Month: July 2017

Regulation of Hemostasis

July 23, 2017 Anticoagulant Therapy, Cardiology, Hematology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , ,

Key events that initiate and propagate coagulation are the redistribution of negatively charged phospholipids to the cell surface and the exposure of tissue factor to the blood. The appropriate negatively charged phospholipids, primarily phosphatidylserine, can arise as a result of either cellular activation with strong agonists like thrombin together with collagen in the case of platelets or tissue damage or death. The negatively charged phospholipids promote the activation of factor X and IX by the tissue factor-factor VIIa pathway, the activation of prothrombin by factors Va and Xa, and the activation of factor X by factors VIIIa and IXa. In addition, it has been suggested that oxidation of a specific disulfide in tissue factor is important for expression of its procoagulant activity, a process that may be regulated by protein disulfide isomerase, although this concept remains controversial.

Normally tissue factor is not present on cells in contact with blood. Tissue factor is found on extravascular cells surrounding the blood vessel so that a potent procoagulant surface is exposed when the endothelium is breached. This helps to seal the breach. Intravascularly, inflammatory stimuli can induce tissue factor synthesis and expression on leukocytes, particularly monocytes, providing a mechanism for the initiation of coagulation. This response likely contributes to disseminated intravascular coagulation (DIC). Animal studies suggest that this coagulation response plays a role in innate immunity and prevents the dissemination of infectious agents.

Other key events that can play a major role in the pathogenesis of thrombosis, at least in animal models, involve the release of intracellular components, including ribonucleic acid (RNA) and polyphosphates. These can trigger activation of factor XII, which initiates coagulation via the contact pathway. Although factor XII does not appear to contribute to hemostasis, it drives several models of thrombosis, including pulmonary embolism and myocardial infarction.

Polyphosphates are stored in the dense granules of platelets and when released, contribute to the procoagulant potential of the platelet. In regions of cellular death or severe inflammation, histones released from the tissue can bind to these polyphosphates, increasing the procoagulant activity more than 20-fold. Heparin analogues can block polyphosphate stimulation of coagulation by histones. In addition, neutrophils in hyperinflammatory environments can release their nuclear contents to form neutrophil extracellular traps (NETs). These NETs are effective in killing bacteria and other pathogens and also provide a potent agonist for the activation of platelets and the development of thrombi. Interestingly, heparin, an anticoagulant often used in the setting of inflammation, can disrupt the NETs and diminish the activation of platelets by histones and NETs.

Inhibition of Coagulation

There are three major natural anticoagulant mechanisms that serve to limit the coagulation process. These are tissue factor pathway inhibitor (TFPI), which blocks the initiation of coagulation by tissue factor-factor VIIa; the antithrombin-heparin mechanism, which inhibits thrombin and factors VIIa, Xa, and IXa; and the protein C pathway, which inactivates factors Va and VIIIa.

  1. Tissue factor pathway inhibitor (TFPI)
  2. Antithrombin-heparin mechanism
  3. Protein C pathway

Tissue Factor Pathway Inhibitor

TFPI is a complex molecule composed of three similar domains related to a protease inhibitor type known as Kunitz inhibitor. To inhibitor the tissue factor-factor VIIa complex, the Kunitz-1 domain of TFPI binds factor VIIa, whereas the Kunitz-2 domain binds factor Xa, either because the factor X is activated on tissue factor or (probably less effectively) by first reacting with factor Xa in solution and then inhibiting factor VIIa bound to tissue factor, thus blocking the initiation of coagulation. The carboxy terminal portion of TFPI is very basic, potentially facilitating interaction with the endothelium. Protein S can augment the activity of TFPI by increasing the rate of TFPI inactivation of factor Xa. The physiologic importance of TFPI is highlighted by the fact that gene deletion results in embryonic lethality apparently because of thrombosis and subsequent hemorrhage.

  1. Inhibiting Xa (Xa-TFPI complex)
  2. Xa-TFPI complex Inhibits FVIIa-TF complex
  3. TFPI is necessary for life

Antithrombin and Heparin

Antithrombin is the major inhibitor of the coagulation proteases thrombin, factor VIIa, factor Xa, and factor IXa. Antithrombin is a member of a large class of protease inhibitors referred to as serine protease inhibitors and abbreviated sermons. Antithrombin forms a very tight complex with these proteases. This reaction is rather slow with a half-life in the order of 30 seconds in plasma. Heparin markedly accelerates the reaction, thus accounting for most of its anticoagulant activity. There is a “bait” region in antithrombin that is involved in its interaction with the proteases. In the absence of heparin, this bait region is only partially available to the protease, resulting in the slow inhibition. Heparin binding to antithrombin induces a conformational change in antithrombin that enhances protease access to the bait loop.

