This drug is a staple of ICU anticoagulation, and one would do well to become very familiar with its properties.

Chemical properties and molecular structure


Heparin is a heterogenous mixture of mucopolysaccharides, termed glycosaminoglycans.

It is essentially a polymerised disaccharide, a starch.

Each repeated disaccharide is variably sulfated. Here's a picture I ripped off from Wikipedia:

unfractionated hepatin molecule

Because the disaccharide polymers are of varying lengths, heparin has an average molecular weight of 3 to 30 kDa. Unless it is fractionated, in which case you can control to only have the low molecular weight version.

Its polymer length is really very very random, mainly because the heparin in your hospital is derived from bovine lung or porcine gut, and those animals are largely disinterested in quality control of industrial chemistry. The first heparin was in fact derived from canine liver cells in 1916, by a second-year medical student.

What the hell is a "unit" of heparin?


One unit of heparin is the quantity required to keep 1ml of cats blood liquid for 24 hrs at 0 degrees Celsius. This unusually animal-unfriendly definition comes from one WH Howell, who left some cats blood overnight in the refrigerator. It didn't clot - it half-clotted- but it remained liquid all the same. These days the International Heparin Standard uses sheep plasma, presumably because sheep are easier to capture and exsanguinate.

Chemical Relatives

I suppose that would be the fractionated heparins (eg. Enoxaparin).

Functional relatives are all the other indirect thrombin inhibitors among which is Fondaparinux

Administration and absorption


It is typically given intravenously, or subcutaneously (wherefrom it gradually dissociates).

    • The subcutaneous route of administration takes 1-2 hrs to reach peak effect.

Thereafter, its volume of distribution is 40-70ml/kg, essentially confined to the intravascular volume.

It does not penetrate the placenta, which makes it especially useful in pregnancy.

What if I drank it?


Oral heparin has very poor bioavailability. It is too large a molecule, and its charge is too negative to be absorbed easily.  For this reason it is distributed almost solely in the circulating volume. Brave men have tried cooking with heparin to make it more orally bioavailable. Additionally, 45 brave individuals drank 20,000 units of heparin and then allowed their APTT to be tested - turns out it increases by 2.3 seconds on average, which is not much, but which demonstrates that there is some absorption. The study is not available to me, but I would love to hear from a volunteer about what the heparin tasted like.

Metabolism and clearance


There are 2 mechanisms: rapid saturable clearance and slow first-order clearance.

heparin clearance

The half-life depends on the dose.

Half-life of 25 units per Kg = 30 minutes

Half-life of 100 units per Kg = 60 minutes

Half-life of 400 units per Kg = 150 minutes

At lower doses, the half-life is very short (because most of the heparin you infuse binds straight to macrophages and endothelial cells, where it gets depolymerized). This mechanism becomes saturated at higher doses, and elimination becomes slower, with a rate which is related to dose.

Rapid Saturable Zero-Order Clearance:
  • Due to binding to heparin-binding-proteins, macrophages and endothelial cells.
  • Thus bound, heparin becomes useless, and is eventually depolymerized.
  • This is the zero-order linear elimination seen at low doses.
Slow First-Order Clearance:
  •  Renal excretion… maybe? To be honest, it’s probably not renal.  After huge doses, a small amount is excreted in the urine.
  • Currently, MIMS admits that “the metabolic fate of heparin is poorly understood”, but mentions that the reticuloendothelial system may play a role in sequestering and destroying heparin. 

Mechanism of action

Heparin is present in the body in the secretory granules of mast cells. It is also found in numerous animals, including various invertebrates which don't have anything even remotely resembling the human coagulation cascade. Which is weird.
So nobody really knows exactly what its purpose is.
But, in humans…

Heparin enhances the activity of Antithrombin-III by a factor 1000.

It does this by binding to antithrombin III and causing the active site to undergo a conformational change.

heparin binding to antithrombin

In my childish diagram, the flicking away of the Antithrombin-III molecular tail represents the increased availability of the active site.

Thus activated, Antithrombin III inactivates several factors – but most notably, Xa and IIa (Thrombin).

Now we get to an important point.

Inactivation of thrombin depends on heparin molecule length:

18 disaccharide units is the key number (about 5kDa)

Inactivation of Xa is independent of length:  so long as any sort of heparin is bound to it, Antithrombin-III will inactivate Xa.

This underlies the difference in pharmacokinetics of low molecular weight heparin and unfractionated heparin.

effect of heparin polymer length on Xa and thrombin binding

Thus, in summary, unfractionated heparin affects thrombin, whereas low molecular weight heparin only affects Xa.

