Blood and Brain Hemorrhage - Essay Example

1. Blood and brain hemorrhage a. Characteristics of blood Even if it is usually in liquid form, blood is a dynamic tissue that contains cells and dissolved chemicals. Its main function is delivering to and from organs for their sustainability, as evidenced by the fatal consequences of poor blood perfusion. One of the more important molecules delivered by blood is oxygen, which is necessary for efficient energy production and subsequent sustenance of cellular machineries. Oxygen delivery is conducted through red blood cells (RBCs), which are de-nucleated cells specialized to carry oxygen molecules. They do it by membrane proteins called hemoglobin, which binds or releases oxygen, depending on the concentration of the gas in the tissue. Thus, it is oxygenated in lungs, and de-oxygenated once it passes through tissues (Guyton and Hall, 2006). b. Causes and effects of brain hemorrhage Because of its liquid nature, it is able to seep through spaces once a vascular injury occurs. We usually see it as bruising of the skin, when trauma causes breakage in the thin-walled capillaries in the dermis. The bruising then recedes with time, and the skin goes back to its previous appearance as if nothing happened. The same may not be applicable to other organs, more notably the brain. Although there is no obvious bruising similar to that seen on the skin, brain hemorrhages present with more serious signs of paralysis or changes in the sensorium, as caused by the ischemia and neuronal death of the area in the brain that should have been perfused by the injured vessel. Soon, ischemia of some brain tissue results to irreversible neurologic dysfunction. Prompt management is thus needed before neurologic defects become permanent (Kumar et al., 2010). c. Different stages of hematoma The age of hemorrhage is important because it determines the management of intracranial hemorrhage, as will be discussed later. The stages of hematoma are based on the form of hemoglobin in RBCs. Initially, during the hyper-acute phase or hours after the development of the lesion, hematoma is made up of a liquid suspension of intact RBCs containing oxy- or deoxy-hemoglobin. If the blood came from an arterial source, which is the case in most non-traumatic etiologies such as aneurysm, approximately 95% of hemoglobin molecules are oxygenated. Later, water is resorbed by the brain tissue, resulting to a solidified aggregation of RBCs. As the blood ages further, the hemoglobin denatures from oxy- or deoxy- to met-hemoglobin. This transformation is dependent on the oxidation of ferrous (Fe+2) heme iron contained by oxy- and deoxyhemoglobin to ferric (Fe+3) state, turning the protein into methemoglobin. After which, met-hemoglobin becomes hemichromes. When RBCs are lysed, hemichromes are broken down into heme iron and globins. Phagocytosis of these organic molecules by macrophages and glial cells result to protein-bound ferritin or water-insoluble hemosiderin (Nitz, et al., 2010). The necrosis of intracranial hematoma thus may thus result to cavitation (Durbridge, 2012). Still, it should be noted that hemorrhages cause heterogeneous signal intensity. Thus, in determining the age of hematoma, it is beneficial to get both T1- and T2 weighted images. Based on Table 1, hemorrhages that are hypo-dense in T2-weighted MRI can be old hemorrhage, containing ferritin and/or hemosiderin, sub-acute hemorrhage, with predominantly intracellular methemoglobin, or acute hemorrhage, containing oxy- and deoxy-hemoglobin. However, sub-acute hemorrhage can also produce hyper-intense lesion in T2-weighted MRI. Thus, to confirm the true age of the hemorrhage, we can obtain a T1-weighted MRI. Although the information about the hemorrhage obtained from this sequence is relatively limited, since the hematoma is usually hypo- or iso-dense, sub-acute hemorrhages are distinctly hyper-dense. Thus, a finding of hyper-dense hematoma in T1-weighted MRI is definitive for sub-acute hemorrhage. Aside from sub-acute hemorrhage, hyper-acute and chronic hematomas also have a distinct MRI imaging. The hours old hemorrhages are hyper-dense in TW-weighted imaging, while they are hypo-dense in T1-weighted imaging, because of the longer T1 times of water. Since MRI imaging is highly dependent on water in the early stages of hemorrhage, it is more advantageous to use Computer Tomography. On the other hand, chronic hematomas in T2-weighted imaging, as seen in Figure 1, have a characteristic hypo-dense ring surrounding the lesion. This is the hemosiderin membrane, which is prone to susceptibility effects of MRI (Nitz, et al., 2010). 