis, aphasia, seizures, focal deficits, coma, & death
5. Renal disease, which is usually mild with moderate > creatinine & urine protein.
6. Less commonly, hepatic failure, ischemic infarcts of skin, bowel, bone, heart failure & arrhythmia
7. - usually appears between 10-40 yrs of age, peak at age 25, very rarely in >50 yrs.

Diagnosis is suggested by:

• Microangiopathic hemolysis, thrombocytopenia, above symptoms & signs, negative direct Coombs' test, & significant neutrophilic leukocytosis.
• Coagulation tests are usually normal.

Therapy (as suggested by Dr. Stanley Schrier of Stanford:)

• a simple fresh frozen plasma infusion 10-12 units or 2500-3000 ml over 24 hrs, then 3 units daily,
  if the thrombocytopenia is moderate & the pt has no neurologic impairment,
• intense plasmapheresis should be inititated, if the pt has CNS Sx
• Prednisone 60 mg/d in divided doses, , dipyridamole 100 mg q6h, aspirin 300 mg bid (? risk for bleeding complication in severe thrombocytopenic pts)

Therapy for Thrombotic Thrombocytopenic Purpura    NEJM August 22, 2002 - Joel L. Moake

Infants or young children with familial thrombotic thrombocytopenic purpura
produce a functionally defective ADAMTS.  Their episodes of thrombotic thrombocytopenic purpura are reversed or prevented by the infusion of platelet-poor fresh-frozen plasma, cryoprecipitate-poor plasma (cryosupernatant), or plasma that has been treated with a mixture of an organic solvent and detergent  (all contain the active metalloprotease) about every 3 weeks.  Plasmapheresis is not required.    Since a plasma level of only about 5 percent is sufficient to prevent or shorten episodes of thrombotic thrombocytopenic purpura, gene therapy may induce lasting remissions in children with the chronic relapsing form of the disease.

Adults and older children with acquired acute idiopathic thrombotic thrombocytopenic purpura
require daily plasma exchange - the combination of

• plasmapheresis (which may remove unusually large multimers of von Willebrand factor and autoantibodies against ADAMTS 13) and
• infusion of fresh-frozen plasma or cryosupernatant (containing additional metalloprotease).

Plasma exchange allows about 90 percent of these patients to survive an episode of thrombotic thrombocytopenic purpura, usually without permanent organ damage.

Some patients with acquired acute idiopathic thrombotic thrombocytopenic purpura and high titers of antibodies against ADAMTS 1397 do not respond to plasma exchange alone. It may be possible to interfere with autoantibody production through treatment with glucocorticoids or splenectomy or to depolymerize platelet microtubules and alter exposure of surface receptors by infusing vincristine.  Rituximab, the monoclonal antibody against CD20 on B-lymphocytes, is under investigation. In the absence of life-threatening hemorrhage or intracranial bleeding, it is prudent to avoid platelet transfusions, which can exacerbate microvascular thrombosis.
* Aspirin may provoke hemorrhagic complications in patients with severe thrombocytopenia.

Improved survival with plasma exchange in patients with TTP-hemolytic uremic syndrome
AJ Med, Dec. 1999;107:6:573-579  - Primo N. Lara, etc.
PURPOSE: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are uncommon disorders that are generally fatal if left untreated. Plasma exchange therapy is associated with high response rates and improved short-term survival, but most previous studies have been limited by small numbers of patients or short duration of follow-up.

RESULTS: The overall 30-day mortality was 10% of the 122 patients who received plasma exchange as their principal treatment (a median of 9 exchanges and a mean cumulative infused volume of 43 ± 77 L fresh frozen plasma); 56% were complete responders and 21% were partial responders. The relapse rate was 13%. The estimated 2-year survival was about 60%; among patients without serious underlying comorbid conditions, the estimated 2-year survival was about 80%. Each unit increase in clinical severity score (on a 0 to 8 scale) was associated with a 2.2-fold (95% confidence interval [CI]: 1.3 to 3.9) increase in the odds of 30-day mortality. Patients who were febrile at presentation were substantially less likely to suffer a relapse (odds ratio = 0.2; 95% CI: 0.03 to 0.9).

CONCLUSION: Plasma exchange therapy produced high response and survival rates in this large cohort of patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. The Clinical Severity Score may be useful in predicting 30-day mortality, whereas fever at onset was associated with a lesser risk of relapse. Prospective studies should stratify patients according to these prognostic factors.

REF:
E-Medicine  TTP  

TTP-hemolytic uremic syndrome: Dx & Rx  - Cleveland Clinic J Med  Oct. 2001  

Quinine is a common cause of drug-associated TTP–HUS and can cause death and chronic renal failure. When the disorder is described as TTP–HUS rather than only as HUS, the severity of neurologic abnormalities and the occasional absence of renal failure are emphasized. If recurrent disease is to be prevented, clinicians must recognize quinine as a possible cause.  Ann Intern Med. Dec. 18, 2001;135:1047-1051.  (Full text)

REVIEW: Thrombotic Microangiopathies (TTP & Hemolytic-Uremic Synd.)
NEJM August 22, 2002 - Joel L. Moake

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