Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH independent of its effects on hemolysis and microparticle formation

Ilene C. Weitz, Pedram Razavi, Leanne Rochanda, Jeffrey Zwicker, Bruce Furie, David Manly, Nigel MacKman, Ralph Green, Howard A. Liebman

Research output: Contribution to journalArticle

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Abstract

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal bone marrow disorder which results in the loss of glycosylphosphatidyl inositol (GPI) anchors from cell membranes. As a consequence, membrane inhibitors of complement are lost rendering the cells more susceptible to complement mediated destruction. This results in hemolysis, leukopenia, thrombocytopenia and thrombophilia. Eculizumab, a monoclonal antibody to complement protein 5, has been approved for the treatment of PNH and is associated with a significant reduction in hemolysis, thromboembolic events and fatigue. We prospectively studied the effect of Eculizumab therapy on plasma markers of thrombin generation (D-Dimers, TAT), inflammation (IL-6), soluble P-selectin (sP-selectin), antigenic (TFMP) and functional (fTFMP) tissue factor bearing microparticles and total plasma microparticle ex vivo factor Xa generation (MPFXa) in eleven Eculizumab naive PNH patients. Blood sampling occurred day 1, prior to Eculizumab treatment, then on days 8,15,22,29, 43, 90. Our results demonstrate a statistically significant reduction in D-Dimer, TAT, IL-6, sP-selectin, and TFMP during the induction phase of treatment (day 1-29) which was sustained during the maintenance treatment (day 29-90). Although the serum LDH levels decreased rapidly, there was no correlation between the change in LDH and the markers of thrombin generation and inflammation. Although there was a statistically significant decrease in TFMP, this decrease did not correlate with changes in markers of thrombin generation or inflammation. Ex vivo MPFXa generation did not decrease with Eculizumab treatment suggesting continued microparticle formation despite inhibition of hemolysis. Ex vivo total microparticle FXa generation was found to have an inverse correlation with markers of thrombin generation, suggesting that in PNH patients in vivo thrombin generation occurs by a pathway independent of hemolysis and microparticle generation.

Original languageEnglish (US)
Pages (from-to)361-368
Number of pages8
JournalThrombosis Research
Volume130
Issue number3
DOIs
StatePublished - Sep 2012

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Paroxysmal Hemoglobinuria
Hemolysis
Thrombin
Inflammation
P-Selectin
Complement Inactivating Agents
Interleukin-6
Therapeutics
Complement C5
Factor Xa
Thrombophilia
Leukopenia
Thromboplastin
Inositol
Thrombocytopenia
Fatigue
eculizumab
Complement System Proteins
Bone Marrow
Monoclonal Antibodies

ASJC Scopus subject areas

  • Hematology

Cite this

Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH independent of its effects on hemolysis and microparticle formation. / Weitz, Ilene C.; Razavi, Pedram; Rochanda, Leanne; Zwicker, Jeffrey; Furie, Bruce; Manly, David; MacKman, Nigel; Green, Ralph; Liebman, Howard A.

In: Thrombosis Research, Vol. 130, No. 3, 09.2012, p. 361-368.

Research output: Contribution to journalArticle

Weitz, Ilene C. ; Razavi, Pedram ; Rochanda, Leanne ; Zwicker, Jeffrey ; Furie, Bruce ; Manly, David ; MacKman, Nigel ; Green, Ralph ; Liebman, Howard A. / Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH independent of its effects on hemolysis and microparticle formation. In: Thrombosis Research. 2012 ; Vol. 130, No. 3. pp. 361-368.
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AU - Zwicker, Jeffrey

AU - Furie, Bruce

AU - Manly, David

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AU - Green, Ralph

AU - Liebman, Howard A.

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