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VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and
Michael Schwameis, Christian Schörgenhofer, Alice Assinger
1Bernd Jilma, MD, Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria, Tel.: +43 1 40400 29810, Fax: +43 1 40400 29990,
Abstract:
Absent or severely diminished activity of ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) resulting in the intravascular persistence and accumulation of highly thrombogenic ultra large von Willebrand factor (UL-VWF) multimers is the pathophysiological mechanism underlying thrombotic thrombocytopenic purpura. Reduced VWF-cleaving protease levels, however, are not uniquely restricted to primary thrombotic microangiopathy (TMA), e. g. thrombotic thrombocytopenic purpura, but also occur in other life-threatening thrombocytopenic conditions: severely decreased ADAMTS13 activity is seen in severe sepsis, disseminated intravascular coagulation (DIC) and complicated malarial infection. The clinical relevance of these secondary thrombotic microangiopathies is increasingly recognised, but its therapeutic implications have not yet been determined. The presence of a secondary TMA in certain diseases may define patient groups which possibly could benefit from ADAMTS13 replacement or a VWF-targeting therapy. This short-review focuses on the role of UL-VWF multimers in secondary TMA and discusses the potential of investigational therapies as candidates for the treatment of TTP. In conclusion, prospective clinical trials on the effectiveness of protease replacementin vivo seem reasonable. Carefully selected patients with secondary TMA may benefit from therapies primarily intended for the use in patients with TTP.
Insights
Reduced ADAMTS13 activity causes thrombotic thrombocytopenic purpura (TTP) by accumulating ultra-large von Willebrand factor (UL-VWF) multimers. Secondary thrombotic microangiopathies (TMA) also show low ADAMTS13 activity, suggesting potential benefits from VWF-targeting therapies.
Area of Science:
- Hematology
- Pathophysiology
- Thrombotic Microangiopathies
Background:
- Thrombotic thrombocytopenic purpura (TTP) is caused by absent or diminished ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) activity.
- This deficiency leads to the accumulation of ultra-large von Willebrand factor (UL-VWF) multimers, causing intravascular thrombosis.
- Reduced VWF-cleaving protease levels are also observed in secondary thrombotic microangiopathies (TMA), including severe sepsis, disseminated intravascular coagulation (DIC), and malaria.
Purpose of the Study:
- To review the role of UL-VWF multimers in secondary TMA.
- To discuss the potential therapeutic implications of targeting VWF or using ADAMTS13 replacement in secondary TMA.
- To evaluate investigational therapies for TTP and their potential application in secondary TMA.
Main Methods:
- Literature review focusing on ADAMTS13 activity, UL-VWF, and TMA.
- Analysis of pathophysiological mechanisms in primary TTP and secondary TMA.
- Discussion of current and investigational therapeutic strategies.
Main Results:
- Severely decreased ADAMTS13 activity is not exclusive to primary TTP but also occurs in severe sepsis, DIC, and complicated malaria.
- The clinical relevance of secondary TMA is increasingly recognized.
- Patient groups with secondary TMA may potentially benefit from ADAMTS13 replacement or VWF-targeting therapies.
Conclusions:
- Secondary TMA, characterized by reduced VWF-cleaving protease activity, represents a significant clinical entity.
- Investigational therapies for TTP, such as protease replacement, warrant consideration for carefully selected patients with secondary TMA.
- Prospective clinical trials are needed to determine the effectiveness of protease replacement in vivo for secondary TMA.
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