As part of our continued partnership with High-Yield Med Reviews, I’m excited to share with you a huge give-away! I’m offering two FREE packages for the NAPLEX or the BCCCP exams.
Here’s the catch: you have to write a post for the blog. The post could be about anything relevant to pharmacy (not just EM), and could be any length (one paragraph to a ten thousand word rant). For each package, the post with the most views over a 1 week period is the winner! As a bonus, all posts submitted will be featured on the blog. So win or loose, you get a great opportunity!
All you have to do is submit your post to me (iempharmd@gmail.com) by March 4th, 2019. Winners will be announced in April. Good luck!
For the NAPLEX package, you get:
NAPLEX Premium Bundled Course:
Online Classroom: 4 hour online classroom instruction with Dr. Busti for 4 weeks: Int
egrated case studies to solidify your knowledge
$429 value
100% money back guarantee you will pass the NAPLEX (see website)
200+ Online NAPLEX Lectures
NAPLEX Q-Bank with 2,200+ questions
2 Course books with all lecture notes & high-yield tables
If interested, as a Premium Member – they would get free access to all of our Spring 2019 Study Group for BPS Exams with Dr. Busti. This is a popular study group that includes 13 case-based sessions to help integrate the content our members are studying.
Free Premium Member access to our new Landmark Clinical Trials Series with Dr. Busti starting this spring
Like many people in North America, I have close ties to diabetes and insulin. We likely all have someone in our lives be it family, friends or ourselves who are diabetic. My connection is somewhat different. Growing up in London, Ontario, most of my family went to high school at a school named Banting. Not really bothering to make any sort of connection beyond the name itself, it wasn’t until I was working at Rutgers and read the The Discovery of Insulin (great book) that the connection made sense. (spoiler alert) Charles Banting was one of the founders of insulin, which transformed the way diabetics were cared for (essentially living in a treatment facility, titrated down to a caloric intake of 500-1000 calories/day and just dealing with that) to regaining a quality of life that resembled someone without diabetes. Most fascinating of all, after their Nobel-Prize, the group of Banting and Best sought a pharmaceutical manufacturer that allowed the patent to remain open. Eli Lilly was the only manufacturer that agreed, and intended for money to never be an issue for someone who needed insulin. Also, Lilly, located near Chicago, had access to a virtually unlimited source of beef and pork pancreas to make the insulin. When I hear about the cost of insulin these days, I often wonder back to what Charles Banting would think of his discovery now.
As dramatic and remarkable the story of insulin is, so too are the actions of insulin in the extremes of diabetes. From a complete deficiency/total resistance leading to ketoacidosis/hyperosmolarity to fatal (or near fatal) hypoglycemia, the spectrum of potential clinical effects of insulin make it one of the most potent drugs in use today. I won’t spout off the ISMP medication safety data, but I’m sure we all know how often insulin is the culprit in drug errors.
A deficiency or resistance to insulin is of course the core pathophysiology of diabetes. In the USA, the ever growing obesity epidemic fuels development of type 2 diabetes. While a major public health concern, and focus of many inpatient and outpatient programs, the extremes of diabetes often lead patients to the emergency department. Diabetic ketoacidosis (DKA) and hyperglycemic-hyperosmolar nonketotic syndrome (HHS) are the hyperglycemic emergencies most often encountered in the ED. While the treatment of DKA and HHS is rather straight forward, there are critical nuances to ensure the most effective and safest care.
A 22 year old male is brought to the ED via EMS for abdominal pain. He’s writhing in pain on the stretcher, retching, and is very agitated. His medical history is significant for type 1 diabetes, for which he had run out of his insulin for a week and has had a flu like symptoms for the past 2 days. He’s tachycardic on the monitor (130’s), normal pressure (105/80), but is tachypneic (95% on RA), temp of 99.8F and the point of care glucose reads 350 mg/dL. The team is having a hard time getting IV access since the patient is so dehydrated, there is a discussion about whether to give NS or LR first.
Fluid – Chloride rich/Chloride poor
There are numerous therapies that should be simultaneously started in the ED for patients in hyperglycemic crisis.[1-3] The most accessible and easiest to begin, however, are IV fluids. Very often IV fluids are started on patients in the ED with little thought in regards to the particular formulation, dose/rate, and therapeutic goal. With hyperglycemic emergencies, IV fluids are best treated as a drug. In the most ideal state, IV fluids would always be treated as such, but few cases illustrate the potential risks and harms of various fluids better than DKA/HHS.
The underlying pathophysiology of DKA is an insulin deficiency (or resistance) and glucagon excess, producing an excess glucose concentration along with dehydration and electrolyte disturbances. [4] With this hyperglycemic state, the kidneys secret glucose into the urine, producing a hyperosmolar diuretic effect (also pulling in several electrolytes: Na, K, Mg, Ca, P). This excessive diuretic effect and volume loss, combined with decreased oral intake due to vomiting (gastroparesis/glucagon), patients with DKA can present with profound total body water deficits. [4]
Dehydration sets off numerous neurohormonal responses that do nothing to help improve the physiologic problems with DKA.[4] The release of cortisol, epinephrine, glucagon, and somatostatin act to either enhance ketogenesis via lipolysis or through inhibiting glycolysis. Furthermore, dehydration impairs peripheral tissue perfusion which may lead to decreased use of ketones by these tissues as a energy source.
Volume resuscitation with IV crystalloids have the potential to improve the volume depletion, replace electrolyte imbalances and dilute glucose in plasma to reduce hyperosmolarity. The two fluids most commonly recommended as first line are sodium chloride 0.9% (NS, normal saline) and Lactated Ringer’s (LR).
The contents of NS compared to LR shed light on the not so nuanced differences. NS contains a 1:1 ratio of sodium to chloride. Each 100 mL of NS contains 900 mg of sodium, and works out to 154 mEq/L each of sodium and chloride with a final osmolarity of 308 mOsmol/L and pH of 5.0. This ratio of sodium to chloride, osmolarity and pH are hardly ‘normal’ physiological ranges. Compared this to LR which contains the following: Na 130 mEq/L, K 4 mEq/L, Cl 109 mEq/L, Ca 1.4 mEq/L, Lactate 28 mOsmol/L with a osmolarity of 272 mOsmol/L and pH of 6.5. The more physiologic ratio of sodium to chloride with LR can reduce the risk of iatrogenically inducing a hyperchloremic acidosis, falsely closing the anion gap, and may increase the risk of acute kidney injury.[5,6]
Plasmalyte, a branded balanced electrolyte solution (BES), is a crystalloid fluid that has been adjusted to be as physiologic as possible. This crystalloid has Na 140 mEq/L, K 5 mEq/L, Cl 98 mEq/L, Mg 3 mEq/L, acetate 27 mEq/L, gluconate 23 mEq/L with a osmolarity of 294 mOsmol/L And pH of 6.5. In studies comparing standard NS therapy for DKA to BES use, improve lab-based outcomes such as anion gap, and bicarbonate, but have not proven superiority in patient-oriented outcomes.[7-9]
Given the theoretical benefits, and lack of high quality data, most guidelines either make no preference as to which fluid to use initially, or simply suggest using clinical judgement.[1-3] While the total body water deficit may be as high as 3 to 5 L in patients with DKA, there is no agreed upon calculation for fluid replacement. [10] It is reasonable to use a bolus of 20 mL/kg in adult DKA patients with a systolic blood pressure less than 80 mmHg. [10] Slower rates of infusion can be targeted for patients who are hemodynamically stable, but the same total volume should be administered over roughly 3 hours. Subsequent fluid choices, after the bolus, should be based on patient specific findings with electrolytes and based on their response to insulin (ie, the need for dextrose containing fluids).
