Introduction

Heparin exists in many species as polysaccharide chains of glucosamine, glucuronic and iduronic acid. These chains are covalently linked to a polypeptide matrix forming a heparin proteoglycan. In mammalian species, including man, it is found in mast cells in a variety of organs, including the liver.

In 1916 McLean reported the isolation of an anticoagulant material from a crude extract of macerated liver leading to the name heparin. Clinical trials date back to the 1930s and 1940s and its widespread use over many years has made physicians very comfortable with its use. However, heparin is probably responsible for more drug induced complications than any other drug in hospital use.

The single most common complication is bleeding, but a far more devastating complication is probably thrombocytopenia, especially when, paradoxically, it is accompanied by thrombosis.

Discussion

One of the early uses of heparin was to anticoagulate blood specimens for laboratory testing such as cell counts. This was soon abandoned, for it became obvious that a reliable platelet count could not be obtained because the platelets would clump.

Clumping can occur in all human blood specimens and is presumably a non-immunologic phenomenon, but may be the mechanism of the very common acute and nonidiosyncratic heparin induced thrombocytopenia (HIT) seen with heparin use.(1) Some studies have reported incidences of 25 to 30% (defined by setting an arbitrary level or percentage decrease in the platelet count). A modest fall, to levels that are not considered thrombocytopenia, is even more common.

The most severe form of heparin induced thrombocytopenia (HIT) is accompanied by thrombosis and is often called heparin induced thrombocytopenia with thrombosis syndrome (HITTS). It is almost certainly immunologically mediated.

Recent studies have begun to elucidate the mechanism which appears to be a complex multistep process.(3) Activated platelets release a highly charged granule protein called platelet factor 4 (PF4) which complexes with the highly negatively charged heparin molecules to form a heparin-PF4 complex. This heparin-PF4 complex serves as a neoantigen which elicits antibody production. As the antibody titer rises, the antibody binds to the heparin-PF4 complexes as well as to similar complexes formed at the vascular endothelial cell surfaces where the PF4 has bound to heparan sulfate, a chemically related material. Thus, a single antibody leads to the formation of antigen-antibody complexes that can both aggregate platelets and damage endothelium, leading to thrombocytopenia and thrombosis.

Clearly, this is not the entire story because the clinical setting strongly influences the incidence of HITTS. Patients with multiple exposures to heparin and underlying vascular disease or vascular intervention are most vulnerable. Cardiothoracic surgery patients who have received heparin for myocardial ischemia treatment, for cardiac catheterization, for cardiopulmonary bypass extracorporeal circulation during surgery and, subsequently, for some reason postoperatively are a particularly high risk group.(4)

Case Report

A 65-year-old man with a history of past myocardial infarction, hypertension, hypercholesterolemia and progressive angina underwent coronary artery bypass graft surgery using heparin anticoagulation during the cardiopulmonary bypass. Postoperatively, his platelet count was noted to be 118,000 per microliter. Mild thrombocytopenia after cardiopulmonary bypass is very commmon due to consumption and dilution and typically recovers spontaneously over a few days. Heparin was avoided postoperatively (which is now common practice). The patient's platelet count rose spontaneously and returned to a normal level of 172,000 on the fifth postoperative day, when he was discharged home clinically well. Eight days later he noted fever, cough and confusion. Physical examination revealed dullness half way up the right side of the chest and left pedal edema. He was readmitted and found to have a ventilation and perfusion lung scan, with two mismatches on the left and one on the right interpreted as high probablity for a pulmonary embolus.

Day 1

Day 2

Day 3

The platelet count on this second admission was low at 92,000 and the patient was started on heparin. Over the next two days the platelet count fell to 60,000 and heparin was discontinued. Dextran was substituted and the patient improved clinically. The platelet count rose to 194,000 and the patient was switched to warfarin anticoagulation at a later date and subsequently recovered fully. A test for heparin induced platelet aggregation, using the patient's own platelet rich plasma, was done when his platelet count rose to 125,000 and was positive. A test for heparin related antiplatelet antibodies using the serotonin release assay was performed at a reference laboratory and was subsequently also reported positive.

Case Discussion

Individuals who have developed immunologic heparin induced thrombocytopenia are at high risk for thrombosis, not only during the initial episode of thrombocytopenia, but also for some time thereafter. This case illustrates that well. The development of thrombocytopenia several days after discharge and discontinuation of the heparin is an unusual feature in this case It is unclear if the thrombocytopenia was immunologically mediated or due to consumption in the very extensive thrombosis and embolization that occurred in this case.

This patient also illustrates the difficult clinical situation when an individual has an active thrombotic event and can not receive heparin. Current textbooks suggest the use of heparinoids, Ancrod or hirudin, as alternative antithrombotic agents.(5) However, none of these is commercially available in the United States. The use of dextran in this setting has been reported, but is not supported by prospective clinical trials, and its efficacy is not really known. Clinical trials with new synthetic antithrombins unrelated to heparin hold some promise.(6)

The incidence of HIT and HITTS appears to be lower with the lowmolecular weight heparins (LMWH) which have come on the market but can occur even with their use subcutaneously for prophylaxis.(7)

Case Report: HITTS with LMWH

A 51-year-old man developed progressive weakness of his legs leading to hospitalization. This eventually progressed to paraplegia and he was diagnosed as having transverse myelitis. He was started on standard unfractionated heparin at a dose of 5000 units subcutaneously every 12 hours for prophylaxis against deep vein thrombosis. He was subsequently transferred to a rehabilitation service where prophylaxis was continued, but now with a new LMWH at a dose of 30 mg subcutanously every 12 hours. Two weeks later thrombocytopenia developed progressively over a period of five days. On examination the patient was found to have developed a resting tachycardia and right axis deviation on his EKG. A ventilation/perfusion scan was diagnostic of three separate areas of pulmonary embolization. A test for heparin associated antiplatelet antibodies was positive. The heparin was discontinued and dextran was used as an antithrombotic agent for a week until warfarin anticoagulation was started. The patient remains paraplegic, but has had no further thrombotic complications while on long term anticoagulation with warfarin.

In summary, heparin induced thrombocytopenia remains a fearful complication that is difficult to treat. Early recognition is the key to successful treatment, but current clinical trials suggest that help is on the way.