Heparin-induced thrombocytopenia mechanism

[HereWeGo21]

As I understand it:

1. Heparin binds Platelet factor 4 (PF4)
2. Heparin-PF4 complex is immunogenic, and causes IgG directed against it
3. Heparin-PF4-IgG complex binds platelets via their Fc receptors. This causes activation of the platelets
4. Platelet activation and thrombosis.

However, this seems strange to me. Why is it only IN THIS CASE that IgG binds and activates platelets? You'd think we could get widespread activation any time IgG is deployed, like in an infection for example, not to mention in multiple myeloma. What makes this case different?

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[masaraksh]

perhaps because platelet factor 4 is on platelets?

 

[Phloston]

In UWorld Step3 they distinguish between type I which is non-immune and platelets stay >100,000 generally, and type II which is as you describe above, and platelets tend to nadir ~30,000, or >50% below baseline. Tx is direct-thrombin inhibitor, not warfarin. Not 100% sure what your question is, but in type II the patient makes IgG Abs against the heparin-PF4 complex.

 

[HereWeGo21]

In UWorld Step3 they distinguish between type I which is non-immune and platelets stay >100,000 generally, and type II which is as you describe above, and platelets tend to nadir ~30,000, or >50% below baseline. Tx is direct-thrombin inhibitor, not warfarin. Not 100% sure what your question is, but in type II the patient makes IgG Abs against the heparin-PF4 complex.

Yeah, so the patient make antibodies against heparin-PF4 complex. But then it doesn't stop there: the only reason we get HIT is that the platelets express the Fc receptor, and so the platelets then bind the IgG-heparin-PF4 complex, and become activated. This last step is necessary for the pathophysiology of HIT, and this is the part I'm interested in.

perhaps because platelet factor 4 is on platelets?

I wasn't aware that PF4 is on platelets. Actually Wiki says that PF4 is a cytokine released from the platelet's alpha granule.

Regardless, though: either way it doesn't answer my question. My question is:
so platelets express the Fc receptor, and thus recognize the IgG-heparin-PF4 complex. But how do these platelets KNOW that the IgG-heparin-PF4 complex, in particular, has bound? Or do they just become activated any ole time an IgG binds the platelet's Fc receptor?

Thanks

 

[DandyLion]

When an IgG's Fab region binds an antigen its conformation changes leaving the IgG's Fc region more exposed for binding to the Fc receptors on phagocytes, or in this case platelets. The Fc receptor on platelets have particularly low affinity for IgG. Because of this, they are less likely to bind free floating IgG (with Fc region less exposed) and more likely to bind IgG bound to antigen.

The role of Fc receptor platelet activation in our immune system is not completely clear but yes, the platelet's Fc receptor is capable of binding other IgG-antigen complexes other then IgG-heparin-PF4. There's evidence of platelets participating in the clearance of microbial infections as IgG-antigen coated platelets are cleared in the spleen by macrophages with a corresponding Fc receptor. There also appears to be signaling cross talk between activated platelets and other immune cells.

The severe maladaptive activation of platelets in HIT happens because 1) heparin binds PF4 exposing immune epitopes leading to the formation of IgG, 2) the platelets Fc receptor binds the exposed Fc region of IgG-heparin-PF4, 3) platelet activation leads to even more PF4 release creating a positive feedback loop of 1 & 2. This process is also mediated by a) the binding of heparin to PF4 which is dependent on the molecular characteristics of the specific sample of heparin you are administering, b) the ability to form anti heparin-PF4 antibody which varies based on the patient population, the type of heparin used (greater risk with bovine unfractionated), and even the setting of heparin administration (more common in post surgical cardiac patients), and c) the binding of antibody-heparin-PF4 to platelets which is influenced by the titer and type of antibody created.

So yes, platelets can be activated through binding of other IgG-antigen to their Fc receptor. This response is just exaggerated in HIT with certain patients because of the circumstances.

Sources:
http://m.circ.ahajournals.org/content/111/20/2671.full
http://www.medscape.org/viewarticle/569661
http://onlinelibrary.wiley.com/doi/10.1111/jth.12905/abstract
http://www.ncbi.nlm.nih.gov/m/pubmed/17046568/
http://m.jimmunol.org/content/162/7/4311.full
https://en.m.wikipedia.org/wiki/Fc_receptor

Hope that helps!

 

[HereWeGo21]

When an IgG's Fab region binds an antigen its conformation changes leaving the IgG's Fc region more exposed for binding to the Fc receptors on phagocytes, or in this case platelets. The Fc receptor on platelets have particularly low affinity for IgG. Because of this, they are less likely to bind free floating IgG (with Fc region less exposed) and more likely to bind IgG bound to antigen.

The role of Fc receptor platelet activation in our immune system is not completely clear but yes, the platelet's Fc receptor is capable of binding other IgG-antigen complexes other then IgG-heparin-PF4. There's evidence of platelets participating in the clearance of microbial infections as IgG-antigen coated platelets are cleared in the spleen by macrophages with a corresponding Fc receptor. There also appears to be signaling cross talk between activated platelets and other immune cells.

The severe maladaptive activation of platelets in HIT happens because 1) heparin binds PF4 exposing immune epitopes leading to the formation of IgG, 2) the platelets Fc receptor binds the exposed Fc region of IgG-heparin-PF4, 3) platelet activation leads to even more PF4 release creating a positive feedback loop of 1 & 2. This process is also mediated by a) the binding of heparin to PF4 which is dependent on the molecular characteristics of the specific sample of heparin you are administering, b) the ability to form anti heparin-PF4 antibody which varies based on the patient population, the type of heparin used (greater risk with bovine unfractionated), and even the setting of heparin administration (more common in post surgical cardiac patients), and c) the binding of antibody-heparin-PF4 to platelets which is influenced by the titer and type of antibody created.

So yes, platelets can be activated through binding of other IgG-antigen to their Fc receptor. This response is just exaggerated in HIT with certain patients because of the circumstances.

Sources:
http://m.circ.ahajournals.org/content/111/20/2671.full
http://www.medscape.org/viewarticle/569661
http://onlinelibrary.wiley.com/doi/10.1111/jth.12905/abstract
http://www.ncbi.nlm.nih.gov/m/pubmed/17046568/
http://m.jimmunol.org/content/162/7/4311.full
https://en.m.wikipedia.org/wiki/Fc_receptor

Hope that helps!

Awesome, thanks so much, that totally helps! I had never thought of the positive feedback factor, but that totally makes sense now and explains why the immune response in HIT is particularly brisk. Thanks for your incredibly comprehensive and helpful response.