While insulin therapy is fundamental to DKA/HHS management, fluid resuscitation alone may lower plasma glucose by up to 18%. [4] Therefore, early aggressive insulin therapy with fluid resuscitation may cause excessively rapid glucose correction (or over correction) which can lead to potentially harmful fluid shifts (ie, cerebral edema). This is why, while insulin is critical, the impact of IV fluid therapy on glucose must be considered prior to insulin initiation.
Bottom line
IV fluid is fundamental for DKA/HHS management
BES seems to be, at least theoretically, more helpful with DKA/HHS.
Cost is the biggest drawbacks to physiologic branded BES. LR is a great, cheap alternative
The 22 year old male with DKA now has two large bore peripheral IV lines, running one liter of LR each. A repeat point of care glucose reading still reads 325 mg/dL and the physician orders an insulin infusion to begin STAT. Should this patient recieve an insulin bolus?
Insulin
While the hyperglycemia of DKA and HHS can be lowered substantially with IV fluids alone, the underlying physiologic process cannot be treated without insulin. Whether the patient has no baseline insulin secretion from their pancreas (DKA) or are profoundly resistant (HHS), exogenous insulin is needed to correct the underlying pathophysiology.
Insulins numerous secondary messenger actions begin by its binding to the alpha subunit of the insulin receptor on muscle, liver, renal, adipose and other tissues.[11,12] This receptor activity initiates a conformational change in the beta-subunits of the insulin receptor to be capable of phosphorylation actions. Tyrosine residues on these beta-subunits are phosphorylated and the subsequent activity of tyrosine kinases then activates phosphatidylinositol-3 and MAP-protein kinase pathways. These pathways set off further intracellular actions that result in reversal of the catabolic action of insulin deficiency of particular benefit in DKA/HHS. In the liver, insulin inhibits glycogenolysis, conversion of fatty acids to keto acids, and conversion of amino acids to glucose as well as improving glycogen synthesis (GLUT-2 receptors). In muscle tissue, insulin promotes glycogen synthesis through increased glucose transportation (through GLUT-4 receptors in muscle, cardiac and adipose tissue), and in adipose tissue insulin promotes the esterification of fatty acids. Other effects of insulin extend to promoting protein synthesis, regulating gene transcription and cell proliferation. Thus, many of the underlying metabolic derangements leading to fatty acid beta-oxidation are resolved and reversed by insulin and cannot be done without insulin.
Insulin available today is a recombinant form of human insulin. While porcine and bovine preparations are still available internationally, the human recombinant forms are the mainstay in the USA. Among the various types of insulin products available, the most rationale classification is based on their onset of action and duration of action: rapid acting, short acting, and long acting insulins.
While these recombinant insulins are administered with the goal of controlling glucose, they fail to match physiologic insulin responses. Since the administration of exogenous insulin is first absorbed to the peripheral circulation, not the portal circulation where endogenous insulin distributes to, it influences hepatic glucose metabolism differently than normal physiologic insulin.[11,12] Similarly, peripherally administered insulin does not act as rapidly in response to prandial glucose changes in both rapidly increasing and decreasing concentrations. The available recombinant insulin preparations, and drug therapy strategies using them in combinations, aims to match this process as closely as possible.
Fortunately in the case of DKA/HHS, we aren’t necessarily concerned with matching physiologic insulin. In this extreme of diabetes, we aim to administer insulin to reach near-maximal glucose uptake, inhibition of gluconeogenesis and lipolysis.[11] In order to do so, insulin is administered via continuous IV infusion. To determine the appropriate insulin preparation for IV administration, let’s review the types of insulin based on their subclass.
Rapid acting insulin
The pharmacokinetics of insulin products are depended on specific substitutions on the underlying amino acid chain of insulin.[11,12] Insulin aspart is created by substituting the B-28 aspartic acid for proline (Novolog). Insulin lispro (Humalog) is produce with the reversal of proline-lysine on positions B-28, B-29 and insulin glulisine (Apidra) has two substitutions of lysine at B-3 and glutamic acid at B-29. These substitutions allow these insulins to be administered subcutaneously and rapidly absorbed. Their rapid absorption is a result of the insulin dissociating to monomers almost immediately after injection.
Short acting insulin
Insulin regular, as the name would suggest is simply the recombinant version of the endogenous human insulin amino acid chain.[11,12] The absorption of insulin regular following subcutaneous injection is slower than that of rapid acting insulins since hexamers are formed at neutral pH and dissociates slowly at physiologic pH. For many outpatients managing diabetes, this makes insulin regular administration less convenient since for a basal/bolus regimen it must be given 30-45 min prior to a meal compared to 15 minutes before a meal with rapid acting and potentially after a meal with insulin glulisine. Furthermore, the duration is up to 2 hours longer. This may have benefits, but also can lead to hypoglycemia if the dose is high.
Insulin regular is the most commonly administered insulin preparation via IV. While it is possible to administer aspart or lispro IV, regular insulin has maintained its role for this route. There is no evidence comparing the theoretically easier titratability of the rapid acting products given IV, however, they can be used if certain institutions aim to reduce the number of different insulin preparations in a medication safety initiative.
Intermediate and long acting insulin
Intermediate and long acting insulin preparations are not ideal for management of DKA/HHS. Since their pharmacokinetics have been optimized to have longer onsets (to prevent a ‘peak’ effect hypoglycemia) and longer durations of activity, it makes rapid titration for DKA/HHS not feasible.[11,12] There may be an emerging role for long acting insulin preparations in patients with mild or borderline DKA, however, this role is not practice ready at this point.
