Heparin inhibits which factors

Various protocols differ slightly. The below protocol isn't recommended for daily use. Rather, it's merely intended as a rough guide to the significance of various PTT and Xa levels. Other causes include pregnancy, malignancy, liver disease, and renal disease Kennedy et al. The PTT makes it appear that the patient isn't therapeutically anticoagulated, but in fact the patient is experiencing clinical anticoagulation!

This is potentially dangerous, because persistent up-titration of heparin in attempts to increase the PTT could actually lead to iatrogenic hemorrhage due to excessively high heparin concentration. Factor VIII and fibrinogen levels may also be measured directly, to provide some indirect support to the diagnosis although these tests often take a while to return. Management: Pseudo-heparin resistance is fundamentally a monitoring failure.

Management involves avoiding the use of PTT to titrate the heparin infusion, for example: 1 If anti-Xa monitoring is available, this should be used to titrate the heparin infusion. As many hospitals are shifting towards the routine use of anti-Xa levels for all monitoring of heparin infusions, the entity of pseudo-heparin resistance may disappear.

Unfortunately, a similar phenomenon can occur with direct thrombin inhibitors — which may be even harder to diagnose more on this below. This usually results from systemic inflammation. Increased heparin clearance e.

Titrating heparin infusion to target an Xa level is generally superior to targeting PTT in the context of heparin resistance Levine If Xa levels aren't available, an alternative strategy might be to titrate heparin based on thromboelastography. This avoids the entire issue of heparin resistance. There is no high-quality evidence regarding optimal management here. Transition to a direct thrombin inhibitor might be superior, for the following reasons: 1 Evidentiary support for the use of direct thrombin inhibitors in the ICU is greater than for the use of antithrombin-III concentrates.

For example, many studies describe the use of argatroban infusions among ICU patients, including specifically patients with heparin resistance Bachler et al. Alternatively, the use of antithrombin-III concentrate supplementation seems to be limited to case studies. As such, the safety of antithrombin-III is difficult to evaluate. The two drugs interact in a synergistic fashion, so they must be combined with considerable caution and sophistication.

In contrast, transitioning to argatroban monotherapy is straightforward and easily achieved with standard ICU protocols. Administration of antithrombin-III won't fully resolve this situation. Thus, continuing heparin may theoretically perpetuate an iatrogenic cycle of heparin use, antithrombin-III reduction, and antithrombin-III repletion. Thus, enoxaparin is a preferred agent — especially in patients with unusual weight or pharmacokinetics.

However, enoxaparin doses may be roughly correlated into dalteparin doses as follows below. Dosing with tinzaparin and nadroparin is less clear, as different formulations may have variable amounts of anti-Xa activity.

Dalteparin is typically measured in terms of anti-Xa units, rather than in milligrams. For example, units of dalteparin is roughly equivalent to 50 mg of enoxaparin. However, the ratio of anti-Xa vs. Recently, some authors have suggested dosing enoxaparin in a more finely graded fashion as shown below for patients with borderline renal function Shaikh This dosing scheme has yet to gain widespread acceptance, but it might be a consideration in very select situations with close monitoring of anti-Xa levels.

Numerous recent studies seem to be converging on a dose of 0. This dose has the following advantages: i Twice-daily dosing avoids sub-therapeutic trough levels it's possible that the trough levels are the primary determinant of efficacy. Correcting the dose for weight increases the likelihood of obtaining target drug levels. Using a single formula is simpler to apply and more closely mirrors the pharmacokinetics of enoxaparin which is linear.

For patients with very unusual weight or borderline renal function, consider obtaining an anti-Xa level to monitor the heparin effect. This is typically done after the third dose, but could probably be done sooner unless renal function is really awful, the trough heparin levels will be low and won't contribute substantially to the following peak level.

For twice-daily prophylactic enoxaparin, the target anti-Xa level is 0. It is provided in relatively fixed doses, usually q24hrs. It works via enhancing anti-thrombin's inhibition of factor Xa. Use of fondaparinux can help avoid unnecessary workup and empiric therapy for possible HIT.

Use of 2. Disadvantages of fondaparinux compared to LMWH Fondaparinux has a very long half-life at hours. This can be problematic if the patient needs an urgent procedure or develops bleeding. Thus, full therapeutic anticoagulation with fondaparinux is not generally very useful in the ICU. Fondaparinux may be more expensive. Possible procedure in near-term.

Weight kg: 7. Medscape monograph on fondaparinux. Monitoring generally isn't necessary, but may be indicated in specific situations e. An anti-Xa level may be obtained three hours after a dose of fondaparinux.

However, a specific calibration curve should be used for fondaparinux — if doubt exists about which test and cutoff values to use, discuss with the laboratory. Many hospitals will lack a fondaparinux-calibrated anti-Xa level assay. This has numerous physiologic effects as shown above e.

They are active against both fluid-phase and clot-bound thrombin unlike heparin, which acts only on fluid-phase thrombin. PTT prolongation is generally used to titrate the dose of a direct thrombin inhibitor. INR prolongation is problematic, as this can make it difficult to transition to warfarin.