2. Locations of brain hemorrhage MRI is currently the best imaging for the diagnosis of hemorrhage. Brain hemorrhages can either be located at the brain parenchyma within the pia mater (intra-axial), or in the brain’s directly adjacent intracranial structures (extra-axial). In turn, intra-axial hemorrhages can either be intra-parenchymal or intra-ventricular. a. Intra-axial hemorrhages Intra-parenchymal hemorrhage is either within the brain parenchyma, such like within the cerebrum (intra-cerebral hemorrhage) or at the gray matter of the spinal cord. i. Intra-parenchymal hemorrhages within the brain Head injury, malformation, malignancy, hypertension, infarction, or intrinsic brain gliomas can cause bleeding within the brain parenchyma. The collection of blood may be discrete and well-circumscribed by a hemosiderin membrane, or it may be interspersed within the normal tissue, like a contusion. As discussed above, the development of a membrane may thus reveal a chronic hematoma. Figure 2 shows that the gradient echo sequence of the lesion produces a hypo-dense image, as compared to the hyper-dense normal parenchyma of the brain. In contrast, intra-parenchymal hemorrhage is generally hyper-dense in T1-weight, T2-weight and FLAIR sequences (Parizel, et al., 2010). Based on the information in Table 1, intra-parenchymal hemorrhages are generally month old, sub-acute hematomas. Comparing the four sequences, gradient echo provides the clearest image of the pathology, due to the contrast of the hemorrhage with the hyper-dense parenchyma, while the hemorrhage detected using T1-weighted imaging is the least distinct, since it provides the least contrast with the surrounding brain parenchyma. On the other hand, the hypo-dense brain parenchyma from T2-weighted or FLAIR sequence images contrasts with the hyper-dense lesion (Creasy, 2011). ii. Intra-parenchymal bleeding and syrinx formation in the spinal cord Similarly, intra-parenchymal spinal cord hemorrhage, usually located within the central gray matter, may also occur. If the lesion is due to back trauma, the bleeding is usually found at the level at which the force was directed. For imaging of such lesion, a sagittal T2-weighted MRI is usually done, although T1-weighted imaging may also be included to make more definitive findings (Durbridge, 2012). A serious complication of spinal cord hemorrhage is syringomyelia. Further down the natural course of intra-parenchymal hematoma in the spinal cord, necrosis of the trapped blood will result to formation of micro-cysts within the cord spinal parenchyma. The merging of these cysts causes the formation of a bigger cavity. Cysts not larger than 5 mm in size are referred to as intramedullary cysts, while those who span more than 5 mm are called true syrinxes. What makes cysts and syrinxes more dangerous is the direct connection between the central canal and cavity, causing the flow of CSF into the cavity, and the subsequent continuous enlargement of syrinxes. This may present as pain, numbness, increased motor deficits, autonomic dysreflexia, as well as depression of tendon reflexes (Durbridge, 2012). Radiographically, this can be seen as well-circumscribed cavities iso-dense with CSF as well as hypo-intense compared to spinal cord parenchyma and vertebrae on all pulse sequences. Likewise, both sagittal and axial images should be obtained (Durbridge, 2012). Figure 3 provides an MRI image of syrinxes. iii. Intra-ventricular hemorrhages On the other hand, intra-ventricular hemorrhage is caused by the rupture of blood vessels that line the ventricles. However, hemorrhage adjacent to ventricles can rupture into the ventricles as well. The blood is characterized by high ambient oxygen levels, leading to its relatively slow aging and higher proportion of oxy-hemoglobin. Intra-ventricular hemorrhages are thus generally sub-acute. Figure 4 shows examples of intra-ventricular hemorrhages seen through sagittal and axial MRI. As compared to hematomas in other brain locations, bleeding inside the ventricle is more hyper-dense, and this can be attributed to the relatively greater proportion of CSF in intra-ventricular hemorrhage (Nitz, et al., 2010). T1-weighted image produces an image of the intra-ventricular hemorrhage having equal density as that of the brain parenchyma. On the other hand, the lesion is more distinct using T2-weighted imaging because of its contrast with the hypo-dense normal parenchyma (Creasy, 2011). Because of the high oxygen level in intra-ventricular hemorrhage, FLAIR sequence is also highly sensitive and specific for detection of intra-ventricular blood. In fact, it is the MRI imaging