IV Insulin regular – IV administration Insulin bolus vs no bolus
As previously discussed, DKA and HHS cannot be managed without exogenous insulin. Given the pharmacokinetic, lack of prospective research and years of practical experience, insulin regular is often used as the IV infusion insulin. In determining the initial dose of insulin, it’s important to recall the goals of therapy. In particular, the effect of insulin on plasma glucose. With any administration of insulin, the plasma glucose should decrease. However, this is not the goal for DKA/HHS management. In fact, it’s probably best to consider this an adverse event that must be managed. Insulin administration supports the correction of the metabolic derangement while the causative (infection, myocardial infarction, dehydration, other illness) event is resolved.[10]
Insulin infusion rapidly achieves near-maximal glucose uptake to the liver and skeletal muscle, inhibits gluconeogenesis as well as lipolysis.[11-13] These actions shift metabolism away from fatty acid beta-oxidation back towards glycolysis thereby preventing further production of ketones. In the process of rebalancing metabolism, blood glucose will decline ideally at a rate of 50-75 mg/dL/hr. Once plasma glucose levels of 200 mg/dL for DKA and 300 mg/dL for HHS are achieved, maintenance fluids should include dextrose. Without the understanding of the pathophysiology we’ve been discussing, this would seem counter productive. But since we understand both glucose (d-glucose aka dextrose) and insulin are necessary for aerobic cellular respiration, glucose supplementation at some point in treatment will be necessary to allow for clearance of ketone bodies and correction of acidemia. Furthermore, understanding of the management euglycemic DKA caused by the newer diabetes agents (gliflozins), starvation or pregnancy will help solidify the understanding of the role of insulin in DKA.[Euglycemic DKA post]
Insulin infusions may be preceded by a IV bolus of 0.1 units/kg.[1] While there is evidence to suggest that there is no benefit to insulin boluses in adults with DKA, they may solve a more operational pharmacy problem.[14] That being, the time from order entry, IV compounding and delivery of the insulin drip to the bedside. If this process will take more than 15 minutes, a reality in many pharmacies, then an insulin bolus MAY be reasonable in sick DKA patients (those with very low bicarb, very high anion gaps and likely ICU admission). However, in other cases where patients are not as ill, or pharmacy turnaround times are rapid, it is preferable to start the insulin drip at a rate of 0.14 units/kg/hour.[14,15]
Determining the therapeutic goal for the insulin drip may be dependent on the institutional protocol and geographic location of your practice. The three major guidelines for DKA each recommend a different endpoint.[1-3] For the American guidelines, insulin is to be titrated to a particular glucose level.[1] For DKA, once glucose reaches 200 mg/dL the insulin rate should decrease to 0.02-0.05 units/kg/hour or transition to 0.1 units/kg subcutaneous rapid acting insulin every 2 hours to a goal glucose of 150-200 mg/dL. For HHS the same strategy is recommended by targeting a glucose goal of 200-300 mg/dL. Canadian guidelines on the other hand, recommend adjusting the rate to target a closure of the anion gap and supplementing dextrose as needed.[2] British guidelines suggest a middle of the road approach, using both ketone clearance and correction of glucose as a marker of therapy.[3] Given the variations in recommendations, and low quality of evidence, any of the above strategies may be reasonable.
Bottom line
Insulin is necessary to treat DKA/HHS, but it should not distract from the underlying problem
Hypoglycemia is an adverse event, not a therapeutic goal for insulin
IV insulin can be regular, aspart or lispro.
The insulin drip finally arrived from pharmacy, but the patient received a bolus of 0.1 units/kg IV insulin regular. After 20 mL/kg of LR, the patient was also started on an infusion of LR at a rate of 150 mL/hr. On a repeat VBG, the potassium now reads 2.8 mmol/L.
Potassium
Alongside the declining glucose level, potassium concentrations will also decrease on top of already total body potassium deficit due to osmotic diuresis and insulin administration. [15-18] In fact, prior to insulin administration, potassium levels should be collected. If the potassium is less than 3.3 mmol/L, insulin should be held until potassium supplementation increases this level to somewhere between 4-5 mmol/L. It is also possible for patients to initially present with a mild hyperkalemia due to osmotic shifts. In these patients, who are still potassium depleted, once insulin (and perhaps bicarb) is started, the potassium will rapidly decline.
In order to achieve normokalemia, IV administration of potassium chloride is often necessary. As many traditional pharmacy beliefs note that PO potassium “sticks” better, it may not be feasible to administer via this route given the nausea and vomiting often present with hyperglycemic crisis. To replace potassium, while there is little guidance from the guidelines, it is reasonable to administer runs of 10-20 mEq/100mL, with the empiric assumption each 10 mEq will increase serum potassium by 0.1. So in order to go from 3.3 to 4.0, a total of 70 mEq to be administered over 7 hours (10 mEq/hr) or 3.5 hours (20 mEq/hr) depending on patient tolerance. Once maintenance fluids are started, it is reasonable to add 40 mEq of potassium chloride to each liter of fluid.
Magnesium administration should be a consideration whenever potassium supplementation is necessary. Unacknowledged hypomagnesemia can further potassium losses in the kidneys and worsen the adverse effects of hypokalemia on specific tissues.[19]
Bottom line:
In DKA/HHS there is likely a potassium deficit, which can go unrecognized.
Potassium supplementation is necessary before insulin in many cases where hypokalemia is already present
Potassium can’t be bolused, and magnesium should be a concomitant intervention
Along with the VBG findings of hypokalemia, the admitting team is also concerned that the bicarb is still less than 12, despite the pH being 7.25. An order for sodium bicarbonate 150 mEq in 1000mL of D5W is ordered.
Bicarb
The role of sodium bicarbonate in hyperglycemic emergencies are a matter of controversy. [20] While the evidence for, or against, bicarbonate therapy is limited, it offers some guidance. A review of nine studies (434 patients total) in diabetic ketoacidosis that saw 217 patients receive bicarbonate therapy and 178 patients not receive bicarbonate therapy, did not demonstrate improvements in patient oriented outcomes including cardiac or neurological functions, rate of recovery of hyperglycemia, and ketoacidosis.[20]
While there may be no upside to sodium bicarbonate, there is certainly downside. Sodium bicarbonate therapy increases the already high risk of hypokalemia, may decrease tissue oxygen uptake, induce cerebral edema, and can trap protons in the CNS leading to a local acidosis.[21] The ADA guidelines remain bearish on sodium bicarbonate therapy and suggest there may be a role if pH is less than 6.9. Provided that the patient has the minute ventilation to expire the produced CO2, this may be a reasonable therapy. However, for patients who are tiring from Kussmaul’s respirations or who are intubated without subsequent ventilator setting adjustments, sodium bicarbonate may worsen acidemia.
One small upside to sodium bicarbonate is in its potential role in fluid resuscitation. From the previous discussion regarding chloride rich vs chloride poor solutions, sodium bicarbonate can be substituted for sodium chloride to reduce the risk for iatrogenic hyperchloremic metabolic acidosis, or premature closure of the anion gap. However, sodium acetate, LR or other BES products can achieve the same goal.