Assays for clotting factors and fibrinogen may be falsely prolonged causing the lab to register falsely low values. They are not dependent on anti-thrombin III levels Pharmacokinetics are generally more predictable than those of heparin especially bivalirudin, which doesn't bind to plasma proteins. Bivalirudin's short half-life 25 minutes may make it easier to stop, compared to a heparin infusion with half-life close to 45 minutes.

Lack of any reversal agent. This could be problematic for patients with hepatic dysfunction on argatroban — wherein the half-life may be considerable. Bivalirudin has traditionally been used more in the cardiac catheterization laboratory. Properties of the two agents are compared here: direct thrombin inhibitor pseudo-resistance True resistance doesn't seem to occur with direct thrombin inhibitors because unlike heparin, their pharmacology is more predictable and their efficacy doesn't depend on anti-thrombin III.

Pseudo-resistance can occur with both argatroban and bivalirudin Kennedy et al. This is essentially the same as pseudo-heparin resistance discussed above. Since its first description by Rappaport in 35 the aPTT has served many purposes, among which its use for quantifying the effect of heparins. Its utility for that purpose is widely doubted, however 1 , We can add to this discussion that in the above mentioned experiment with 12 human volunteers 22 we injected four different heparins in 12 subjects at 9 time points between 0.

This clearly shows the insufficiency of the aPTT. Often the aXa-activity is suggested as an alternative [e. This is not a useful suggestion, however. In the first place because it co-estimates a lot of irrelevant molecules, i. In the second place because the measurement of a concentration cannot replace the measurement of the pharmacological effect. We will see below that he same concentration of heparin in different plasmas will indeed have a very different inhibitory result.

The common practice that LMWH administration is given at standard doses is based on clinical trials that show that in this way lung-embolism can be prevented and bleeding is not increased to an unacceptable degree [for references see 18 ]. This does not answer the question whether results would improve when doses would be personalized.

It will be clear from the above that this question cannot be answered by measuring aPTT nor by estimating anti-factor Xa activity but the ETP serves its purpose here. In the abovementioned study 22 we also determined the variability of the over-all anticoagulant response between the 12 healthy volunteers Figure 7 and Table 1 , last column.

It appeared that there was a very large difference in anticoagulated response. Figure 7. Inhibition profiles of a high left and a low right responder. Legend as in Figure 5. In the highest responder an about two times higher anticoagulant effect was obtained as in the lowest responder Figure 7. The variability was only partly explained by the variation in body-weight. We also measured the inhibitory effect of 0. Bloemen et al. An as yet unpublished study [ Table 2 , cited by courtesy of Drs.

Selmeszi Debrecen and R. Table 2. The variation of the inhibitory effect of heparins in different plasmas. This large variation in the individual heparin response shows that on a standard dose of any heparin many patients must be over- or under-treated.

That there is nevertheless a well-defined beneficial effect on thrombosis -prevention shows that there must be a significant latitude between the risk of re- thrombosis or bleeding and the actual manifestation of these complications. This is nothing new: mild hemophilia can go unnoticed until middle age and congenital antithrombin deficiency will not show up until in the late teens.

In view of the large variability of response, we surmise that personalization of heparin dosage could considerably reduce the risks of heparin treatment, that of re-thrombosis as well as that of bleeding. The question is whether current practice can be significantly ameliorated by personalized dosage.

We surmise it would, but the cost-benefit relation remains an open question. In conclusion: If one wants to control heparin pharmacokinetics, use aIIa activity, if one wants to know about pharmacodynamics, use thrombin generation. Heparin activities are still expressed in aIIa- and aXa-units relative to a standard, often using clotting times aPTT to establish the equivalence. When Howell discovered heparin around this was the only possible modus operandi but in this century, it is hopelessly outdated.

Therefore, the aPTT—as prescribed by the pharmacopeias, does not detect adulterated heparins, with disastrous consequences 3 , There is a simple and unequivocal manner to determine heparin activity in terms of standard independent, SI-based units A SIU-Xa is defined analogously.

We described a very simple end-point assay to determine these decay constants Because the assay uses a solution of purified antithrombin it will not co-estimate HCII-dependent contaminants. Such contaminants can be quantified by a similar test using heparin cofactor II instead of antithrombin.

The concentration of high affinity moieties HA5 can be determined by fluorescence titration As a consequence, of any heparin preparation one can determine the activity in standard independent units per mole of high affinity material. If one, for convenience, wants to use a standard, than any heparin preparation with a chain-length distribution of between 30 and 45 sugar units — kD can be used, because in the range the inhibitory power is for all practical purposes constant per high-affinity molecule Figure 4.

The ideal heparin is the lowest molecular weight heparin that has a good inhibitory potency, i. The longer the heparin the shorter the half life time and the lower the bioavailability. The best heparin therefore presumably has MW-distribution of 10—20 kD. The pure Choay domain, i. Present day synthetic efforts still focus on aXa-activity 41 — 43 and attain a chain length of 12 sugar residues. It is clear, in the light of the above that a pure Choay-domain would be over fold more effective than molecules with anti-factor Xa activity only.

We hope that this paper might lead to rounding up experts in the field in order to start and perform a collaborative study that proves the suitability of ETP for this purpose. HH wrote the first draft. SB and RA commented on it and the final text is the result of several amelioration loops.

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