The platelet cells and clotting factors then react to thicken the blood and stop the bleeding. Problems in the blood, such as low levels of clotting factors or platelets, can keep blood from clotting normally and cause too much bleeding. Clotting factors are usually made by the liver. Prothrombin is one type of clotting factor. When bleeding occurs in the body, prothrombin quickly changes to thrombin. The prothrombin time test measures how quickly prothrombin changes to thrombin to stop the bleeding.
If the prothrombin doesn't change as quickly as normal, you may have a blood clotting disorder. The test may be used to help diagnose inherited disorders and other conditions that may affect blood clotting. These include:. You may need this test if you have symptoms of a bleeding disorder. These can include:. You may need this test regularly if you are taking a blood thinner such as warfarin. This is to help make sure you are taking the right dose.
You may also need this test before you have surgery or a procedure. You may need other tests that measure the ability of your blood to clot normally. These may include:. Other tests that measure aspects of blood clotting, such as platelet function. Test results may vary depending on your age, gender, health history, the method used for the test, and other things.
The prothrombin test specifically evaluates the presence of factors VII, V, and X, prothrombin, and fibrinogen. A prothrombin time within the 11 second range depends on the source of thromboplastin used indicates that the patient has normal amounts of the above clotting factors. A prolonged prothrombin time indicates a deficiency in any of factors VII, X, V, prothrombin, or fibrinogen.
It may mean that the patient has a vitamin K deficiency vitamin K is a co-factor in the synthesis of functional factors II prothrombin , VII, IX and X or a liver disease the liver is the site of synthesis of the plasma protein factors. The prothrombin time of patients receiving a vitamin K-competing coumarin drug such as warfarin anticoagulation therapy used in deep venous thrombophlebitis will also be prolonged, usually in the range of one and one half to two times the normal PT time.
Activated Partial Thromboplastin Time test The activated partial thromboplastin time aPTT is a test performed to investigate bleeding disorders and to monitor patients taking an anticlotting drug such as heparin which inhibits factors X and thrombin, while activating anti-thrombin. The aPTT test uses blood which is decalcified to prevent clotting before the test begins.
The plasma is separated by centrifugation. Ionized Calcium and activating substances are added to the plasma to start the intrinsic pathway of the coagulation cascade. The substances are: kaolin hydrated aluminum silicate and cephalin. Kaolin serves to activate the contact-dependent Factor XII, and cephalin substitutes for platelet phospholipids. The partial thromboplastin time is the time it takes for a clot to form, measured in seconds. Normally, the sample will clot in 35 seconds.
Note that: the two pathways converge, so that the final steps are common to the two schemes although clotting can be initiated via either the more rapid secs extrinsic scheme or the slower mins intrinsic scheme , the division into two pathways is only an artifact of in vitro testing: the two pathways interconnect at several levels.
Despite its contribution to fibrin formation in vitro , FXII seems not to be essential for hemostasis in vivo 21 , However, under pathological conditions, FXII participates in thrombus formation and thromboembolic disorders, such as stroke Figure 1. Only factors that are involved in inflammation are shown.
Tissue factor finally leads to the release of thrombin FIIa that can directly bind several receptors and activates fibrinogen to fibrin. Deposition of fibrin is regulated by plasmin. Figure 2. Overview of the contact system. These findings suggest a potential novel link between FXII and the immune system in neuroinflammation. Strikingly, we also found significantly increased FXII plasma activity in individuals with relapsing—remitting MS and secondary progressive MS, as compared to healthy donors, thus, indicating a role for this factor in human MS pathogenesis Table 1.
Studies of intrinsic and contact system factors: effects on neuroinflammatory processes in transgenic mice or using pharmacological substances. However, studies from our laboratory indicate that the latter factor has no significant role in EAE see also Table 1 , suggesting that not the entire intrinsic coagulation system is involved, but rather that the effect of FXII in neuroinflammation is dependent on other pathways triggered by FXII While three reports described a protective role of genetic or pharmacological inhibition of one distinct bradykinin receptor bradykinin receptor 1, B1R , another study demonstrated enhanced inflammation by B1R blockade see also Table 1 25 — For MS patients, B1R has been shown to have a detrimental effect, as it is upregulated on T-lymphocytes from patients with either secondary progressive MS or relapsing—remitting MS during active relapse Levels of B1R expression on mononuclear cells correlate positively with the Expanded Disability Status Scale, with occurrence of clinical relapses and lesion volumes on T2-weighted images, but not with gadolinium-enhancing lesions FXII has the capacity to activate the classic complement pathway by direct cleavage of C1q However, it has been shown that C1q has no influence on neuroinflammation, at least in terms of clinical symptoms It is known that PK can activate the complement components C3 and C5 However, reports on these members of the complement system in the context of neuroinflammation remain elusive.