In addition to the conformational change in antithrombin, heparin has additional roles in the inhibition of coagulation proteases. High-molecular-weight heparin can bind to both antithrombin and the protease, creating a situation where both reactants are brought into close proximity, thus increasing the reaction rate. This function is of variable importance with different proteases of the cascade. It is essential for thrombin inhibition, but plays a less important role in the inhibition of factor Xa. High-molecular-weight heparins accelerate factor Xa inhibition somewhat better than low-molecular-weight forms, but in contrast to most of the other heparin-mediated inhibitory functions, the additional acceleration gained by the high-molecular-weight forms is dependent on calcium ions. It is of interest that as heparins become processed to generate lower-molecular-weight fractions, such as enoxaparin, the capacity to promote thrombin inhibition versus factor Xa inhibition decreases. With the smallest functional form of heparin, the synthetic pentasaccharide fondaparinux, the ability to augment thrombin inhibition is almost completely lost, while good inhibition of factor Xa is maintained. Although heparin is a potent antithrombin-dependent anticoagulant, it is not effective against clot-bound thrombin or the factor Va-factor Xa complex assembled on membrane surfaces.

The importance of antithrombin is documented by the clinical observation that antithrombin deficiency, even to 50% of normal, is associated with significant thrombotic problems in humans and mice. Deletion of the gene in mice causes embryonic lethality, apparently in a mechanism that involves thrombosis followed by hemorrhage. Although heparin-like proteoglycans have been proposed to be important in modulating antithrombin function, immunohistochemical analysis indicates that most of these are localized to the basolateral side of the endothelium. No definitive deletion of heparin sulfate proteoglycans has been reported, possibly because there are alternative mechanisms for its biosynthesis. However, deletion of ryudocan, another heparin-like proteoglycan, is associated with a thrombotic phenotype.

  1. Antithrombin is ineffective against clot-bound thrombin or the factor Va-factor Xa complex assembled on membrane surfaces
  2. Heparin itself has no anticoagulation effect
  3. Heparin accelerates the anticoagulation capacity of antithrombin
  4. Deficiency of heparin-like proteoglycan potentiates patients at risk of thrombosis

The Thrombomodulin and Protein C Anticoagulation Pathway

The protein C pathway serves many roles, probably the primary role being to work to generate activated protein C (APC) that in turn inactivates factors Va and VIIIa to inhibit coagulation. The importance of this anticoagulant activity is readily apparent because patients born without protein C die in infancy of massive thrombotic complication (purport fulminans) unless provided a protein concentrate.

The protein C anticoagulant pathway serves to alter the function of thrombin, converting it from a procoagulant enzyme into the initiator of an anticoagulant response. This occurs when thrombin binds to thrombomodulin, a proteoglycan receptor primarily on the surface of the endothelium. Thrombomodulin binds thrombin with high affinity, depending on the posttranslational modifications of thrombomodulin. Binding thrombin to thrombomodulin blocks most of thrombin’s procoagulant activity such as the ability to clot fibrinogen, activate platelets, and activate factor V but does not prevent thrombin inhibition by antithrombin. The thrombin-thrombomodulin complex gains the ability to rapidly activate protein C. In the microcirculation, where there is high ratio of endothelial surface to blood volume, it has been estimated that the thrombomodulin concentration is in the range of 100 to 500 nM. Thus a single pass through the microcirculation effectively strips thrombin from the blood, initiates protein C activation, and holds a coagulantly inactive thrombin molecule in place for inhibition by antithrombin or protein C inhibitor. Activation of protein C is augmented approximately 20-fold in vivo by the endothelial cell protein C receptor (EPCR). EPCR binds both protein C and APC with similar affinity. The EPCR-APC complex is capable of cytoprotective functions, but at least with soluble EPCR, this complex is not an effective anticoagulant. Instead, when APC dissociates from EPCR, it can interact with protein S to inactivate factors Va and VIIIa and thus inhibit coagulation. Factor V increases the rate at which the APC-protein S complex inactivates factor VIIIa.

Thrombomodulin also increases the rate at which thrombin activates thrombin-activatable fibrinolysis inhibitor (TAFI) to a similar extent as it dose protein C. Once activated, TAFI releases C-terminal lysine and arginine residues of fibrin chains. C-terminal lysine residues on fibrin enhance fibrin degradation by serving as plasminogen- and tissue plasminogen activator-binding sites. Consequently, their removal by activated TAFI (TAFIa) attenuates clot lysis.

