Let's HIT the topic
Heparin-induced Thrombocytopenia (HIT)
!
This #tweetorial is a deep dive into Episode 43 of Run the List (RTL) on Thrombocytopenia: https://bit.ly/32feVfQ
Thanks @LeelaChock for covering this week’s topic!


This #tweetorial is a deep dive into Episode 43 of Run the List (RTL) on Thrombocytopenia: https://bit.ly/32feVfQ
Thanks @LeelaChock for covering this week’s topic!
Thrombocytopenia is a broad topic!
In Ep. 43 of RTL, Dr. Robert Stern, @NavinKumarMD, & @sonorato11 go over a general approach to thrombocytopenia
Broadly, there are THREE umbrellas:
1.
destruction
2. Splenic sequestration
3.
production
https://www.runthelistpodcast.com/s/RTL_Thrombocytopenia.pdf
In Ep. 43 of RTL, Dr. Robert Stern, @NavinKumarMD, & @sonorato11 go over a general approach to thrombocytopenia

Broadly, there are THREE umbrellas:
1.

2. Splenic sequestration

3.

https://www.runthelistpodcast.com/s/RTL_Thrombocytopenia.pdf
HIT (Heparin-induced thrombocytopenia), is classified under “
destruction”
HIT in-depth:
It is *common*, occurring in 1 out of 5,000 hospitalized patients
It’s a can’t miss dx! 50% of patients w/ HIT who are not appropriately treated go on to develop a thrombosis

HIT in-depth:




HIT risk factors?
duration/dose of heparin administration (can even happen w/ simple heparin flush!)
Type of heparin used: UFH > LMWH > fondaparinux
Surgical, trauma, cardiopulm bypass pts at
risk (maybe 2/2 increased heparin use, but MoA unknown)
Patient sex (F>M)

Type of heparin used: UFH > LMWH > fondaparinux



Patient sex (F>M)
HIT mechanism:
Heparin
complexes w/ platelet factor 4 (PF-4), a protein released by platelets
B-cells make IgG antibodies (~5-7 days after heparin exposure) to the PF4-heparin complex 
IgG then binds these heparin-PF4 complexes to platelets and then…





(HIT MoA cont.):
IgG-PF4-heparin complexes bind platelets causing BOTH:
Thrombocytopenia by marking the platelets for
destruction
via splenic macrophages (type II hypersensitivity rxn)
AND
Paradoxical PRO-thrombotic state by IgG Ab complexes
activating
platelets!
IgG-PF4-heparin complexes bind platelets causing BOTH:



AND



Sequelae include:
Thrombocytopenia to ~50-80k (usually >20K)
Paradoxical thrombosis (venous > arterial), despite thrombocytopenia!
(Rarely) anaphylaxis; HIT Ab may activate leukocytes
Skin necrosis at *heparin injection sites* (seen below) immediately suggests HIT!





Let’s review timing
of HIT!
Suppose heparin is given on day 0:
d0-d1 = Rapid 50% drop (pt already has IgG Ab 2/2 heparin exposure w/i last 3 months)
d5-d7 = Rapid 50% drop (no prior heparin exposure)
d7-d14 after heparin withdrawal = Rapid drop ("delayed-onset HIT")

Suppose heparin is given on day 0:



If suspecting HIT calculate a "4-T score"
The 4 T's are:
Thrombocytopenia
Timing
of Onset
Thrombosis
oTher causes of Thrombocytopenia.
A LOW score (<4 points) has a very HIGH negative predictive value (NPV) of 97 to 99%, and essentially *rules out* HIT
The 4 T's are:





A LOW score (<4 points) has a very HIGH negative predictive value (NPV) of 97 to 99%, and essentially *rules out* HIT
The positive predictive value (PPV) of a 4-T score of 4-5 is 10-20%, but a score >=6 is 40-80%
A 4-T score >=4 requires:
Stopping all heparin products immediately
!
An Anti–PF4–heparin ELISA test 
Starting therapeutic NON-heparin anticoagulation (e.g. Argatroban
)
A 4-T score >=4 requires:






Anti-PF4 test has high NPV (98-99%), but low PPV
a
anti-PF4 result requires confirmation w/ *gold standard functional test*: serotonin release assay (SRA)
How does SRA work?
If pt's serum has active heparin-PF4 IgG Ab
activate donor platelets
releasing serotonin
a