Bottom line:
Bicarbonate is often a reflex order for DKA/HHS. It’s not that it’s unreasonable, it just has to be a conscious decision of all the physiologic benefits, and potential harms.
Bicarbonate could be a useful chloride sparing strategy
Don’t count on it fixing the blood gas, and it will make hypokalemia worse
Reference
Kitabchi AE, et al. Hyperglycemic Crises in Adult Patients With Diabetes. Diabetes Care Jul 2009, 32 (7) 1335-1343
Goguen J, Gilbert J. Clinical Practice Guideline: Hyperglycemic emergencies in adults. Can J Diabetes, 2013;37:S72-S76
Cydulka RK, Maloney GE: Diabetes Mellitus and Disorders of Glucose Homeostasis; in Marx JA, Hockberger RS, Walls RM, et al (eds): Rosen’s Emergency Medicine: Concepts and Clinical Practice, ed 8. St. Louis, Mosby, Inc., 2014, (Ch) 126: p 1652-1668.
Nor’azim Mohd Yunos, Rinaldo Bellomo, Michael Bailey, et al. Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults. JAMA 2012; 308(15): 1566-1572.
Van Zyl DG, Rheeder P, Delport E. Fluid management in diabetic-acidosis–Ringer’s lactate versus normal saline: a randomized controlled trial. QJM. 2012 Apr;105(4):337-43.
Mahler SA, Conrad SA, Wang H, Arnold TC. Resuscitation with balanced electrolyte solution prevents hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med. 2011 Jul;29(6):670-4
Chua HR, Venkatesh B, Stachowski E, et al.Plasma-Lyte 148 vs 0.9% saline for fluid resuscitation in diabetic ketoacidosis. J Crit Care. 2012 Apr;27(2):138-45
Oliver WD, Willis GC, Hines MC, Hayes BD. Comparison of Plasma-Lyte A and Sodium Chloride 0.9% for Fluid Resuscitation of Patients With Diabetic Ketoacidosis. Hosp Pharm. 2018 Oct;53(5):326-330.
Cydulka RK, Maloney GE. Chapter 118 Diabetes mellitus and disorders of glucose homeostasis. In; Rosen’s Emergency Medicine: Concepts and Clinical Practice, 9th Edition. Elsevier
Powers AC, D’Alessio . Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=172482821. Accessed January 18, 2019.
Kitabchi AE et al. Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis? Diabetes Care. 2008;31(11):2081
Goyal N, et al. Utility of initial bolus insulin in the treatment of diabetic ketoacidosis. J Emerg Med;4 doi:10.1016/j.jemermed.2007.11.033
Mahoney CP, Vlcek BW, DelAguila M. Risk factors for developing brain herniation during diabetic ketoacidosis. Pediatr Neurol 1999;2:721e7.
Murthy, K et al. Profound Hypokalemia in Diabetic Ketoacidosis: A Therapeutic Challenge. Endocrine Practice. 2005; 11:5 p 331
Huang CL, Kuo E. Mechanism of Hypokalemia in Magnesium Deficiency. JASN Oct 2007, 18 (10) 2649-2652
Viallon A, Zeni F, Lafond P, Venet C, Tardy B, Page Y, Bertrand JC . Does bicarbonate therapy improve the management of severe diabetic ketoacidosis? Crit Care Med 1999; 27: 2690– 2693
Glaser N, et al. Risk factors for cerebral edema in children with diabetic ketoacidosis. N Engl J Med 2001; 344: 264– 269
The coagulation cascade, at least the way I learned it in pharmacy school, needs to be burned. The next time you’re looking at an adaptation of this pathway, point out the platelet. If you can’t, don’t continue to read that source.
66 year old male being discharged from the ED with diagnosis of DVT. Will be started on oral anticoagulation, and followed in clinic. Which DOAC is preferred and should there be any bridge with heparin or low-molecular weight heparin?
In order to really comprehend the drug therapy for DVT and PE, or any thromboembolic disease for that matter, a sound understanding of coagulation is fundamental. At this point, most lectures and texts would stop and review the coagulation cascade – the extrinsic/intrinsic/common pathways. There exists, however, a more evolved understanding of the various elements of coagulation and their interplay that has all but rendered the conventional cascade irrelevant. To understand the modern drug therapies for anticoagulation, we must also understand the modern interpretation of coagulation. That is coagulation in the initiation, amplification, and propagation phases.[1-4]
Initiation, Amplification, Propagation
Tissue factor (TF) is the glycoprotein that starts everything off.[2,5] Under normal physiologic conditions, TF exists in the vascular smooth muscle (vessel walls), surrounds large organs and circulates TF-expressing cells (microparticles). In doing so, TF creates a defense mechanism and hemostatic barrier that initiates coagulation should vessel walls, or organ tissue become damaged. While TF can be stimulated by other means, vessel damage appears to be the most common trigger, whereas patients with cancer may have systemic activation of circulating TF containing microparticles. TF can be released by endothelial cells due to inflammation, endotoxins, growth factors or oxidised LDL; TF also exists in very small amounts in the bloodstream.
Upon vessel injury or endothelial damage, two critical events take place that ultimately lead to homeostasis: platelet activation and exposure of TF.[6,7] TF bound to these endothelial or vessel tissues complexes with FVIIa. In turn, this TF-FVIIa complex (extrinsic tenase) activates factor IXa and Xa. The factor Xa that is produced here associates with factor Va (creating the prothrombinase complex), which cleaves prothrombin to generate very small amounts of thrombin (IIa). The thrombin generated in this initiation phase, is not really enough to be able to ultimately form a clot. It’s purpose is to initiate (in part) the amplification phase.
Simultaneously, a small quantity of platelets are activated as a result of this vessel injury or endothelial damage due to the exposure of collagen and von Willebrand factors.[6,7] The amplification phase begins on these platelet surfaces where small amounts of thrombin signals further platelet aggregation and activation (as well as other platelet aggregators: TXA2, ADP, 5-HT). [6,7] This thrombin also generates a positive feedback loop (ie amplification) through activation of factors Va, VIIIa (liberating and activating von Willebrand factor), and platelet bound XIa. Activated platelets further enhance the coagulation initiation phase via P-selectin which sequesters more TF from blood-borne microparticles and supplements the TF in the initiation process.
In the propagation phase, the activated platelet surface continues to be where the action takes place. On these activated platelets, the factor XIa produced in amplification takes over the role of activating IXa (originally produced in initiation by TF-VIIa). [6,7] This IXa complexes with VIIIa to form intrinsic tenase. Intrinsic tenase and the prothrombinase complex (Va and Xa, as described above) accelerate the generation of factor Xa and thrombin on the surface of activated platelets. This thrombin generation, is often referred to as the thrombin “burst.”