More than any other regulatory pathway except tissue factor, the protein C pathway is sensitive to regulation by inflammatory mediators. Tumor necrosis factor-alpha and IL-1beta downregulate thrombomodulin both in cell culture and in at least some patients with sepsis. Downregulation of thrombomodulin has been observed in animal models of diabetes, inflammatory bowel disease, reperfusion injury in the heart, over human atheroma, and in villitis, in addition to sepsis.

  1. Protein C, thrombomodulin, and EPCR are essential for life
  2. Protein C targets against factors Va and VIIIa
  3. EPCR increases the protein C activation by thrombin-thormbomodulin complex by about 20-fold
  4. Protein C’s anticoagulation function needs the help of protein S
  5. Thrombin-thrombomodulin complex removes the C-terminal lysine residues of fibrin, which attenuates clot fibrinolysis.

Regulation of Fibrinolysis

Fibrinolysis is the process by which fibrin clots are dissolved, either through natural mechanisms or with the aid of pharmaceutical interventions. Plasmin is the serine protease that solubilizes fibrin. Plasmin is generated by the activation of its precursor plasminogen either by natural activators, tissue plasminogen activator (tPA), the major activator in the circulation, or urokinase plasminogen activator (uPA), or by administration of recombinant tPA or streptokinase, a bacterial protein that promotes plasmin generation and aids in dissemination of the bacteria. Staphylokinase, a protein from Staphylococcus aureus, is similar to streptokinase and also has been examined as a potential therapeutic.

Fibrin plays an active role in its own degradation because it binds plasminogen and tPA, thereby concentrating them on the fibrin surface and promoting their interaction. The resultant plasmin cleaves fibrin and exposes C-terminal lysine residues that serve as additional plasminogen and tPA binding sites. TAFIa attenuates fibrinolysis by releasing these C-terminal lysine residues. Furthermore, lysine analogues, such as ε-aminocaproic acid or tranexamic acid, bind to tPA and plasminogen. Consequently, these lysine analogues can be used to treat patients with hyperfibrinolysis and can reduce bleeding complications.

Plasmin is not specific for fibrin and degrades a variety of other proteins. Consequently, plasmin is tightly controlled. There are two major inhibitors of fibrinolysis: α2-antiplasmin, and serpin that inactivates plasmin, and plasminogen activator inhibitor 1 (PAI-1), which inhibits tPA and uPA. α2-Antiplasmin is cross-linked to fibrin by activator factor XIII. PAI-1 is an intrinsically unstable serpin that can be stabilized by interaction with vitronectin. Because of its instability, the antigen and functional levels of PAI-1 are often quite different and can vary among individuals. PAI-1 is upregulated by lipopolysaccharide, tumor necrosis factor, and other inflammatory cytokines. PAI-1 levels are increased in vascular diseases such as atherosclerosis and in metabolic syndrome, sepsis, and obesity. Increased levels of PAI-1 result in decreased fibrinolytic activity, which increases the risk for thrombosis. PAI-1 is also stored in platelets and is released with platelet activation. Platelet-derived PAI-1 may limit the degradation of platelet-rich thrombi, such as those that trigger acute coronary syndromes.

Overall the fibrinolytic system is dynamic and responsive to local phenomena, such as platelet-derived PAI-1, as well as to systemic alterations like obesity and inflammation. In this sense, the fibrinolytic control mechanisms share many similarities with the control of coagulation, in which similar considerations affect their function.

Renal Handling of Urea

July 22, 2017 Laboratory Medicine, Nephrology, Physiology and Pathophysiology, Urology No comments , , , , , , ,

Renal Handling of Urate

Urate, an anion that is the base form of uric acid, provides a fascinating example of the renal handling of organic anions that is particularly important for clinical medicine and is illustrative of renal pathology. An increase in the plasma concentration of urate can cause gout and is thought to be involved in some forms of heart disease and renal disease; therefore, its removal from the blood is important. However, instead of excreting all the urate it can, the kidneys actually reabsorb most of the filtered urate. Urate is freely filterable. Almost all the filtered rate is reabsorbed early in the proximal tubule, primarily via antiporters (URAT1) that exchange urate for another organic anion. Further on the proximal tubule urate undergoes active tubular secretion. Then, in the straight portion, some of the urate is once again reabsorbed. Because the total rate of reabsorption is normally much greater than the rate of secretion, only a small fraction of the filtered load is excreted.

Although urate reabsorption is greater than secretion, the secretory process is controlled to maintain relative constancy of plasma urate. In other words, if plasma urate begins to increase because of increased urate production, the active proximal secretion of urate is stimulated, thereby increasing urate excretion.