How does SRA work?
If pt's serum has active heparin-PF4 IgG Ab




All pts w/ suspected or confirmed HIT need therapeutic (non-heparin) anticoagulation (AC)!
Why
?
HIT Abs activate platelets
clots despite thrombocytopenia
For HIT: continue AC until platelet count >150K
For HIT-related clot: continue AC for 3 months (like any provoked clot)
Why

HIT Abs activate platelets

For HIT: continue AC until platelet count >150K
For HIT-related clot: continue AC for 3 months (like any provoked clot)
[on AC]
@ASH_hematology suggests the following tx as initial anticoagulants in acute HIT
:
Argatroban, bivalirudin, fondiparinux, danaparoid, or a DOAC
Argatroban or bivalirudin = short half-lives (!)
Short half-lives = indicated for critically ill or bleeding risk pts
@ASH_hematology suggests the following tx as initial anticoagulants in acute HIT




If pt is on warfarin,
hold warfarin
& reverse with IV Vitamin K 
Seems strange right?
Warfarin has been shown to paradoxically WORSEN the hypercoagulable state in HIT 
Once platelet count stabilizes, can re-start warfarin



Seems strange right?




in SUM:
1) HIT complexes both activate *and* deplete platelets (thrombocytopenia)
2) Use the 4-T score
to assess for HIT
3) If >=4
heparin products, start non-heparin anticoagulation (not warfarin!), & send labs
4) Have a low threshold to look for thrombotic complications
1) HIT complexes both activate *and* deplete platelets (thrombocytopenia)
2) Use the 4-T score

3) If >=4

4) Have a low threshold to look for thrombotic complications
REFs (1/2):
[1] https://theawkwardyeti.com/comic/blood-clot/
[2] https://www.runthelistpodcast.com/s/RTL_Thrombocytopenia.pdf
[3]
[4] https://www.aruplab.com/testing/HIT
[5] http://www.nejm.org/doi/full/10.1056/nejmcp1411910#article_citing_articles
[6] https://www.semanticscholar.org/paper/Heparin-induced-thrombocytopenia-(HIT):-Review-of-Hogan-Berger/a1ab31b2e9ba719a81855a790145f86045842283/figure/0
[7] https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-heparin-induced-thrombocytopenia?search=HIT&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H19880151
[8] http://www.nejm.org/doi/full/10.1056/nejmcp1411910#article_citing_articles
[9] http://www.nejm.org/doi/full/10.1056/nejmcp1411910#article_citing_articles
[1] https://theawkwardyeti.com/comic/blood-clot/
[2] https://www.runthelistpodcast.com/s/RTL_Thrombocytopenia.pdf
[3]
[4] https://www.aruplab.com/testing/HIT
[5] http://www.nejm.org/doi/full/10.1056/nejmcp1411910#article_citing_articles
[6] https://www.semanticscholar.org/paper/Heparin-induced-thrombocytopenia-(HIT):-Review-of-Hogan-Berger/a1ab31b2e9ba719a81855a790145f86045842283/figure/0
[7] https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-heparin-induced-thrombocytopenia?search=HIT&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H19880151
[8] http://www.nejm.org/doi/full/10.1056/nejmcp1411910#article_citing_articles
[9] http://www.nejm.org/doi/full/10.1056/nejmcp1411910#article_citing_articles
REFs (2/2):
[11] https://www.slideshare.net/skyecreativeone/medical-sample-13
[12]
[13a] https://ashpublications.org/bloodadvances/article/2/22/3360/16129/American-Society-of-Hematology-2018-guidelines-for?searchresult=1&_ga=2.242345538.1943646382.1604025310-250888369.1604025310
[13b] https://www.jahjournal.org/viewimage.asp?img=JApplHematol_2015_6_4_141_171993_f1.jpg
[15] https://www.runthelistpodcast.com/s/RTL_Thrombocytopenia.pdf
[11] https://www.slideshare.net/skyecreativeone/medical-sample-13
[12]
[13a] https://ashpublications.org/bloodadvances/article/2/22/3360/16129/American-Society-of-Hematology-2018-guidelines-for?searchresult=1&_ga=2.242345538.1943646382.1604025310-250888369.1604025310
[13b] https://www.jahjournal.org/viewimage.asp?img=JApplHematol_2015_6_4_141_171993_f1.jpg
[15] https://www.runthelistpodcast.com/s/RTL_Thrombocytopenia.pdf