Clot formation
From this burst of thrombin (approximately 1000x more than the thrombin produced in initiation phase), fibrinogen is converted to fibrin and factor XIII is activated. [6,7] Fibrin polymerizes to form protofibrils and are subsequently stabilized by the XIIIa that was just generated. These fibrin protofibrils create a mesh linking platelets via the GPIIb/IIIa receptor (which was mobilized to the surface via P2Y12 receptor activation). Thrombin activatable fibrinolysis inhibitor (TAFI), activated by thrombin-thrombomodulin complex (see below) removes the C-terminal lysine residues from fibrin, thus slowing the rate of fibrin degradation and ultimately yielding fibrin resistant to lysis.[8]
This newly established platelet-fibrin plug allows for tissue hemostasis, vessel repair and for physiologic functions to continue to take place. However, without a counterbalancing mechanism, these clots would continue to expand to the entire circumference of the vessel lumen or for local coagulation process to extend systemically. Numerous regulators of coagulation occur at various steps along this coagulation pathway.
Regulation of initiation phase
The TF-VIIa complex, producing both Xa and IXa is regulated by tissue factor pathway inhibitor (TFPI) and heparan sulfate (similar to, but not heparin).[6,7,9] TFPI is released from endothelial surfaces by thrombin, heparin (exogenous), or shear forces. Activated protein S (aPS) is a cofactor for TFPI activity and enhances its inhibition of factor Xa by a factor of 10. Additionally, aPS increases the affinity of TFPI to activated platelets. This process shuts down initiation phase and thus clot formation.
Antithrombin (AT, the anticoagulant formerly known as AT-III) inhibits free coagulation enzymes (namely IIa and Xa from the initiation phase) and acts to limit the expansion of the coagulation process to other anatomic sites. AT requires heparan liberated on the surface of endothelial cells to augment it’s activity to anything physiologically relevant, and AT is only capable of inactivating free factors. Essentially, think of the mechanism of indirect anticoagulants such as heparin or low-molecular weight heparins.
Regulation of the amplification and propagation phase
Free circulating thrombin that is otherwise not regulated by the previous process, can actually exert an anticoagulant effect, in addition to its procoagulant effects.[6,7] This free circulating thrombin can become bound to thrombomodulin (TM) present on intact endothelial surfaces. This thrombin-TM complex activates protein C (aPC) and along with aPS modulates the activity of factors VIIIa and Va (thus decreasing formation of prothrombinase and the tenase complexes). While thrombin itself can activate small quantities of aPC, as a complex with TM, the activation of aPC is 100 times greater.
The activity of the thrombin-TM complex has numerous other targets.[6,7] Thrombin-TM complex consumes circulating thrombin, decreasing free thrombin prevents thrombin activity on activation of platelets and production of fibrin. As described above, the thrombin-TM complex can activate TAFI thereby strengthening fibrin clots. Fortunately, the activation of aPC by thrombin-TM can inhibit the action of plasminogen activator inhibitor-1 (confusing double-negative…plasminogen activator=lysis; plasminogen activator-inhibitor=no lysis; inhibition of plasminogen activator inhibitor=lysis). The interplay and balance between these processes determines the end result: clot formation or lysis.
DVT/PE Management
Let’s turning our attention back to therapeutic application of anticoagulant drugs. Having an understanding of the mechanism of anticoagulants and their action on the particular phase of coagulation, and underlying pathophysiology can help provide a sort of clarity when determining therapeutic goals. For example, when we start to consider how to treat a DVT/PE, a drug that exclusively works on the initiation phase of coagulation would be useless, since the clot is already established. However, if we’re trying to prevent clot formation in the first place (ie, prophylaxis), targeting this very initiation phase is rational.
In a patient with a diagnosed DVT or PE, anticoagulation should be initiated, and with the consideration that there is an established clot and that the goals of therapy are to stop the propagation of that clot and promote the body’s fibrinolysis. Because, of course, if left untreated, a DVT (which isn’t generally life threatening in and ofitself) can embolize into the pulmonary vasculature (PE). In the most extreme circumstances, exogenous fibrinolysis is needed for acute life threatening PE.
The current iteration of the CHEST guidelines recommends the DOACs as first line agents to treat DVT or PE.[10] These guidelines require some context considerations since not all patients with DVT or PE should be started on these medications. For example, patients who are hemodynamically unstable, unfractionated heparin would be the more ideal choice. A more detailed explanation will occur in a subsequent section. But back to the DOACs, whether a patient is being admitted, or discharged for an acute stable DVT/PE there is evidence and mechanistic rationale for these selection.
The DIRECT oral anticoagulants (DOACs, Table 1) have important effects that differ themselves to the indirect anticoagulants. These direct agents, as the name would suggest, do not require an existing cofactor (for example AT) to exert their actions. Furthermore, the DOACs generally only target a single element of the coagulation pathway (which gave rise to one of the previous iterations of their numerous acronyms; the TSOACs).
Direct Xa Inhibitors
Apixaban, rivaroxaban and edoxaban belong to the direct Xa-inhibitor (DXa) subclass. These agents, as the name would suggest, directly inhibit factor Xa. However, there is more to the story here. The DXa agents are capable of inactivating both free, complex-bound, and clot-bound Xa.[11,12] This action is in contrast to their indirect cousins which require AT for their action and can only inactivate free coagulation factors. The DXa agents’ ability to inactivate free Xa prevents the initiation phase of coagulation and prothrombinase complex bound Xa which inhibits the propagation phase. Furthermore, clot-bound Xa inhibition exerts a localized effect and limits clot growth due to thrombin.[13,14] Additional benefits include anti inflammatory and antiproliferative effects.[13,14]
The clinical result of these mechanisms yields improved anticoagulants effects, while balancing risk of hemorrhage. Since DXa agents to do not affect already formed thrombin, they may also preserve the actions of thrombin-TM complex, and generation of aPC, aPS and TFPI, further supporting physiologic anticoagulation.
Among the available DXa agents, the preferred agents (as of this writing) are rivaroxaban and apixaban. However, the most recent guidelines do not make a distinction among the DOAC agents.[10] Vitamin K Epoxide Reductase Inhibitor (VKA) or LMWH therapy should be restricted for patients where the date is currently insufficient to recommend DOAC therapy such as renal impairment, cancer and VTE, antiphospholipid syndrome). Mindyou, these are the guideline recommendations and I emphasise GUIDElines. Therefore, clinical practice variation may exist, and may be justifiable based on clinical context. The ARISTOPHANES study is the most robust comparison between the DOAC agents and VKAs.[15] It is early in the interpretation of this study, but it supports the theory that of the available agents, apixaban may be the preferred agent given its balance of efficacy and bleeding risks.