of choice for intra-ventricular hemorrhage (Parizel, et al., 2010). b. Extra-axial hemorrhages Bleeding can also occur between the brain tissue and the skull. Extra-axial hemorrhages occur specifically at the subarachnoid, subdural and epidural spaces. Closest to the brain parenchyma, subarachnoid hemorrhages are located in between the pia and arachnoid maters. Between the arachnoid and dura maters can be infiltrated by subdural hemorrhages. Finally, epidural hemorrhages can be seen between the dura mater and the skull (Durbridge, 2012). These structures are illustrated in Figure 5. MRI of hemorrhages at these areas is seen in figure 6. It is notable that sub- and epidural hemorrhages take a longer time to age because of the high vascularity of the dura mater. The chronic ones, unlike those in the parenchyma, do not have hemosiderin ring, due to the absence of macrophages in this area. Epidural and subdural hematomas can be differentiated by shape, with the former assuming a concave shape, while the latter being convex (Nitz, et al., 2010). Bleeding at subarachnoid space, because of its closer proximity to capillaries in arachnoid granulation, has higher ambient oxygen level as compared to other extra-axial bleeding locations. Subarachnoid hemorrhage thus age more slowly than sub- and epidural hemorrhages. Moreover, like intra-ventricular hemorrhages, it has a relatively higher intensity than hematomas in other locations due to the CSF it likely contains (Nitz, et al., 2010). In this regard, sub-arachnoid hemorrhages are best seen through FLAIR sequence (Parizel, et al., 2010). Similarly, extra-axial hemorrhages can also be found along the spinal cord. Spinal epidural hematomas results from shearing of a portion of the epidural venous plexus, causing blood accumulation in the anterior epidural space. However, unlike in the brain, the dura of the spinal cord is not immediately proximal to the vertebral canal. Thus, a larger hematoma can develop asymptomatically (Durbridge, 2012). . In summary, T2- and T1-weighted imaging of the brain are combined to ascertain the age of hematoma. However, protocol for imaging of acute stroke, if indicated in the history, recommends the use of FLAIR, particularly to detect subarachnoid or intra-ventricular hemorrhages. In addition, T2 or gradient echo can be used to look for hemorrhage and blood breakdown products (Parizel, et al., 2010). 3. Ischemic Stroke and Tissue Plasminogen Activator a. Pathophysiology of Ischemic Stroke Ischemic stroke is usually caused by acute thrombosis of intracranial artery. A thrombus is a formation of blood cells coagulated by a matrix of fibrin. Due to this blockage, the tributaries of the occluded vessel are hypo-perfused. Without oxygenated blood reaching these tissues (ischemia), oxygen becomes depleted (Vivien, et al., 2011). In the acute stage, particularly as early as 20 minutes after the onset of ischemia, subcellular damage already occurs. 4 to 6 hours after, neurons shrink because of subcellular disintegration. Edema, presenting as effacement of adjacent gyri, can be noticed in a maximum of 1 to 2 days. Within days to weeks following the ischemic event (sub-acute stage), the necrotic brain tissue will be resorbed from the periphery inward, causing cystic cavities within the parenchyma. Resorption continues for months to a year, during the chronic stage. The volume loss of brain tissue may be replaced with CSF, and accompanying dilatation of the ipsilateral ventricle may be seen (Durbridge, 2012). b. Mechanism of action of tissue plasminogen activator Because of the irreversible brain damage that occur once ischemic stroke progresses along its natural history, the most effective way of managing the pathology is doing so in the acute stage. A rational approach to management of ischemic stroke is the rapid reperfusion of ischemic tissue. This can be done by clot thrombolysis. For this, tissue plasminogen activators (tPA) can be used. tPA are serine proteases, which convert the pro-enzyme plasminogen into the active plasmin. Plasmin, a trypsin-like serine protease, in turn, degrades several extracellular components, such as fibrin, as well as coagulation factors V, VIII, XII, and prekallikrein (Smith and Grady, 2006).Because of this mechanism, the drug is more likely to be more effective on dissolving fibrin-rich clots than platelet-rich ones. In effect, tPA causes better recanalization of cardio-embolic ischemic stroke than the non-cardio-embolic type (Vivien, et al., 2011). tPA has been seen clinically and experimentally to optimally work if given no longer than three hours after the onset of symptoms, and if