Given these mechanisms of renal urate handling, the reader should be able to deduce the 3 ways by which altered renal function can lead to decreased urate excretion and hence increased plasma urate, as in gout: 1) decreased filtration of urate secondary to decreased GFR, 2) excessive reabsorption of urate, and 3) diminished secretion of urate.

Urate, and some other organic solutes, although more membrane permeable in the neutral form, are less soluble in aqueous solution and tend to precipitate. The combination of excess plasma urate and low urinary pH, which converts urate to the neutral uric acid, often leads to the formation of uric acid kidney stones.

Renal Handling of Urea

Urea is a very special substance for the kidney. It is an end product of protein metabolism, waste to be excreted, and also an important component for the regulation of water excretion. Urea differs from all the other organic solutes in several significant ways. 1) There are no membrane transport mechanisms in the proximal tubule; instead, it easily permeates the tight junctions of the proximal tubule where it is reabsorbed paracellularly. 2) Tubular elements beyond the proximal tubule express urea transporters and handle urea in a complex, regulated manner.

Urea is derived from proteins, which form much of the functional and structural substance of body tissues. Proteins are also a source of metabolic fuel. Dietary protein is first digested into its constituent amino acids. These are then used as building blocks for tissue protein, converted to fat or oxidized immediately. During fasting, the body breaks down proteins into amino acids that are used as fuel, in essence consuming itself. The metabolism of amino acids yields a nitrogen moiety (ammonium) and a carbohydrate moiety. The carbohydrate goes on to further metabolic processing, but the ammonium cannot be further oxidized and is a waste product. Ammonium per se is rather toxic to most tissues and the liver immediately converts most ammonium to urea and a smaller, but crucial amount to glutamine. While normal levels of urea are not toxic, the large amounts produced on a daily basis, particularly on a high protein diet, represent a large osmotic load that must be excreted. Whether a person is well fed or fasting, urea production proceeds continuously and constitutes about half of the usual solute content of urine.

The normal level of urea in the blood is quite variable, reflecting variations in both protein intake and renal handling of urea. Over days to weeks, renal urea excretion must match hepatic production; otherwise plasma levels would increase into the pathological range producing a condition called uremia. On a short-term basis (hours to days), urea excretion rate may not exactly match production rate because urea excretion is also regulated for purposes other than keeping a stable plasma level.

The gist of the renal handling of urea is the following: it is freely filtered. About half is reabsorbed passively in the proximal tubule. Then an amount equal to that reabsorbed is secreted back into the loop of Henle. Finally, about half is reabsorbed a second time in the medullary collecting duct. The net result is that about half the filtered load is excreted.

pH Dependence of Passive Reabsorption or Secretion

Many of the organic solutes handled by the kidney are weak acids or bases and exist in both, neutral and ionized forms. The state of ionization affects both the aqueous solubility and membrane permeability of the substance. Neutral solutes are more permeable than ionized solutes. As water is reabsorbed from the tubule, any substance remaining in the tubule becomes progressively more concentrated. And the luminal pH may change substantially during flow through the tubules. Therefore, both the progressive concentration of organic solutes and change in pH strongly influence the degree to which they are reabsorbed by passive diffusion through regions of tubule beyond the proximal tubule.

At low pH weak acids are predominantly neutral, while at high pH they dissociate into an anion and a proton. Imagine the case in which the tubular fluid becomes acidified relative to the plasma, which it does on a typical Western diet. For a weak acid in the tubular fluid, acidification converts much of the acid to the neutral form and therefore, increases its permeability. This favors diffusion out of the lumen (reabsorption). Highly acidic urine tends to increase passive reabsorption of weak acids (and promote less excretion). For many weak bases, the pH dependence is just opposite. At low pH they are protonated cations. As the urine becomes acidified, more is converted to the impermeable charged form and is trapped in the lumen. Less is reabsorbed passively, and more is excreted.

Ammonia and Urea Cycle

July 20, 2017 Gastroenterology, Medicinal Chemistry, Nephrology, Physiology and Pathophysiology No comments , , , , ,

Ammonia (NH3) is a small metabolite that results predominantly from protein and amino acid degradation. It is highly membrane-permeant and readily crosses epithelial barriers in its nonionized form.

Ammonia does not have a physiologic function. However, it is important clinically because it is highly toxic to the nervous system. Because ammonia is being formed constantly from the deamination of amino acids derived from proteins, it is important that mechanisms exist to provide for the timely and efficient disposal fo this molecule. The liver is critical for ammonia catabolism because it is the only tissue in which all elements of the urea cycle, also known as the Krebs-Henseleit cycle, are expressed, providing for the conversion of ammonia to urea. Ammonia is also consumed in the synthesis of nonessential amino acids, and in various facets of intermediary metabolism.

