DVT / PE

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.

Table 1 – Anticoagulant Classes

ClassAgents
Direct oral anticoagulant (DOAC) – Xa inhibitorsApixaban
Rivaroxaban
Edoxaban
DOAC – IIa inhibitorsDabigatran
Direct Thrombin InhibitorsArgatroban
Bivalirudin
Lepirudin
Vitamin K Epoxide Reductase InhibitorWarfarin
Indirect anticoagulants – Unfractionated heparinHeparin
Indirect anticoagulants – Low molecular weight heparinDalteparin
Enoxaparin
Indirect Xa inhibitorFondaparinux

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

DOACNormal starting dose
Apixaban10 mg PO BID for 7 days5 mg PO BID
Rivaroxaban15 mg PO BID for 21 days20 mg PO daily
DabigatranParenteral 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

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  3. Roberts HR, Hoffman M, Monroe DM. A cell-based model of thrombin generation.Semin Thromb Haemost 2006; 32 (Suppl 1): 32-38.
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  7. 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
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  13. 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
  14. Walenga JM, Jeske WP, Hoppensteadt D, et al. Factor Xa inhibitors: today and beyond. Curr Opin Investig Drugs 2003; 4: 272–281
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  17. Witt DM, Clark NP, Vazquez SR. Venous Thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146057236. Accessed January 06, 2019
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  19. Blackmer  AB, Oertel  MD, Valgus JM. Fondaparinux and the management of heparin-induced thrombocytopenia: The journey continues. Ann Pharmacother 2009;43:1636–1646.
  20. Alteplase. In; Lexi-comp online. Available at http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6310 Accessed January 06, 2019
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