While three reports showed a significant role of C3, as C3-deficient animals had an attenuated EAE disease course and reduced T-cell infiltration 31 , 33 , 34 , another study showed no clinical differences, but a tendency to enhanced inflammation and demyelination For C5, a dual role in EAE has been suggested: One study revealed that C5 leads to reduced inflammation and tissue repair in acute lesions, while this factor seemed to be responsible for increased axonal damage and enhanced gliosis in chronic lesions Furthermore, it has been shown that C5 can limit oligodendrocyte apoptosis in EAE, thus promoting remyelination Use of transgenic mice that express C5 under the astrocytic-specific glial fibrillary acidic protein promoter revealed no significant contribution to disease development of this component in the CNS 37 , so that the role of complement in EAE remains contradictory.
Studies from our laboratory have demonstrated high levels of CD87 on DC. In this context, we could show that FXII exerts its immunoregulatory effects directly via CD87 and by regulating cyclic adenosine monophosphate cAMP and thereby cytokine levels e. In contrast, we could rule out the involvement of alternative FXII-triggered pathways, such as the intrinsic coagulation, the contact and complement systems, for EAE pathogenesis.
Figure 3. FXII acts on dendritic cells through the urokinase-type plasminogen-activator receptor CD87 to enhance the release of interleukin IL -6 and However, reports on the relevance of CD87 inhibition, per se , in EAE remain contradictory: while two reports indicated a protective role in terms of clinical score and inflammation, when CD87 was missing 15 , 39 , and another showed enhanced inflammation In conclusion, the data so far indicate a significant role of FXII and downstream factors and pathways in neuroinflammation.
However, further studies are needed to clarify remaining contradictions. Fibrinogen Factor I is a kDa glycoprotein that is synthesized in the liver It is activated to fibrin by thrombin, exposing several polymerization sites that are crosslinked to an insoluble fibrin clot under the involvement of activated factor XIII 41 , Although activation of the coagulation system and thereby fibrin formation is essential for stopping lethal hemorrhage, the deposition of fibrin is carefully regulated to avoid thrombotic incidents This is achieved by the fibrinolytic system in which plasmin especially counterbalances the procoagulatory signals, leads to clot dissolution, and results in the generation of soluble fibrin fragments, such as fragments D and E, and d -dimers Plasmin generation is regulated by two proteases, tissue plasminogen activator tPA and uPA 45 , which are controlled by plasminogen activator inhibitor-1 PAI-1; Figures 1 and 4 Similarly, elevated levels of fibrin degradation products, such as d -dimer, are used in clinical practice as indicators of inflammation and risk predictors of thrombotic events In addition, fibrinogen-dependent effects of platelets may also contribute to EAE disease pathogenesis Figure 4.
Fibrinogen as a mediator of inflammation. Fibrinogen acts on different cells through integrin and non-integrin receptors to induce specific inflammatory effects. In line with this finding, it has been shown that fibrinogen can directly activate microglia, enhance their phagocytic ability, induce peripheral macrophage recruitment and local CNS activation of myelin antigen-specific T H 1 cells 58 , Table 2.
Studies of coagulation system factors: effects on neuroinflammatory processes using transgenic mice or pharmacological substances. Interestingly, none of these inhibitory approaches interferes with the clotting function of fibrinogen 53 , Enhanced fibrin deposition is usually counterbalanced by plasmin that is generated by tPA and uPA.
Results concerning tPA activity remain contradictory; while one report indicates a reduction in tPA activity in normal-appearing white and gray matter and lesions of individuals with MS 70 , others describe a significant increase of activity in lesions and the cerebrospinal fluid of MS patients during the acute, but not the chronic disease phase This finding was accompanied by enhanced microglial activation see also Table 2 Results of EAE experiments in tPA-deficient animals remain contradictory: while two publications described increased severity and a delayed recovery with enhanced demyelination and axonal damage after genetic depletion of tPA, disease onset was reported to be either earlier or delayed in the literature see also Table 2 39 , Due to the significant upregulation of PAI-1 in MS patients, EAE induced in PAIdeficient animals was shown to have moderate clinical protection with reduced perivascular cuffs, but no difference in terms of demyelination or axonal damage was observed Nonetheless, data so far indicate a significant role of local fibrin deposits in neuroinflammation and indicate a promising anti-inflammatory therapeutic potential of targeting this pathway.
Prothrombin factor II is a soluble kDa protein that is produced by the liver. Activated thrombin leads to cleavage of fibrinogen into fibrin monomers that, upon polymerization, form a fibrin clot.
