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Why Clotting Happens When Platelets Are Low

— A hematologist explains the counterintuitive concept of clots with low platelets

Last Updated April 26, 2021
MedpageToday
A computer rendering of a thrombosis in a blood vessel with platelets floating by

Reports of unusual blood clots in the setting of low platelets associated with COVID-19 vaccines have brought attention to these tiny cell fragments tasked with preventing humans from fatally bleeding.

The that, as of April 20, there have been 287 reports of rare blood clots with low platelets after administration of the AstraZeneca vaccine, eight with Johnson & Johnson, 25 with Pfizer, and five with Moderna. The clots are notable because some have occurred in unusual and deadly locations in the veins that drain the brain (known as cerebral venous sinus thrombosis) and the abdomen (known as splanchnic vein thrombosis).

have a concave shape that looks like, well, a plate. They're colorless, and have a lifespan of about 10 to 12 days. When a blood vessel becomes damaged, platelets crowd to the site and become : they change shape, release substances that promote clotting, and recruit clotting factors along with other platelets to promote more clotting. It's a delicately balanced process. In a healthy person, the end result is a clot, which is normally a good thing because it prevents fatal bleeding.

It seems intuitive that having low platelets would increase the risk of bleeding. After all, without very many platelets around, it gets harder to form a clot. So why have these potentially vaccine-related clots occurred in the presence of low platelets?

Two Distinct Processes Lead to Low Platelets

In general, two distinct processes can result in thrombocytopenia, or low platelets. The first process involves platelet clearance, and it's an immune process. Typically, macrophages engulf and clear old platelets when they've reached the end of their lifespans. If the clearance process gets out of control -- say, with an autoimmune condition -- it can lead to excess clearance and low platelets, according to Manila Gaddh, MD, of Emory University in Atlanta.

"With clearance, the body's immune system actually destroys the platelets, which brings the platelet count down and can lead to bleeding," Gaddh said.

The second process involves consumption of platelets when they become activated, and go about their normal job of stimulating the clotting system and aggregating to form blood clots. If the consumptive process gets out of control, platelets get used up and their numbers drop.

"In consumption, platelets are actually getting activated. That activates the clotting system to make the platelets aggregate together, which brings down the platelet count and favors clotting in the body," Gaddh said.

Low Platelets and Vaccines

Both high clearance and consumption have been linked to vaccine-associated thrombocytopenia. These two distinct processes involve at least two different autoantibodies, according to Gaddh.

Immune thrombocytopenia (ITP) occurs when the body produces antibodies against platelets and directly attacks them. These autoantibodies clear platelets at a much faster pace than in normal people -- even younger platelets get destroyed -- and that lowers the platelet count. ITP has been associated with some medications, infections, and vaccines.

"It is generally associated with increased risk of bleeding if the platelet count is severely low," Gaddh said.

Recently, the term "vaccine-induced immune thrombotic thrombocytopenia" (VITT) has been coined to refer to cases of low platelets with unusual clots reported after COVID-19 vaccines. Gaddh says that VITT is a consumptive process similar to an autoimmune condition called heparin-induced thrombocytopenia (HIT), in which heparin paradoxically activates platelets, leading to platelet depletion and clotting. HIT is a well-known, but rare, complication of heparin use that develops in about 1% to 2% of patients.

In VITT, scientists have identified an autoantibody called platelet factor 4 (PF4) antibody that activates platelets, rather than directly attacking and destroying them, as in ITP. That, in turn, promotes clotting and eventually low platelet levels.

"In VITT, we believe these autoantibodies are activating platelets, causing them to be more functionally active and causing a consumptive thrombotic process and increased risk of clots," Gaddh said.

Andreas Greinacher, MD, of the University of Greifswald in Germany, recently involving experiments that he said confirms that this cascade is prompted by PF4 antibodies, but he also pointed to a potential role for a certain preservative.

When it comes to management, because of the similarity of VITT to HIT, experts are advising IV immunoglobulin, use of non-heparin anticoagulants, and avoidance of platelet transfusions. The International Society on Thrombosis and Haemostasis has provided for the diagnosis and treatment of VITT, as has the .