Ammonia Formation and Disposition

Ammonia in the circulation originates in a number of different sites. A diagram showing the major contributors to ammonia levels is shown in 14-1. Note that the liver is efficient in taking up ammonia from the portal blood in health, leaving only approximately 15% to spill over into the systemic circulation.

Intestinal Production

The major contributor to plasma ammonia is the intestine, supplying about 50% of the plasma load. Intestinal ammonia is derived via two major mechanisms. First, ammonia is liberated from urea in the intestinal lumen by enzymes known as ureases. Ureases are not expressed by mammalian cells, but are products of many bacteria, and convert urea to ammonia and carbon dioxide. Indeed, this provides the basis for a common diagnostic test, since H. pylori, which colonizes the gastric lumen and has been identified as a cause of peptic ulcer disease, has a potent urease. Therefore, if patients are given a dose of urea labeled with carbon-13, rapid production of labeled carbon dioxide in the breath is suggestive of infection with this microorganism.

Second, after proteins are digested by either host or bacterial proteases, further breakdown of amino acids generates free ammonia. Ammonia in its unionized form crosses the intestinal epithelium freely, and enters the portal circulation to travel to the liver; however, depending on the pH of the colonic contents, a portion of the ammonia will be protonated to ammonium ion. Because the colonic pH is usually slightly acidic, secondary to the production of short-chain fatty acids, the ammonium is thereby trapped in the lumen and can be eliminated in the stool.

Extraintestinal Production

The second largest contributor to plasma ammonia levels is the kidney. Ammonia is also produced in the liver itself during the deamination of amino acids. Minor additional components of plasma ammonia derive from adenylic acid metabolism in muscle cells, as well as glutamine released from senescent red blood cells.

Urea Cycle

The most important site for ammonia catabolism is the liver, where the elements of the urea cycle are expressed in hepatocytes. Ammonia derived from the sources described earlier is converted in the mitochondria to carbamoyl phosphate, which in turn reacts with ornithine to generate citrulline. Citrulline, in turn, reacts in the cytosol with aspartate, produced by the deamination of glutarate, to yield sequentially arginine succinate then arginine itself. The enzyme arginase then dehydrates arginine to yield urea and ornithine, which returns to the mitochondria and can reenter the cycle to generate additional urea. The net reaction is the combination of two molecules of ammonia with one of carbon dioxide, yielding urea and water.

Urea Disposition

A “mass balance” for the disposition of ammonia and urea is presented in Figure 14-2. As a small molecule, urea can cross cell membranes readily. Likewise, it is filtered at the glomerulus and enters the urine. While urea can be passively reabsorbed across the renal tubule as the urine is concentrated, its permeability is less than that of water such that only approximately half of the filtered load can be reabsorbed. Because of this, the kidney serves as the site where the majority of the urea produced by the liver is excreted. However, some circulating urea may passively back diffuse into the gut, where it is acted on by bacterial ureases to again yield ammonia and (CO2?). Some of the ammonia generated is excreted in the form of ammonium ion; the remainder is again reabsorbed to the handled by the liver once more.

EKG Findings Related to Myocardial Infarction

July 15, 2017 Cardiology, EKG/ECG No comments , , , , , ,

In most infarctions, the EKG will reveal the correct diagnosis. An EKG should be performed immediately on anyone in whom an infarction is even remotely suspected. However, the initial EKG may not always be diagnostic, and the evolution of electrocardiographic changes varies from person to person; therefore, it is necessary to obtain serial cardiograms once the patient is admitted to the hospital. During an acute myocardial infarction, the EKG evolves through three stages: 1) T-wave peaking followed by T-wave inversion, 2) ST-segment elevation, 3) the appearance of new Q waves.

T Wave

With the onset of infarction, the T waves become tall and narrow, a phenomenon called peaking. These peaked T waves are often referred to as hyperacute T waves. Shortly afterward, usually a few hours later, the T waves invert. These T-wave changes reflect myocardial ischemia, the lack of adequate blood flow to the myocardium. Ischemia is potentially reversible: if blood flow is restored or the oxygen demands of the heart are eased, the T waves will revert to normal. On the other hand, if actual myocardial cell death (true infarction) has occurred, T-wave inversion will persist for months to years. T-wave inversion by itself is indicative only of ischemia and is not diagnostic of myocardial infarction. T-wave inversion is a very nonspecific finding. Many things can cause a T wave to flip. One helpful diagnostic feature is that the T waves of myocardial ischemia are inverted symmetrically, whereas in most other circumstances, they are asymmetric, with a gentle downslope and rapid upslope. In patients whose T waves are already inverted, ischemia may cause them to revert to normal, a phenomenon called pseudonormalization. Recognition of pseudonormalization requires comparing the current EKG with a previous tracing. In young persons without any cardiac-related symptoms, T-wave inversion isolated to one geographic region of the heart, particularly one or two midprecordial leads, for example, V3 and V4, is usually a normal variant.

