Investigation of the Tendency to Bleeding in Patients with low Activity of Plasminogen Activator Inhibitor-1 (PAI-1)

Investigation of the Tendency to Bleeding in Patients with low Activity of Plasminogen Activator Inhibitor-1 (PAI-1)

W. Miesbach, N. Noormalal, T. Vigh and I. Scharrer

The relationship between increased values of plasminogen activator inhibitor-1 (PAI-1) and atherosclerosis as well as thrombotic disease, especially of the cardiac system has been well established.

The risk for ischemic heart disease might be due to impaired thrombolysis after plaque ruptur [1].

The progression of atherosclerosis is supposed by inhibiting the clearance of fibrin incorporated into atherosclerotic plaques [2]. PAI-1 may also affect cellular migration, matrix remodeling, and the activation of growth factors [3].

PAI-1 is elevated in many solid tumors, too and is associated with a poor pro- gnosis in cancer [4].

The proteolytic activity of fibrin (fibrinolysis) is mediated by plasminogen and its activators, the serine proteases, tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA).

PAI-1 was initially isolated and purified from the medium of vascular wall endo- thelial cell cultures by van Mourik et al in 1984 [5].

PAI-1 is a member of the serine protease inhibitor super-family (Serpin), the primary inhibitor of t-PA in plasma and an important physiologic factor which regulates fibrinolytic activity by inhibiting fibrinolysis.

Platelets, vascular endothelial cells, and vascular smooth muscle cells also contain PAI-1, suggesting that it is an important regulator of fibrinolysis at sites of vascular injury and thrombus formation.

The balance between serin proteases and serpins may affect the clinical mani- festation of hemorrhage.

PAI deficiency leads to increased fibrinolysis. Individual reports of sometimes dramatically bleeding events in patients with low PAI levels have already been published [6, 7].

Congenital PAI-1 deficiency has been reported in very few cases [8].

Considerable information regarding the in vivo function of PAI-1 has been obtained from analyses of PAI-1 deficient mice generated by homologous recombi- nation in embryonic stem cells [9].

The aim of this study was to identify patients with PAI-1 deficiency and charac- terize the typical manifestations of bleeding.

I. Scharrer/W. Schramm (Ed.)

34

Hemophilia Symposium Hamburg 2003

” Springer Medizin Verlag Heidelberg 2005

Material and Methods

We investigated retrospectively clinical manifestations in 216 patients with PAI activity of 0 U/ml to test the relationship between lower PAI levels and a tendency to bleeding.

Testing of PAI activity was ordered due to a history of unexplained bleeding or a recently thrombotic disorder.

PAI activity was assayed by means of the Bioimmunoassay Chromolize TM PAI-1. PAI antigen was assayed by means of the enzyme-linked immunosorbent assay (ELISA) TintElize PAI-1 and t-PA-antigen by TintElize tPA.

Results

Of the 216 patients 77 % were female and 23 % male. The median age was 42 years (9–91 years). The median PAI antigen-level was 6.1 ng/ml (0.5–68.7 ng/ml, normal value: 3–25 ng/ml). The median t-PA antigen-level was 4.3 ng/ml (0.9–31.7 ng/ml, normal value: 1.9–8.4 ng/ml). 71 patients reported a tendency to bleeding, of which 96 % (68/71) were female. 13/71 patients were receiving anticoagulation therapy or treatment with aspirin due to a recently thrombotic disorder. In patients with tendency to bleeding and a PAI activity of 0 U/ml the values of PAI antigen and t-PA antigen were significantly lower than in patients without any tendency to bleeding (4.8 ng/ml vs. 7 ng/ml and 3.6 ng/ml vs. 4.6 ng/ml). Other possible causes of bleeding such as von Willebrand syndrome, deficiency of coagulation factors or dysfunction of platelets could be excluded in patients with a history of bleeding.

The majority of the patients (57 %) reported bleeding after surgical procedures or traumata (Fig. 1). They also mentioned easy bruising (18 %), abnormal long or heavy menstrual bleeding (13 %), noise bleeding (8 %) or gum bleeding (4 %). The extent of bleeding was reported by 52 % as being very high, by 25 % as high. It was possible to cure it by the application of tranexamic acid.

386 W. Miesbach et al.

57%

18%

13%

8% 4%

Bleeding after surgery Easy bruising Menstrual Nose

Gum Fig. 1. Type

of bleeding

Discussion

PAI-1 plays an important role in haemostasis and is considered as a critical regula- tor of the fibrinolytic system. Elevated and reduced levels of PAI-1 may cause severe complications.

In this retrospective investigation of patients with a PAI activity of 0 U/ml we have seen especially in patients with additionally lower values of t-PA and PAI anti- gen a particularly severe tendency to bleeding. It was striking that mostly women were affected by hemorrhagic symptoms.

The characteristic clinical manifestations of these patients comprised prolonged abnormal bleeding after trauma, dental extractions and surgical procedures.

Spontaneous bleeding such as petechiae or intra-articular hemorrhages could not be found in these patients. After initially stop of bleeding there was a common ten- dency toward rebleeding after a few hours at the wound site.

The administration of tranexamid acid clearly improved the hemorrhagic symptoms in these patients. But also other bleeding symptoms were reported, such as easy bruising, gum bleeding or menstrual bleeding. In the literature we found only one report of a female patient with PAI deficiency and menorrhagia [8].

PAI-1 deficiency can be homozygous or heterozygous. Mostly heterozygous PAI-1 deficiency does not result in a increased tendency of bleeding indicating that a single functional PAI-1 gene probably is sufficient for normal hemostasis.

It can also be suspected that some patients contain a mutation in the PAI-1 gene or an altered PAI-1 expression. There are cases in the literature with decreased fun- ctional activity of PAI-1 where the molecular basis for PAI-1 deficiency could not be determined. For example Schleef et al. described a 76-year-old man with a lifelong history of severe bleeding after trauma or surgery but normal plasma PAI-1 anti- gen, but low PAI-1 activity [10].

A spectrum of abnormal bleeding can be suspected in patients with PAI-1 defi- ciency. Although bleeding occurs mostly in response to trauma or surgery, it can be severe and even life-threatening.

Therefore, it appears reasonable that PAI-1 deficiency should be classified as a moderate bleeding disorder. Correct diagnosis is important because this disorder can be treated effectively with fibrinolysis inhibitors. In our ambulance patients with PAI deficiency get an emergency document with exact therapeutic recom- mendations. Oral fibrinolysis inhibitors, such as tranexamid acid and e-amino- caproid acid are effective in preventing and treating patients with bleeding events and PAI-1 deficiency.

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