Therefore, activation of prothrombin is crucial in physiological and pathophysiological coagulation. For instance, various rare disorders, such as congenital hypoprothrombinemia a blood disease in which deficiency of prothrombin results in impaired blood clotting and acquired hypoprothrombinemia e. Beyond its key role in coagulation, thrombin can mediate further effects, e. In terms of neuroinflammation, thrombin activity was found to be significantly increased in the spinal cord of mice with EAE Thrombin activity precedes the onset of neurological signs and correlates with the amount of fibrin deposition, microglial activation, demyelination, axonal damage, and clinical severity.
Interestingly, inhibition of thrombin activity by hirudin leads to a significant improvement of disease severity 13 see also Table 2. This is accompanied by decreased immune cell proliferation and cytokine secretion, as well as a reduction in the number of inflammatory lesions Furthermore, it has been shown that levels of thrombin inhibitors are significantly increased during EAE.
Additionally, it was recently shown that prothrombin levels are elevated in plasma of patients suffering from relapsing-remitting MS or secondary progressive MS indicating a prominent role of this coagulation factor in neuroinflammation An increasing body of evidence also supports a decisive role of coagulation factors in regulating inflammatory responses in non-neurological inflammatory diseases.
For instance, a substantial contribution of different coagulation factors has been suggested in RA or inflammatory joint disease as fibrin depositions can be found in the joints of patients with RA Moreover, the degradation products of fibrin, such as d -dimer, are used as common biomarkers for disease activity 77 , In vitro , it was shown that fibrinogen can enhance IL-8 secretion and intercellular adhesion molecule 1 expression from human synovial fibroblasts, leading to enhanced lymphocyte adhesiveness Furthermore, pharmacological inhibition of thrombin via hirudin resulted in a significant reduction in synovial inflammation and disease severity in two different animal models of RA see Table 3 80 , In this context, it could be shown that the plasmin activity is decreased, while PAI-1 levels are increased in both blood and inflamed joints of mice with collagen-induced arthritis CIA Table 3.
Studies of coagulation system factors: effects on inflammatory processes using transgenic mice or pharmacological substances. While treatment with uPA and tPA improves plasmin activity and removes fibrinogen depositions in joints, disease severity remains unchanged, challenging the pathophysiological role of fibrinogen in this context Nonetheless, a significant contribution of uPA could be seen in other studies, but this remains contradictory for different arthritis models: in monoarticular models, uPA-deficient mice had an aggravated disease course 90 , In contrast, other studies using polyarticular animal models demonstrated resistance to or suppression of disease and reduced inflammation in animals lacking uPA, indicating a distinct role of uPA in different types of arthritis 91 , 92 , 94 — The same result was observed in plasminogen-deficient animals 90 — In contrast to uPA, studies using tPA-deficient animals have so far indicated an aggravated disease course with enhanced inflammation 93 , A substantial role for the contact system in arthritis has been discussed.
Furthermore, pharmacological blockade of PK by different inhibitors revealed reduced disease severity and inflammation in different models of arthritis 88 , In line with these findings, genetic or pharmacological inhibition of HMWK leads to an attenuation of PK—kinin system activation, local and systemic inflammation, indicating a therapeutic potential in RA 84 — Moreover, arthritis severity is significantly attenuated in mice lacking B1R and B2R 83 or by treatment with a B2R antagonist 87 , In addition to RA, potential drugability of the coagulation system and its factors is under consideration for the treatment of inflammatory bowel disease.
Furthermore, inflammatory bowel disease in humans is associated with higher plasma levels of fibrinogen, prothrombin, factor V, factor VIII, plasminogen, and platelets Since a link between chronic inflammation and tumor development, e. Collectively, these results demonstrate a clear role of the coagulation system, not only in neuroinflammation, but also in other autoimmune and inflammatory disorders.
In this review, we have discussed the links between coagulation and inflammation, focusing on the role of different coagulation factors in neuroinflammatory disorders. Overall, it becomes increasingly clear that the deposition of different coagulation factors in the CNS tissue may trigger exacerbation of inflammation, thereby limiting regenerative mechanisms.
A prominent role was especially described for fibrinogen, thrombin, and factor XII. As novel molecular and cellular binding partners are identified, the role of coagulation factors is evolving from hemostasis regulators to multi-faceted signal molecules, which control the balance between immune defense mechanisms and extensive inflammation.
Interestingly, the binding of coagulation factors to their cellular targets requires distinct non-overlapping epitopes and is usually independent of their protease function. Taking advantage of this knowledge, targeted inhibition of coagulation factors that facilitate disease pathogenesis without affecting their protease activity represents an ideal strategy for pharmacological intervention in different neuroinflammatory disorders without unwarranted side-effects like bleeding.
Therefore, future studies are needed to elucidate the exact contribution of blood proteins to autoimmune neurodegeneration. KG drafted the manuscript. KG and TC funded the study. All authors provided substantial input throughout the process. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Macfarlane RG. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier.
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