  • Peak and inversion
  • Only reflecting ischemia
  • Symmetrical
  • Pseudonormalization

ST Segment

ST-segment elevation is the second change that occurs acutely in the evolution of an infarction. ST-segment elevation signifies myocardial injury. Injury probably reflects a degree of cellular damage beyond that of mere ischemia, but it, too, is potentially reversible, and in some cases the ST segments may rapidly return to normal. In most instances, however, ST-segment elevation is a reliable sign that true infarction has occurred and that the complete electrocardiographic picture of infarction will evolve unless there is immediate and aggressive therapeutic intervention.

Even in the setting of a true infarction, the ST segments usually return to baseline within a few hours. Persistent ST-segment elevation often indicates the formation of a ventricular aneurysm, a weakening and bulging out of the ventricular wall. Like T-wave inversion, ST-segment elevation can be seen in a number of other conditions in addition to an evolving myocardial infarction. There is even a type of ST-segment elevation that can be seen in normal hearts. This phenomenon has been referred to as early depolarization or J point elevation.

The J point, or junction point, is the place where the ST segment takes off from the QRS complex. J point elevation is very common in young, healthy individuals. The ST segment usually returns to baseline with exercise. J point elevation has long been thought to have no pathologic implications. However, some research has reported a slightly increased risk of death from cardiac causes in patients with J point elevation in the inferior leads. How can the ST-segment elevation of myocardial injury be distinguished from that of J point elevation? With myocardial injury, the elevated ST segment has a distinctive configuration. It is bowed upward and tends to merge imperceptibly with the T wave. In J point elevation, the T wave maintains its independent waveform.

  • Elevation
  • Reflecting true infarction
  • Return to baseline within a few hours
  • J point elevation

Q Waves

The appearance of new Q waves indicates that irreversible myocardial cell death has occurred. The presence of Q waves is diagnostic of myocardial infarction. Q waves usually appear within several hours of the onset of infarction, but in some patients they may take several days to evolve. The ST segment usually has returned to baseline by the time Q waves have appeared. Q waves usually persist for the lifetime of the patient.

Other leads, located some distance from the site of infarction, will see an appear increase in the electrical forces moving toward them. They will record tall positive R waves. These opposing changes seen by distant leads are called reciprocal changes. The concept of reciprocity applies not only to Q waves but also to ST-segment and T-wave changes. Thus, a lead distant from an infarct may record ST-segment depression.

Small Q waves can be seen in the left lateral leads (I, aVL, V5, and V6) and occasionally in the inferior leads (especially II and III) of perfectly normal hearts. These Q waves are caused by the early left-to-right depolarization of the interventricular septum. Pathologic Q waves signifying infarction are wider and deeper. They are often referred to as significant Q waves. The criteria fro significance include: 1) The wave must be greater than 0.04 seconds in duration, 2) the depth of the Q wave must be at least one-third the height of the R wave in the same QRS complex. Because lead aVR occupies a unique position on the frontal plane, it normally has a very deep Q wave. Lead aVR should not be considered when using Q waves to look for possible infarction.

Acute Potassium Disorders

July 15, 2017 Cardiology, Clinical Skills, Critical Care, Differential Diagnosis, EKG/ECG No comments , , , , ,

Disorders of potassium homeostasis are common in hospitalized patients and may be associated with severe adverse clinical outcomes, including death. Prevention and proper treatment of hyper- and hypokalemia depend on an understanding of the underlying physiology.

The total body potassium content of a 70-kg adult is about 3500 mmol (136.5 g), of which only 2% (about 70 mmol / 2.73 g) is extracellular. It is not surprising that the extracellular potassium concentration is tightly regulated. In fact, two separate and cooperative systems participate in potassium homeostasis. One system regulates external potassium balance: the total body parity of potassium elimination with potassium intake. The other system regulates internal potassium balance: the distribution of potassium between the intracellular and extracellular fluid compartments. This latter system provides a short-term defense against changes in the plasma potassium concentration that might otherwise result from total body potassium losses or gains.