As a result of good bioavailability, the DXa agents are all administered orally.[16,17] The rapid onset of apixaban and rivaroxaban, generally within 2 hours of administration, allow them to be given without a parenteral anticoagulant bridge. This pharmacokinetic advantage allows for a dose administered in the ED, then subsequent discharge with strict medication compliance instructions. However, that cannot be said for edoxaban, which despite similar pharmacokinetics, requires a parenteral anticoagulant bridge.[10]
While the DXa agents are all eliminated in part via the kidneys, they each have drug-specific and indication-specific recommendations for dose adjustments.[16,17] These adjustments are largely based on mathematical and pharmacokinetic extrapolations, not in human subjects. Therefore, while they should be followed, consideration of the origin of these recommendations is necessary. Furthermore, should monitoring be desired due to uncertainty of renal/liver impairment, good luck. Most assays used in the clinical trials are not routinely available, nor are recommendations of dose adjustments to yield more desirable lab values. As the guidelines suggest, in pharmacokinetic uncertainty, just use warfarin.[10]
Table 2 – DOAC Dosing
DOAC
Normal starting dose
Apixaban
10 mg PO BID for 7 days5 mg PO BID
Rivaroxaban
15 mg PO BID for 21 days20 mg PO daily
Dabigatran
Parenteral anticoagulation for 5 days150 mg PO BID
Direct thrombin inhibitor
Dabigatran, which is actually a prodrug in the form of dabigatran etexilate, is the only oral direct thrombin inhibitor. It’s parenteral cousins are argatroban and bivalirudin. Similar to the DXa agents, dabigatran can bind to both free and clot bound thrombin thereby inhibiting both the initiation phase, but also thrombin induced fibrin crosslinking (inhibits XI, and XIII activation), platelet activation and the positive feedback by thrombin itself (inhibiting activation of V and VIII, needed for tenase, and prothrombinase complexes). However, this does also mean there is less thrombin-TM activation of aPC/aPS as well as reduced induction of vascular endothelial growth factor (VEGF).[6] These effects may partially account for the higher incidences of bleeding and not as robust efficacy compared to other DOAC agents.
Within the class of direct thrombin inhibitors, including the parenteral agents, there are important differences with regards to the thrombin binding sites.[18] Thrombin itself has three relevant binding sites: active enzyme site, exosite 1 and exosite 2. The active enzyme site is where AT normally binds to thrombin. Exosite 1 is known as the fibrin binding site, and exosite 2 is the heparin binding side. Bivalirudin binds to two separate locations of thrombin: exosite 1 and the active binding site. Whereas argatroban and dabigatran bind to a single site on thrombin known as the active enzyme site. This difference in the occupation of the fibrin binding site theoretically leads to the ability of argatroban/dabigatran to bind to thrombin that is already bound to fibrin (via exosite 1) and still exert the drugs inhibitory effects. While the data does not exist to support this theory, it is nevertheless interesting to consider.
Similar to the DXa agents, dabigatran is rapidly bioavailable via oral administration. However, the guidelines still recommend a bridge with a parenteral anticoagulant, similar to edoxaban. [10] While dose adjustments for renal/hepatic impairments share similarities with the DXa agents, 80% of absorbed dabigatran is excreted unchanged by the kidneys. So it would come as no surprise that dabigatran should be adjusted in patients with severe renal impairment (creatinine clearance 15 to 30 mL/min).
While touted as a low risk drug for drug-drug interactions given it’s lack of CYP activity, since it is a p-glycoprotein substrate, numerous inhibitors/inducers/competitors of this system can affect the plasma concentrations of dabigatran. While bleeding is the primary adverse event of concer, dabigatran is also notorious for its dyspepsia which can be so severe that it leads to patients unable to tolerate therapy.
Vitamin K Epoxide Reductase Inhibitor
Referring to warfarin as a vitamin K antagonist is an imprecise term. Primarily because warfarin does not inhibit vitamin K per se. Also, warfarin does not inhibit coagulation factors- it prevents their activation. What warfarin does, is inhibits vitamin K epoxide reductase (VKOR) which reduces oxidised vitamin K back to its reduced form and thus able to gamma-carboxylate the coagulation factors II, VII, IX, X, protein C and protein S. So in essence, warfarin stops the physiologic recycling of spent (oxidised) vitamin K, not it’s action. This makes sense when you consider when we administer exogenous vitamin K, or the patient eats atypical quantities of vitamin K containing foods, this active vitamin K can exert its activation function.
The therapeutic activity of warfarin relies on the ultimate inhibition of thrombin. However, this effect takes about 4-5 days to reach a clinically effective anticoagulated state. Before then, warfarin sequentially prevents the activation of (in order) factor VII, protein C, protein S, factor IX, X, then II. Therefore, in the initial phases of warfarin therapy, there may be an imbalance leaning towards a procoagulant effect (given the inability to activate protein C/S). Therefore, for certain indications where immediate anticoagulation is desired, such as DVT/PE, warfarin should be started with a parenteral anticoagulant and “bridged.” [10]
Further comparing the actions of warfarin to the DOAC agents, warfarin is considered a non-direct anticoagulant both in mechanism (as above), and that it only affects free coagulant factors. Therefore, factor VII in TF-VII complex, X in Va-Xa complex, IXa-VIIIa and bound thrombin are all unaffected. Therefore, while warfarin prevents new clot formation, it does not promote lysis of existing clots.
Warfarin exists as a racemic mixture where the S-warfarin is the more active component. The differences between R and S-warfarin continue with regards to metabolism and thus drug-interactions. S-warfarin is primarily metabolized via CYP-2C9, where R-warfarin is metabolized by CYP-3A4, 1A1 and 1A2. Warfarin is also extensively bound to albumin (greater than 90%). The plethora of drug-drug, drug-food and pharmacogenomic effects are worthy of their own chapter.
Warfarin is quite easily monitored by the international normalized ratio (INR) of the prothrombin time (PT). The PT, and thus the INR, are highly driven by the activity of factor VII, which allows for the monitoring of the therapeutic effects of warfarin. It’s important to consider that a prolonged INR reflects the relative concentration of factor VIIa, and not necessarily the state of coagulation. A more appropriate test to measure coagulation would be a thromboelastography. Nevertheless, the INR is used for warfarin efficacy monitoring and various target ranges exist and are indication specific. In general, for DVT/PE a common target range is between 2 – 3.[10]
Bleeding is the most common adverse event. However, the incidence of intracranial hemorrhages is relatively higher with warfarin compared to the DOAC agents. [10] These findings are supported in the most recent post-marketing analyses of the available oral anticoagulants. [15] However, warfarin can also have adverse events related to fetal development (it is a teratogen), may cause skin necrosis, and skin discoloration.
Bottom line:
The modern understanding of coagulation is the initiation, amplification and propagation phase model.
