We test for this antibody on-site as of December 2004. Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy (especially unfractionated heparin [UFH]), with a high risk of potentially catastrophic venous or arterial thrombosis and high mortality. Our group knows of a local death in 2004 that may have been due to HITTS. As with so many other situations in medical diagnosis, arriving at a correct diagnosis requires discerning clinical acumen. The HT antibody disappears to non-detectibility in about 100 days; so, there is screening testing is not logical.

 Heparin fragments with molecular weights larger than 5,000 Kd...in highest concentration in unfractionated heparin (UFH) preparations...are needed to generate antibodies. LMWH preps have a half-life of 17 hours; UFH preps have a half-life of 90 minutes³. Older data suggest that about 15-40% on UFH develop antibodies; 3-15% on low molecular weight heparin (LMWH) develop antibodies (can mount detectible levels of anti-h/pf4 antibody [synonym, H-PF4] without precipitating any syndrome³). Sensitizing heparin exposure can even come from such unremarkable events as "heparin flushes" of IV lines. Of those who develop the anti-HIT antibody, about a third get an arterial or venous thrombosis if the heparin is not promptly discontinued & a non-coumadin alternative anticoagulation (often using direct thrombin inhibitors) promptly instituted. Thrombosis in HIT is associated with a mortality of approximately 20% to 30%, with an equal number becoming permanently disabled by amputation, stroke, or other causes!

HIT-II Incidence:

• with UFH: 1-4% given this type of heparin.
• with LMWH: 0.5-0.8% given this type of heparin.

Diagnosis:

(a) A transient, non-immune physiological drop in platelet count within 1st 5 days of therapy is seen pretty commonly, is usually clinically inconsequential "HIT-type-I", and HIT-type-I essentially never drops the count by 50%³.
(b) Immunological & potentially dangerous "virginal"...a primary antibody response...HIT-type-II happens between days 5-21 (most commonly days 5-7) after first heparin dose and is defined as a platelet count drop of 50% or to less than 100,000 plus demonstration of the presence of the antibody (which could be relatively consumed & not detected on initial testing).
(c) Caution: a current heparin re-exposure following a subclinical sensitizing event in the past can result in a more rapid anamnestic onset thrombocytopenia in HIT-II which initially resembles HIT-I.

• HIT-I: drop in platelet count in 1st 3-5 days in one never having previously had heparin exposure; physiologic & not due to antibody; not dangerous; DON'T D/C heparin.
• HIT-II: drop in platelet count days 5-7 (to 21); antibody triggered.
• thrombocytopenia NOS: must always keep in mind that there are many other causes

TREATMENT of HITT:

1. if HITT seems possible, D/C heparin promptly, and

2. order  the HIT test, and

3. do not institute Coumadin, and...as to anticoagulation coverage...consider the UFH or LMWH half lives, above, as to length of time patient might be "naked" of anticoagulation effect, and how long it will take to get the HITT test result, and estimated clinical risk of "going naked" until test result is known.

4. consider adding alternative anticoagulation...most commonly being direct thrombin inhibitors such as Lepirudin...especially if the thrombocytopenia is precipitous and obviously associated with new thrombosis. Some cases can mount a much slower antibody rise and be initially test-negative or borderline. And some mount an antibody response that does not seem functionally important clinically.

On site availability of this test allows rapid differentiation of thrombocytopenic onset of dangerous HIT-II from innocuous HIT-I and other thrombocytopenias.

SUMMARY:

HIT-II is due to an antibody (usually an IgG) that recognizes heparin bound to platelet factor 4 (PF4) on the platelet surface. The antibody binds to the heparin/PF4 complex (H-PF4), which then allows the antibody to also bind the Fc (gamma) IIc receptor on the platelet membrane (as well as on monocytes and endothelial cells).¹⁴ It is "anti-h/pf4 antibody" interaction with the Fc receptor that activates the platelet, resulting in immune-type platelet loss (thrombocytopenia) and platelet aggregation (thrombosis). When thrombosis is manifest, the patient has HITT (heparin induced thrombocytopenia with thrombosis) or HITTS (heparin induced thrombocytopenia with thrombosis syndrome) . A minority of cases of HIT may involve an antigen other than the PF4-heparin complex (and, therefore, another platelet activating antibody).¹⁵

At this time, we do not have a functional test to follow up a positive antibody to see if the antibody is actually what is affecting the patient's platelet count.

References:

1. MGH website, lab med. handbook. (for references 14 & 15).
2. Breddin HK, "Introduction: Is Heparin-induced Thrombocytopenia Still a Medical Problem?", 2004.
3. Armstrong WR, memo to LMC physicians. Dec. 2004 & Jan. 2005; & 18 April 2005 note & various personal communications.
4. Breddin HK, "Is Heparin-induced Thrombocytopenia Still a Medical Problem?". Heparin-induced Thrombocytopenia and Beyond, 18 July 2003 Suppl. to Thrombosis & Hemostasis (journal...WRA).