Disorders of Potassium Homeostasis

Disorders of potassium homeostasis may be conveniently divided according to the duration of the disturbance: acute (<48 hours’ duration) or chronic.

Acute Hyperkalemia

Excessive potassium intake. Given an acute potassium load, a normal individual will excrete about 50% in the urine and transport about 90% of the remainder into cells over 4 to 6 hours. It is possible to overwhelm this adaptive mechanism such that if too much potassium is taken in too quickly, significant hyperkalemia will result. Such events are almost always iatrogenic. One’s ability to tolerate a potassium load declines with disordered internal balance and impaired renal potassium excretory capacity. In such circumstances, an otherwise tolerable increase in potassium intake may cause clinically significant hyperkalemia: Doses of oral potassium supplements as small as 30 to 45 mmol have resulted in severe hyperkalemia in patients with impaired external or internal potassium homeostasis.

KCl, used as a supplement, is the drug most commonly implicated in acute hyperkalemia. Banked blood represents a trivial potassium load under most circumstances, because a unit of fresh banked blood, either whole or packed cells, contains only 7 mmol (273 mg) of potassium. Thus, severe hyperkalemia would result only from massive transfusion of compatible blood. However, the potassium concentration in banked blood does increase substantially as the blood ages.

Patients undergoing open heart surgery are exposed to cardioplegic, solutions containing KCl typically at about 16 mmol/L, which may lead to clinically significant hyperkalemia in the postoperative period, especially in patients with diabetes mellitus with or without renal failure.

Abnormal potassium distribution. Acute hyperkalemia may result from sudden redistribution of intracellular potassium to the extracellular space. If only 2% of intracellular potassium were to leak unopposed from cells, serum potassium level would immediately double. Fortunately, such dramatic circumstances are rarely encountered. Nevertheless, smaller degrees of potassium redistribution commonly result in clinically significant hyperkalemia.

Among the most impressive syndromes associated with acute hyperkalemia are those involving rapid cell lysis. The tumor lysis syndrome results from treatment of chemosensitive bulky tumors with release of intracellular contents, including potassium, into the ECF. Extreme hyperkalemia even causing sudden death has featured prominently in some series of patients. Most of such patients were in renal failure from acute uric acid nephropathy, thus impairing their ability to excrete the potassium load. Rhabdomylosis, either traumatic or nontraumatic, may result in sudden massive influx of potassium to the extracellular space. Other circumstances that may result in redistributive hyperkalemia include severe extensive burns, hemolytic transfusion reactions, and mesenteric ischemia or infarction.

Pharmacologic agents. Two drugs may rarely cause acute hyperkalemia by redistribution: digitalis glycosides and succinylcholine. Massive digitalis overdose has been associated with extreme hyperkalemia. Succinylcholine depolarizes the motor end plate and in normal individuals causes a trivial amount of potassium leak from muscle, resulting in an increase in serum potassium level by about 0.5 mmol/L. In patients with neuromuscular disorders, muscle damage, or prolonged immobilization, however, muscle depolarization may be more widespread, causing severe hyperkalemia. Prolonged use of nondepolarizing non depolarizing neuromuscular blockers in critically ill patients may predispose to succinylcholine-induced hyperkalemia.

Hyperkalemic periodic paralysis. This rare syndrome of episodic hyperkalemia and paralysis is caused by a mutation of the skeletal muscle sodium channel, inherited in an autosomal dominant pattern. Attacks may be precipitated by exercise, fasting, exposure to cold, and potassium administration, and prevented by frequent carbohydrate snacks. Attacks are usually brief and treatment consists of carbohydrate ingestion. Severe attacks may require intravenous glucose infusion.

Acute renal failure. Hyperkalemia accompanies acute renal failure in 30% to 50% of cases. It is seen most commonly in oliguric renal failure. Contributing factors include tissue destruction and increased catabolism.

Pseudohyperkalemia. It refers to a measured potassium level that is higher than that circulating in the patient’s blood. It has a number of possible causes. First, it may be caused by efflux of potassium out of blood cells in the test tube after phlebotomy. This may be seen in a serum specimen in cases of thrombocytosis or leukocytosis, when the clot causes cell lysis in vitro. These days, many clinical laboratories measure electrolytes in plasma (unclotted) specimens. Even under these conditions, extreme leukocytosis may cause pseudohyperkalemia if the specimen is chilled for a long time before the plasma is separated, leading to passive potassium leak from cells. Hemolysis during specimen collection with false raise [K+] or plasma potassium concentration by liberating intraerythrocyte to potassium. Second, if the patient’s arm is exercised by fist clenching with a tourniquet in place before the specimen is drawn, the sampled blood potassium concentration will rise significantly as a result of local muscle release of intracellular potassium.

