A classic view of the clotting system is that it functions in a similar manner in all tissues, but recent studies indicate that this is not the case. For instance, TF is expressed at different levels in different organs in both humans and mice. High levels of TF are present in the brain, lung, heart, uterus, placenta, and testis, whereas low to undetectable levels are present in skeletal muscle, joints, and liver ().9,28,29
We speculated that this TF provides additional hemostatic protection to vital tissues. However, this notion was difficult to test. Fortunately, we engineered mice that expressed low levels of TF, so-called “low TF mice.” Low TF mice express low levels of human TF under the control of the human TF promoter.30
This promoter directs a cell type-specific pattern of TF expression that is similar to wild-type mice and is sufficient for survival of embryos and general hemostasis in adult mice. However, we observed tissue-specific hemostatic defects in older low-TF mice, including hemorrhages in the lungs, heart, brain, uterus, placenta, and testis31–34
Similar hemostatic defects were observed in mice engineered to express low levels of FVII.15,33
This indicated that a deficiency in the TF:FVIIa complex was associated with tissue-specific hemostatic defects in mice.
Model for tissue-specific hemostasis. It is proposed that the extrinsic pathway mediates hemostasis in tissues that express high levels of tissue factor (TF), whereas the intrinsic pathway mediates hemostasis in tissues that express low levels of TF.
Childbirth is a major hemostatic challenge because the placenta must be separated from the uterine wall. As noted earlier, high levels of TF are found in the uterus. We found that TF plays a critical role in uterine hemostasis because we observed a high frequency of fatal hemorrhages of low TF female mice postpartum. 31
Surprisingly, mice deficient in components of the intrinsic pathway (FVIII or FIX) have normal postpartum hemostasis. Interestingly, a pharmacological approach also led to tissue-specific hemorrhage in mice. Administration of an inhibitory anti-human TF antibody to mice that expressed human TF induced bleeding in the lung, heart, brain, and testis35,36
What about tissues that have low levels of TF? As mentioned earlier, individuals with hemophilia A or B are prone to hemorrhages in joints and skeletal muscle, which are both sites with low levels of TF. This strongly suggests that hemostasis in skeletal muscle and joints is more dependent on the intrinsic pathway rather than the extrinsic pathway (). Taken together, these observations support our proposal that TF expression in certain tissues provide additional hemostatic protection.
The bleeding sites in low TF mice and low FVII mice (heart and lung) are generally in tissues that are mechanically active. Similarly, bleeding in Hemophilia A and Hemophilia B patients is more common in joints and skeletal muscle. We speculate that blood vessels in these tissues are injured by the mechanical activity of the tissue. In individuals with normal hemostasis, these injuries result in small hemorrhages with rapid repair. In contrast, joint bleeds in individuals with hemophilia lead to inflammation and eventually hemophilic arthropathy. We have found that bleeding into the hearts of low TF mice leads to inflammation and fibrosis. Therefore, the extrinsic and intrinsic pathways of blood coagulation are particularly important for maintaining hemostasis in mechanically active tissues.