This also explains why measuring APTT is not going to tell you whether your clexane dose is therapeutic.

coagulation pathways affected by unfractionated heparin and clexane

The unfractionated heparin also affects the activity of Factor 9, but not the activity of Factor 7. Thus, the intrinsic and common pathways are affected, which increases the APTT. The extrinsic pathway is unaffected, and the PT does not rise very much. Because thrombin is unaffected by low molecular weight heparin, the APTT remains essentially unchanged.

Indications for Use

  • Well, its anticoagulation, which is a much larger topic. APTT monitoring is the key issue.
  • In short, heparin is used in DVT prophylaxis, treatment of thrombosis and thromboembolism, in acute coronary syndromes and in maintenance of slow-flowing dialysis circuits.
  • The pharmacological management of DVT in pregnancy has previously rested on unfractionated heparin. The PROTECT study, which compared unfractionated with LMWH, did not find much difference in the rate of DVT (still around 5.6%), but the LMWH group had fewer PEs and there was a trend towards less HITS.


  • If it causes bleeding, it causes you to rethink heparin. This broadly summarizes the contraindications from a practical point of view. Impending threat of invasive procedures is the main contraindication.
  • The only absolute contraindication is a past history of HIT or HITT.


Apart from the stupidly obvious tendency to increase the risk of bleeding in people who are also anticoagulated with some other sort of anticoagulant medications, heparin has few genuine pharmacological interactions:

Effects of heparin are potentiated by Effects of heparin are antagonised by
Hydroxycholoroquine Antihistamines
Probenecid Digoxin
Sodium Valproate Tetracyclines
  Vitamin C

Chronic complications


Heparin-Induced Thrombocytopenia Syndrome (HITS) plus Heparin-Induced Thrombocytopenia and Thrombosis Syndrome (HITTS)

    • Immune-mediated thrombocytopenia well discussed by Franchini in 2005
          • More frequently associated with unfractionated heparin
          • More frequent in the elderly; unheard of in children
          • Cardiac and orthopedic surgery patients are at greater risk
          • Typically occurs 5-10 days after start of heparin
    • Comes in 2 flavours: type 1 and type 2.
HITS Type 1:
  • Mild transient thrombocytopenia, platelet count above 100
  • Totally reversed by heparin cessation
  • Occurs in up to 10% of patents
  • NOT associated with an increased risk of thrombosis
  • Probably not even immune in origin
HITS Type 2:
  • Nasty severe thrombocytopenia, platelet count might drop to nil
  • Occurs in something like 1% of patents
  • Associated with thrombosis in 30% of cases
  • Due to the formation of antibodies to the complex made up of platelet factor 4 (PF4) and heparin; this complex forms on the surface of platelets.
    • When the HIT antibody binds to this complex, it causes platelet activation and aggregation, and so there is a tendency towards clotting (because all the platelets are activates) as well as a simultaneous tendency towards bleeding (as there is a destruction of antibody-coated platelets in the reticuloendothelial system)

Once your patient has HIT, they should still be anticoagulated.

Direct thrombin inhibitors are the treatment of choice.

Other effects of chronic heparin use

  • Osteopenia
    • Heparin for some reason activates osteoclasts, and bone resorption increases.
  • Mineralocorticoid deficiency
    • Heparin appears to antagonize the effects of ACTH
  • Weird side effects
    • Alopecia- who knows how.
    • Elevation of AST and ALT -  who knows why.

Acute Toxicity and Overdose

  • The major acute adverse event is bleeding. Very few people are genuinely allergic to heparin.
  • Skin necrosis can occur at the subcutaneous injection sites due to small vessel thrombosis.

Management of acute toxicity

If one has overdone one's heparinisation, th APTT will rise dramatically, and one mya have some sort of bleeding complications. One may be caught thinking, "I wish I could put the coagulation cascade back together". This can be accomplished with protamine.

REVERSAL OF HEPARINIZATION with protamine sulfate

  • 1mg reverses 100 units
  • No more than 50mg at any one time
  • Its given SLOWLY as an IV infusion

The dangers of protamine

Protamine sulfate is far from benign. It is a foreign, unusual substance- a strongly alkaline polypeptide which binds to strongly acidic heparin irreversibly, and thereby decreases its anticoagulant effect on antithrombin-3. However, in ridiculous doses, protamine itself will act as an anticoagulant.

Among its many adverse effects are the following:

  • Catastrophic hypotension due to vasodilation, which is thankfully brief (only about 3-4 min) - this seems to be the result of systemic histamine release, triggered in some sort of directly-complement-activating way by the circulation heparin-protamine complexes
  • Pulmonary hypertension due to the localised vasoconstrictor activity of thromboxane, activated by an anaphylactoid reaction to protamine
  • Anaphylaxis (it is after all a fish product)

Resistance to heparin therapy

There are situations in which vast quantities of IV heparin fail to increase the APTT in spite of your every effort. One might call this "heparin resistance", or "heparin insensitivity".