without hemorrhage on CT scan (Lullman, Mohr, Ziegler, and Bieger, 2000; Wang, et al., 2004). Figure 7 shows a diagram of the fibrinolytic activity of tPA. Aside from its clot lysis activity, tPA has been shown in animal models to mediate neuronal precursor migration, neurite and axonal extension, as well as neuronal plasticity through its matrix remodeling ability. These all help in the replacement of damaged tissue, and the subsequent recovery from stroke (Wang, et al., 2004). c. Side effects of tPA Despite this, less than 10% of ischemic stroke patients receive tPA therapy, in large part because of the risks of developing intracranial hemorrhage (ICH). Bleeding secondary to vascular occlusion is likely, since the pressure on the occluded arterial vessel increases until it ruptures. Clinical data shows that symptomatic intra-cerebral hemorrhage is significantly more frequent among those with intra-arterial fibrinolysis, as compared to the negative control. ICH usually occurs in the core of the infarction (Vivien, et al., 2011). tPA contributes to this hemorrhagic transformation of ischemic stroke due to its uncontrolled proteolysis of the neurovascular matrix. The wide spectrum activity of extracellular matrix degradation can include important matrix molecules, such as interneuronal laminin, which is vital to cell-matrix signaling and subsequent neuronal survival (Wang, et al., 2004). The neurovascular unit includes important structures such as microvessels, pericytes, astrocytes, neurons, axons, microglia, and oligodendrocytes (Vivien, et al., 2011). Their damage will thus result to adverse consequences to the brain function. A variety of tPA activity is mediated by membrane-bound lipoprotein receptor-related protein (LRP). tPA also binds with LRP in endothelial cells to increase production of MMP. The tPA-LRP complex also activates platelet-derived growth factor (PDGF), causing BBB opening. On the other hand, binding with LRP in astrocyte membrane induces detachment of its foot process from the vascular wall (Vivien, et al., 2011). These are summarized in Figure 8. The tPA’s interaction with metalloproteinase (MMP) also contributes to extracellular matrix degradation. MMP-9, in particular, are increased in patients who receive tPA. It has been hypothesized that MMP-9 is responsible for degradation of substrates in the neurovascular basal lamina, the subsequent thinning out of the blood-brain barrier (BBB), leakage of plasma, and edema of the adjacent brain tissue. In fact, it has been shown that MMP-9 knockout mice do not incur brain trauma, spinal cord injury and focal cerebral ischemia, and MMP inhibitors decrease the occurrence of brain edema. Clinically, it has been shown that stroke patients with high levels of plasma MMP-9 are more likely to have secondary hemorrhage, to incur greater brain injury and to recover with poor neurologic functions (Wang, et al., 2004). Moreover, tPA has been seen in vitro to interact with the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor complex, causing amplification of harmful calcium currents during ischemic excitotoxicity. This adds on to the neuronal death, initiated by vascular occlusion (Wang, et al., 2004). References Creasy, J. L., 2011. Dating Neurological Injury: A Forensic Guide for Radiologists, Other Expert Medical Witnesses, and Attorneys. Berlin: Springer Durbridge, G. 2012. MRES7013. Fundamental MRI of Brain and Spine. Queensland, Australia: University of Queensland.   Guyton, A. C. and Hall, J. C., 2006. Textbook of Medical Physiology. Amsterdam: Elsevier Kumar, V., Abbas, A. K., Fausto, N., and Aster, J. C., 2010. Robbins and Cotran Pathologic Basis of Disease. Amsterdam: Elsevier. Lullman, H., Mohr, K., Ziegler, A., and Bieger, D., 2000. Color Atlas of Pharmacology. New York: Thieme Stuttgart Nitz, W. R., Balzer, T., Grosu, D. S., and Allkemper, T., 2010. Principles of Magnetic Resonance. In P. Reimer et al., eds. 2010. Clinical MR Imaging. Berlin: Springer-Verlag Parizel, P. M. et al., 2010. Magnetic Resonance Imaging of the Brain. In P. Reimer et al., eds. 2010. Clinical MR Imaging. Berlin: Springer-Verlag Smith, M. L. and Grady, M. S., 2006. Neurosurgery. In F. C. Brunicardi, et al., eds. 2006. Schwartz’s Manual of Surgery. New York: McGraw-Hill. Vivien, D., et al., 2011. Impact of tissue plasminogen activator on the neurovascular unit: from clinical data to experimental evidence. Journal of Cerebral Blood Flow & Metabolism, 31, pp. 2119-2134. Wang, X., et al., 2004. Mechanisms of Hemorrhagic Transformation After Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke. Stroke, 35(suppl I), pp. 2726-2730. Read More