For DVT/PE management in stable patients, DOACs are generally first line, with apixaban nudging into the lead for preference.
Warfarin still has a place in therapy, particularly when drug discount cards run out.
Expanded thoughts
Rivaroxaban daily vs bid dosing – peak/trough effect of daily dosing may lead to periods of no anticoagulation
Pharmacogenomics of warfarin- real world application or still too early to have solid actionable knowledge
Reversal. Oh reversal.
54 year old female being treated for DVT outpatient, comes to the ED with complaints of SOB. She’s tachycardic (110), blood pressure of 105/80 mmHg, afebrile, 100% O2 on room air. No other complaints. Patient admits she has not been taking apixaban because she didn’t think it was working. What are the immediate anticoagulation strategies for this patient?
Heparin vs LMWH vs Fondaparinux
While the DXa agents are rapidly therapeutic after oral dosing, they lack the ability to titrate and closely monitor therapeutic effects. Furthermore, they are extremely challenging/expensive to reverse, should it be necessary for surgery or due to hemorrhaging. In such cases where patients are experiencing a hemodynamically significant PE, intravenous anticoagulation is desired.
Unfractionated heparin
Unfractionated heparin is a cocktail of polysaccharides of different lengths, function and activity. As discussed previously, heparin has no intrinsic anticoagulant effect and requires a cofactor to exert its therapeutic effects.[16] Heparin requires AT to inhibit factors IIa, IXa, Xa, and XIIa. However, heparin-AT’s therapeutic actions are largely a result of the inhibition of factors Xa and IIa. There are interesting differences in the action of heparin-AT on Xa and IIa that help illustrate the action and rationale for the low-molecular weight heparins.
As classically focused on in pharmacy curricula, heparin molecules comprising 18 or more saccharide units (about a third of the total heparin molecules) are the only components of heparin which are sufficiently long enough to bridge antithrombin to thrombin.[16] The inactivation of factor Xa, however, does not require this specific heparin saccharide length. In fact, heparin molecules as short as five saccharide units are able to inhibit Xa effectively. After observing this effect, the development of the low-molecular weight heparins took hold and also helps illustrate their ability to inactivate Xa, but not IIa.
Heparin is dosed in units, and according to the guidelines, both weight based and fixed dose regimens may be used.[10] It is worth noting that the data supporting this recommendation was published prior to 2009. There are two significant items to consider with that. The first, is that the obesity epidemic in the USA has only gotten worse since then, and weight based doses require pharmacokinetic adjustment. The second is that in 2009, the USP unit and the international unit were unified, with the new USP unit being 10% less potent than the old one.[16] Thus, data of fixed doses prior to 2009, may theoretically be higher potency than the equivalent USP unit used today.
After heparin initiation, it may be monitored and adjusted based on the aPTT, or an appropriately calibrated anti-Xa assay.[16] The short half-life and rapid onset of action afford relatively easy titration when administered IV. It should be noted that the half-life of heparin is dose dependent, with larger doses leading to longer half-lives (normal ~1.5 hours, up to 5 hours with 800 units/kg).[16] Platelets should also be followed, given the risk of heparin induced thrombocytopenia (HIT). In addition to HIT, heparin can increase the risk of hemorrhage (obviously), and has been associated with osteoporosis with extended use.
Low-molecular weight heparins (LMWH)
As the name would suggest, LMWH are similar to heparin molecules, however are typically less than 18 saccharide units in length (approximately 50% of a given dose). Consistent with heparin, LMWHs are intrinsically devoid of anticoagulant activity and require AT to exert their effects. As a result of the shorter saccharide length, LMWHs primarily complex with AT to inactivate free-factor Xa (not bound), where very few LMWH molecules are sufficiently long to complex AT with free IIa. As described above with heparin the Xa to IIa inactivation ratio is ~1:1, but with LMWH it ranges from 4:1 to 2:1.[10,16]
Fondaparinux is sometimes considered a LMWH, and other times considered an indirect-Xa inhibitor. This nomenclature variation exists since fondaparinux is the five saccharide unit of heparin that binds to AT. Therefore, its relatively short length only allows AT-fondaparinux complex to inactivate Xa since it is too short to bridge AT to IIa. So while it doesn’t possess the IIa effects of the other LMWH and heparin (ie indirect-Xa effect only), it is still fundamentally a heparin. So perhaps, ultra-low molecular weight heparin is a better name? For the sake simplicity, for the remainder of this section fondaparinux will be considered a LMWH.
These pharmacologic differences between heparin and the LMWH afford agents like enoxaparin, dalteparin, and fondaparinux more predictable anticoagulant dose-response and improved pharmacokinetic behavior. Thus, these agents are able to be administered via subcutaneous injections (rather than continuous IV infusion) and do not generally require monitoring. If monitoring of the therapeutic actions is needed, appropriately a calibrated anti-Xa monitoring can be followed. These agents are eliminated renally and must be adjusted accordingly. Fondaparinux should not be used in patients with a eGFR less than 30 mL/min. Similarly, the structural differences yield a lower incidence of HIT. Some say the risk of HIT with fondaparinux is close to nil, however, since it is still fundamentally a heparin based saccharide, the risk is non-zero.[19]
Agent selection
While the LMWH agents are the easiest, more reliable and potentially safer parenteral anticoagulant to administer to patients with DVT/PE in the ED who are not candidates for oral therapy, there is another consideration to make. That is, whether there is a need for fibrinolysis. Should fibrinolysis be indicated, the prior administration of LMWHs are a relative contraindication given the difficulty in reversing the anticoagulant effect should hemorrhage occur.[20, 21] Preferentially using heparin in the ED in the hyperacute phase of DVT/PE preserves the option for fibrinolysis, since the pharmacokinetics (as described above) allow for rapid clearance of heparin, or the administration of protamine sulfate in appropriate amounts. Additionally, the relative easy on/off of heparin allows for it to be started prior to definitive imaging necessary that may be necessary for PE diagnosis.[22] Thus, despide the guideline suggestions, heparin is commonly used in the ED during DVT/PE workup, and the decision to intensify to fibrinolytics, or conversely, transition to DOAC is deferred.[10]
Bottom line
While LMWHs are preferred in the guidelines, heparin is often started in the ED which leaves a backdoor open to fibrinolytics.
Otherwise, if a patient is healthy enough to receive a LMWH, they’re likely also able to simply be started on a DOAC.
Extended anticoagulants
Heparin/LMWH/Fonda resistance with AT deficiency
Patients with history of HIT – starting argatroban/bivalirudin in the ED
Protamine, the best use of salmon sperm (other than making more salmon)
While in the ED, the 54 year old female here for PE work up gets acutely hypoxic, hypotensive and more tachycardic. She is unstable to leave to get a CTA, and a bedside ultrasound shows RV strain and septal bowing. Can she get fibrinolysis even though she’s on heparin?
rtPA, TNKase
In extreme cases, PE can cause hemodynamic instability necessitating aggressive care given its high mortality. Fibrinolytic agents can play a role in these ‘massive’ PEs.[10, 23-25] While many references name these agents the ‘thrombolytics,’ this is an imprecise term since they are not lysing thrombin bonds, but rather, fibrin crosslinks. Therefore, the more appropriate terminology is fibrinolytic.