There are several reasons one might be resistant to heparin:

  • Increased heparin-binding protein levels (all of them are acute phase reactants)
  • Low antithrombin-III levels (i.e. nothing for heparin to bind)
  • Increased heparin clearance (eg. in liver disease)
  • High Factor VIII levels

UpToDate offers a good article about Antithrombin III deficiency. Either you hereditarily fail to synthesise enough of it, or your liver is so damaged that it cannot produce enough. Or, it has been used up somehow, eg. in the context of DIC, MAHA, or in a bypass circuit. Lastly, it is possible that you are losing it along with other proteins via your leaky nephrotic kidneys.

The management of AT-III deficiency is, predictably, supplementation with AT-III.

If the expensive purified factor is not available, FFP will suffice.

Effective coagulation of the heparin-resistant patient

There are several strategies one can employ. The specific choice relies on what exactly is causing the heparin resistance.

There are some good articles on this. Most of them do not touch upon the routne anticoagulation of some random patient who happens to have escalating doses of heparin; I suppose it is generally assumed that one will continue to escalate the dose until such time as therapetic goals are met. However, there are situations when anticoagulation is critically important, and one such scenario is the cardiopulmonary bypass circuit.

•    Change to low molecular heparin, instead of unfractionated heparin
•    Give  cryoprecipitate  and/or  fresh  frozen  plasma  (if  there  is  confirmed ATIII deficiency )
•    Give antithrombin III concentrate

Or, you could consider using something else, such as a direct thrombin inhibitor (hirudin or argobatran)


A lot of this information comes from “Goodman & Gilman's The Pharmacological Basis of Therapeutics” 11th ed by Brunton et al,and   “Basic & Clinical Pharmacology” 11th ed. By Katzung et al; there is also lot of good stuff in the AHA statement: “Guide to Anticoagulant therapy: Heparin” (Circulation. 2001;103:2994.)

Howell WH. The purification of heparin and its presence in blood. Am J Physiol 1925;11:553-62 - which does not seem to exist online - but is referenced elsewhere:

Hemker HC, Béguin S. Standard and method independent units for heparin anticoagulant activities. Thromb Haemost. 1993 Nov 15;70(5):724-8.

Mousa, Shaker A., et al. "Pharmacokinetics and pharmacodynamics of oral heparin solid dosage form in healthy human subjects." The Journal of Clinical Pharmacology 47.12 (2007): 1508-1520.

Engelberg, Hyman. "Orally ingested heparin is absorbed in, humans." Clinical and Applied Thrombosis/Hemostasis 1.4 (1995): 283-285.

Franchini, Massimo. "Heparin-induced thrombocytopenia: an update."Thrombosis Journal 3.1 (2005): 14.

Anderson, J. A. M., and E. L. Saenko. "Editorial I Heparin resistance." British journal of anaesthesia 88.4 (2002): 467-469.

Young, E., et al. "Heparin binding to plasma proteins, an important mechanism for heparin resistance." Thrombosis and haemostasis 67.6 (1992): 639-643.

Hirsh, J., et al. "Heparin kinetics in venous thrombosis and pulmonary embolism." Circulation 53.4 (1976): 691-695.

Beresford, C. H. "Antithrombin III deficiency." Blood reviews 2.4 (1988): 239-250.

The PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group Dalteparin versus Unfractionated Heparin in Critically Ill Patients N Engl J Med 2011; 364:1305-1314April 7, 2011

Koster, Andreas, et al. "Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation." Journal of cardiothoracic and vascular anesthesia 17.2 (2003): 171-175.

Isil, Canan Tulay, et al. "Management of heparin resistance in an emergency cardiac surgical patient." Indian journal of anaesthesia 56.4 (2012): 430.

Hobbhahn, J., et al. "[Complications caused by protamine. 1: Pharmacology and pathophysiology]." Der Anaesthesist 40.7 (1991): 365-374.

Shapira, N., et al. "Cardiovascular effects of protamine sulfate in man." The Journal of thoracic and cardiovascular surgery 84.4 (1982): 505-514.

Lowenstein, Edward, et al. "Catastrophic pulmonary vasoconstriction associated with protamine reversal of heparin." Anesthesiology 59.5 (1983): 470-472.

Ingles, C. J., et al. "Biosynthesis of protamine during spermatogenesis in salmonoid fish." Biochemical and biophysical research communications 22.6 (1966): 627-634.

Holland, C. L., et al. "Adverse reactions to protamine sulfate following cardiac surgery." Clinical cardiology 7.3 (1984): 157-162.