**3. Summary**

130 Pulmonary Embolism

reoccurrence of PE and contraindication of long-term anticoagulation (Hann & Streiff, 2005). Also, venous filters for PE prophylaxis may be beneficial in trauma patients, but further

Following PE therapy, a switch from heparin/LMWH to oral anticoagulation is recommended. Oral anticoagulation should be continued for 6 months. Following, an extended diagnostic procedure should take place to elucidate possible genetic factors or acquired thrombophylia behind the development of PE. In case of irreversible complications or positive thrombotic predisposition, continuous oral anticoagulation is

Experimental evidence indicated that the pathophysiology of PE implies the activation of matrix metalloproteinases (MMPs) (Uzuelli et al., 2008; Dias-Junior et al., 2009; Souza-Costa et al., 2005; Souza-Costa et al., 2007; Palei et al., 2005; Fortuna et al., 2007). Indeed, hemodynamic derangements associated with this condition improved with the inhibition of MMPs. Neutrophil activation (Eagleton et al., 2002) and rapid release of granules containing large amounts of MMP-9 in inflammation (Van den Steen et al., 2002) and during PE explains how MMPs, especially MMP-9, are involved in pathophysiology of PE. The increased activity and levels of MMP-9 found in ischemic stroke, or the upregulation of the enzyme after cerebral ischemia are interestingly similar to PE (Asahi et al., 2000). The degradation of type IV collagen, laminin, and fibronectin by MMP-9, may contribute to hemorrhagic transformation after cardioembolic stroke as these components are the main structure of the vascular matrix (Rosell et al., 2008; Montaner et al., 2001). Also, tissue plasminogen activator (or alteplase) can amplify MMP-9 levels by upregulation, thus increasing ischemic brain damage (Wang et al., 2004; Burggraf et al., 2007; Ning et al., 2006; Tsuji et al., 2005). There is evidence, that increased plasmin concentration may activate MMPs. Previous experimental work by our group aimed to assess the levels of MMPs following fibrinolysis for acute PE. Circulating levels of MMPs were measured serially (MMP-9 and MMP-2). Their endogenous inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were also measured in alteplase and

in ultra-high dose streptokinase-treated patients with acute PE (Mühl et al., 2010).

In our study MMP levels were assessed by sodium-dodecil-sulphate polyacrylamide gel electrophoresis, TIMP levels were measured with a commercially available ELISA kit (Mühl et al., 2010). Significant increases in pro-MMP-9 concentrations were found after TL therapy in both groups, but these were not associated with significant alterations in TIMP-1 levels. Pro-MMP-9/TIMP-1 ratio increased significantly. Interestingly, earlier increases in pro-MMP-9 levels and in pro-MMP-9/TIMP-1 ratio were found in subjects treated with streptokinase. From the 3rd day pro-MMP-9 levels and pro-MMP-9/TIMP-1 ratio returned to normal. No significant changes in pro-MMP-2 concentrations were measured after TL. Moreover, we found no significant changes in TIMP-2 concentrations or in pro-MMP-

**2.2 Measurements and discussion of TIMP/MMP changes in PE** 

studies are required to draw firm clinical evidence (Rajasekhar et al., 2011).

**1.5.5 Follow-up after PE therapy** 

needed (Kearon et al., 2008).

**2. A new approach to PE** 

2/TIMP-2 ratio.

**2.1 The role of matrix metalloproteinases** 

Following risk stratification, prompt and specific diagnostics are life-saving in acute PE. Recommended diagnostic tools are biomarkers, MDCT and electrocardiography. Systemic TL is the first choice for high-risk PE patients, in case of contraindications surgical embolectomy or catheter clot fragmentation/removal should be considered. The fast resolution of haemodynamic shock indicates accelerated protocol systemic TL (rt-PA, SK or UK), as continuous TL dissolve clot slower and have a higher risk of bleeding disorder. The regular control of fibrinogen and plasminogen during and after TL, and clot formation factor supplement can reduce bleeding complications.

There is emerging evidence of the hypothesized role of the TIMP/MMP system in the development of bleeding complication. In future, pharmacological approach to MMP inhibition in human medicine may decrease the incidence of bleeding complications of TL.