Acute Hypokalemia

Treatment of diabetic ketoacidosis. It is well recognized that patients presenting in DKA are always severely depleted in total body potassium as a result of glucose-driven osmotic diuresis, poor nutrition, and vomiting during the development of DKA. Paradoxically, most patients in DKA have a normal serum potassium level upon admission. Insulin deficiency and hyperglycemia appear to account for the preservation of a normal [K+] despite severe total body potassium depletion. Once therapy for DKA is instituted, however, [K+] typically plummets as potassium is rapidly taken up by cells. Potassium replacement at rates up to 120 mmol (4.68 g) per hour have been reported, with total potassium supplementation of 600 to 800 mmol (23.5 to 31.2 g) within the first 24 hours of treatment. Hypokalemia in this setting may lead to respiratory arrest.

Refeeding. A situation analogous to DKA arises during aggressive refeeding after prolonged starvation or with aggressive “hyperalimentation” of chronically ill patients. The glucose-stimulated hyperinsulinemia and tissue anabolism shift potassium into cells, rapidly depleting extracellular potassium.

Pharmacologic agents. Specific beta2-adrenergic receptor agonists may cause electrophysiologically significant hypokalemia, especially when given to patients who are potassium depleted from the use of diuretic drugs. Epinephrine, given intravenously in a dose about 5% of that recommended for cardiac resuscitation, cause a fall in [K+] by about 1 mmol/L. A rare cause of severe hypokalemia is poisoning with soluble barium salts such as chloride, carbonate, hydroxide, and sulfide. Soluble barium salts are used in pesticides and some depilatories, which may be ingested accidentally or intentionally. Thiopentone, a barbiturate used to induce coma for refractory intracranial hypertension, is associated with redistributive hypokalemia in the majority of treated patients within 12 hours of initiating therapy.

Hypokalemic periodic paralysis. Three forms of this rare syndrome have been described: familial, sporadic, and thyrotoxic. All have in common attacks of muscle weakness accompanied by acute hypokalemia caused by cellular potassium uptake.

Pseudohypokalemia. Severe leukocytosis may cause spuriously low plasma potassium concentrations if blood cells are left in contact with the plasma for a long time at room temperature or higher. This phenomenon results from ongoing cell metabolism in vitro with glucose and potassium uptake. Unexpected hypokalemia and hypoglycemia in the setting of leukocytosis should alert the clinician to this phenomenon.

Summary

Potassium exchange between ECF and ICF: insulin, epinephrine, and [H+]

Potassium renal secretion: [K+], dietary intake of potassium, AngII, aldosterone, tubular sodium delivered to principal cells (at distal nephron).

EKG Changes of Potassium Disturbances

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Hyperkalemia

Hyperkalemia produces a progressive evaluation of changes in the EKG that can culminate in ventricular fibrillation and death. The presence of electrocardiographic changes is a better measure of clinically significant potassium toxicity than the serum potassium level. As the potassium begins to rise, the T waves across the entire 12-lead EKG begin to peak. This effect can easily be confused with the peaked T waves of an acute myocardial infarction. One difference is that the changes in an infarction are confined to those leads overlying the area of the infarct, whereas in hyperkalemia, the changes are diffuse. With a further increase in the serum potassium, the PR interval becomes prolonged, and the P wave gradually flattens and then disappears. Ultimately, the QRS complex widens until it merges with the T wave, forming a sine wave pattern. Ventricular fibrillation may eventually develop.

It is important to note that whereas these changes frequently do occur in the order described as the serum potassium rises, they do not always do so. Progression to ventricular fibrillation can occur with devastating suddenness. Any change in the EKG due to hyperkalemia mandates immediate clinical attention.

Hypokalemia

With hypokalemia, the EKG may again be a better measure of serious toxicity than the serum potassium level. Three changes can be seen, occurring in no particular order, including: ST-segment depression, flattening of the T wave with prolongation of the QT interval, and appearance of a U wave. The term U wave is given to a wave appearing after T wave in the cardiac cycle. It is usually has the same axis as the T wave and is often best seen in the anterior leads. Its precise physiologic meaning is not fully understood. Although U waves are the most characteristic feature of hypokalemia, they are not in and of themselves diagnostic. Other conditions can produce prominent U waves, and U waves can sometimes be seen in patients with normal hearts and normal serum potassium levels. Rarely, severe hypokalemia can cause ST-segment elevation. Whenever you see ST-segment elevation or depression on an EKG, you first instinct should always be to suspect some form of cardiac ischemia, but always keep hypokalemia in your differential diagnosis.