Fibrinolytic therapy for PE may rapidly establish venous patency, reduces elevated pulmonary arterial pressure and relieves right ventricular strain when administered intravenously, or catheter-directed administration.[17] This potential benefit must be balanced with the high risk of hemorrhage associated with these agents. Therefore, contraindications must be considered and identified prior to administration. Additionally, if fibrinolytics are to be administered, heparin should be stopped.
The two agents available for fibrinolytic use in the USA are rtPA, and TNKase. rtPA is a recombinant form of the naturally occuring tPA within the coagulation system and they share a mechanism of action. rtPA can be thought of as a prodrug of sorts since it itself is devoid of fibrinolytic activity, but instead activates plasminogen.[26] This first phase of rtPA activity, plasminogen activation is relatively slow. The second phase accelerates fibrin degradation after the activation of plasmin. This action degrades the fibrin mesh of platelet plugs allowing for dissolution of the clot.
Let’s take a tangent and consider of this second phase of fibrinolysis further. This activated plasmin from tPA cleaves fibrin into fibrin degradation products, and exposes additional binding sites for plasmin, namely C-terminal lysine residues.[26] If you recall back to the discussion of the process coagulation, these lysine residues are cleaved by TAFI as a clot ages, rendering fibrin resistant to lysis. So tPA can preferentially lyse the newer exterior of fibrin based clots, however, their aged cores (considering they may be emboli from a DVT) may be already resistant. On the flip side, if a patient is taking an agent to reduce the activity of thrombin, and thus reduce the TAFI activity, a clots susceptibility to fibrinolysis may be enhanced. Unfortunately, these effects are not specific to the affecting clot and my impact other tissues, leading to hemorrhages at other sites. But it’s food for thought, and targets for future drug development.
Table – 3 – Fibrinolysis Contraindications
Active internal bleeding History of recent stroke Recent (within 3 months intracranial or intraspinal surgery or serious head trauma Presence of intracranial conditions that may increase the risk of bleeding(eg, intracranial neoplasm, arteriovenous malformation, aneurysm) Known bleeding diathesis (including pharmacologic) Severe uncontrolled hypertension
The dose of rtPA for PE is 100 mg IV infused over 2 hours. Should the patient loose pulses and suffer cardiac arrest, rtPA can be administered as 50mg IV bolus over 2 minutes which can be repeated after 15 minutes if return of spontaneous circulation is not achieved.
Tenecteplase (TNKase) is another recombinant variant of tPA. Although TNKase and rtPA demonstrate similar clinical performance (extrapolated from acute myocardial infarction data), TNKase has some theoretical benefits.[27,28] TNKase is thought to be highly fibrin specific, meaning it does not activate feedback components such as PAI-1. The administration of TNKase is simplified compared to rtPA since TNKase can be administered via IV bolus (without infusion). However, either agent is acceptable to administer. [10]
Bottom line:
Fibrinolysis can be sought for massive PE
The differences between rtPA and TNKase are small and may not be clinically relevant
In the case of a cardiac arrest, early and rapid administration of rtPA can be used
Expanded fibrinolysis:
Fibrinolysis for submassive PE is controversial – expert guidance needed
References
Mann KG. Thrombin formation. Chest 2003 124: 4S-10S.
Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol 2006; 26: 41-48.
Roberts HR, Hoffman M, Monroe DM. A cell-based model of thrombin generation.Semin Thromb Haemost 2006; 32 (Suppl 1): 32-38.
Dahlback B. Blood coagulation. Lancet 2000; 355: 1627-1632.
Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359:938–949
Turpie AG, Esmon C. Venous and arterial thrombosis-pathogenesis and the rationale for anticoagulation. Thromb Haemost. 2011 Apr;105(4):586-96
De Caterina R, et al. General mechanisms of coagulation and targets of anticoagulants (Section 1): Position paper of the ESC working group on thrombosis- Task force on anticoagulants in heart disease. Thromb Haemost. 2011 Apr;105(4):569-579
Meltzer ME, Doggen CJ, de Groot PG, et al. The impact of the fibrinolytic system on the risk of venous and arterial thrombosis. Semin Thromb Haemost 2009; 35: 468-477
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-352.
Depasse F, Busson J, Mnich J, et al. Effect of BAY 59-7939 − a novel, oral, direct Factor Xa inhibitor − on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005; 3 (Suppl. 1): Abstract P1104
Jiang X, Crain EJ, Luettgen JM, et al. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb Haemost 2009; 101: 780–782.
Joo SS, Won TJ, Kim JS, et al. Inhibition of coagulation activation and inflammation by a novel Factor Xa inhibitor synthesized from the earthworm Eisenia andrei. Biol Pharm Bull 2009; 32: 253–258
Walenga JM, Jeske WP, Hoppensteadt D, et al. Factor Xa inhibitors: today and beyond. Curr Opin Investig Drugs 2003; 4: 272–281
Lip GYH, Keshishian A, Li X, et al. Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients. Stroke. 2018 Dec;49(12):2933-2944
Hogg K, Weitz JI. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2189§ionid=170271546. Accessed January 05, 2019.
Lee CJ, Ansell EJ. Direct thrombin inhibitors. Br J Clin Pharmacol. 2011 Oct; 72(4): 581–592.
Blackmer AB, Oertel MD, Valgus JM. Fondaparinux and the management of heparin-induced thrombocytopenia: The journey continues. Ann Pharmacother 2009;43:1636–1646.
Kline Ja, Runyon MS. Pulmonary embolism and deep vein thrombosis. In: Rosen’s Emergency Medicine: Concepts and Clinical Practice, 9th Edition. Elsevier
Jaff MR et al. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement form the American Heart Association. Circulation 2011. PMID: 21422387
Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999 Apr 24;353(9162):1386-9
Marshall PS, Matthews KS, Siegel MD. Diagnosis and Management of Life-Threatening Pulmonary Embolism. J Intensive Care Med. 2011 May 23. [Epub ahead of print] PubMed PMID: 21606060.
Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the fibrinolytic system.J Thromb Haemost. 2009 Jan;7(1):4-13
A comparison of reteplase with alteplase for acute myocardial infarction. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators. N Engl J Med 1997;337:1118–1123
Van De Werf F, Adgey J, Ardissino D, et al. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: The ASSENT-2 double-blind randomised trial. Lancet 1999;354:716–722.
EM PharmD 