Welcome back to the tasty morsels of critical care podcast.
This time round we’re going to look at heparin. I’ll try and keep it focused on the old fashioned high molecular weight heparin and steer clear of the new fangled low molecular weight versions. I feel like we use this drug a lot and so a keen understranding of it seems crucial. Now this will be a little unit dependent. We do not have citrate for our CRRT so we use a lot of heparin to keep the circuit running. We also look after a lot of post cardiac surgery patients who need heparin for their valves etc…. I also work in an ECMO centre and we use a lot of heparin to keep those circuits running. I feel like decisions about heparin take up a disproportionate part of my day.
Firstly some basics on what heparin is. It consists of a bunch of polymerised disaccharide, in essence a sort of starch. Typically it’s a mix of these polymers with the weight varying 3-30kda. You can fractionate it and pick out only the low weight ones – hence low molecular weight heparin. The variety of weights mean we dose it in terms of units rather than eg mg. Deranged physiology quotes the definition of a heparin unit as “the quantity required to keep 1ml of cats blood liquid for 24 hrs at 0 degrees Celsius.” As an examiner I’m sure there’s zero marks available for such knowledge but it would definitely bring a smile to my face. You can tell I’m more of a dog person…
In my extensive personal notes on heparin metabolism i have written “complicated”. The few short notes that follow it suggest metabolism varies with doses in the range of 25unit/kg = 30 mins and doses in the range 100 unit/kg = 60mins. The rapid metabolism at low doses seems to be due to the heparin sticking to macrophages that depolymerise it. This pathway gets saturated at higher doses and another (unknown) pathway takes over.
How does it work to keep the blood thin and less clotty? Like all things in clotting it’s never straightforward and seems to involve one molecule triggering another one on a seemingly unending and obscurely named pathway. In heparin’s case it works primarily by increasing activity of antithrombin III by a factor of 1000 or so. Being against thrombin means that it inhibits activity of the aforementioned thrombin. In normal circumstances thrombin spends its time converting fibrinogen to fibrin – the gluey bit that holds clots together. Antithrombin III comes along and says to thrombin – “down with this sort of thing” etc and fibrinogen stops getting converted to fibrin and there’s less clots. Simples
How do we measure its effect? This is really much trickier than we’d like. A basic and rapid test would be an ACT or active clotting time, typically used in cardiac theatre to determine whether or not the patient is anticoagulated enough to go on bypass. The more common test in ICU is the APTT, the activated partial thormboplastin time. The APTT test involves firstly anticoagulating the blood completely in the sample bottle then adding bits to activate the intrinsic pathway and using an optical sensor to see how long it takes to clot. It is very far from being a “heparin level” and it is unfortunately confounded by lots of other clotty type problems we see in ICU (like low fibrinogen levels).
As a result we sometimes reach for a further test called an anti-Xa. Factor Xa acts a step before thrombin and is inhibited by heparins to various degrees depending on their molecular weights. But conveniently for us the anti-xa level is inversely correlated to heparin level. Like all things in haematoology it seems the name is quite confusing. There is no such molecule called “anti-Xa” that is being measured but instead what is actually being measured is the concentration of factor Xa which in turn is inversely correlated to the heparin level. We use the test as a sort of reference or correlation number for our heparin. For example let’s say we’re getting persistently low aPTT levels – is this because there’s some other part of the coagulation cascade that has gone wonky or are we just not giving enough heparin? Pro-tip – 95% of the time you’re just not giving enough heparin.
There is such a thing called heparin resistance. Somewhat loosely defined as doses >35000/day without appropriate anticoagulation. This can happen in ICU patients due to a lack of ATIII which can be depleted in ICU cohorts. Remember heparins whole thing s potentiating ATIII but if there’s none around it won’t work. There does seem to be a degree of controversy over the definition and clinical relevance as it seems that simply giving more heparin is often the answer.
I’ll very briefly mention some complications of heparin, most obviously bleeding which is dealt with by stopping the heparin and occasionally using protamine. Second to this is probably HIT which, despite its rarity, is very important and eminently testable. But that is for the next post.
Reading
Levy, J. H. & Connors, J. M. Heparin Resistance — Clinical Perspectives and Management Strategies. N. Engl. J. Med. 385, 826–832 (2021).
Oudemans-van Straaten, H.M., Kellum, J.A. & Bellomo, R. Clinical review: Anticoagulation for continuous renal replacement therapy – heparin or citrate?. Crit Care 15, 202 (2011)