What is HIT?
Heparin-induced thrombocytopenia is defined as a decrease in platelet count of 50% or more. HIT usually occurs within 5-10 days of heparin administration. Type I HIT is due to non-immune platelet activation. Type I is usually not serious. Type II HIT is due to activation of platelets by the immune system (Greinacher, in: Platelets Fourth Edition, 2019). The binding of HIT antibodies to platelets causes platelet overactivation, generating thrombin. This mechanism can cause thrombosis.
The inaccuracy of "HIT": Sometimes HIT occurs even before heparin is administered
Prescribing heparin derivatives warrants caution when a blood coagulation disorder meets the main features of HIT. The problem with the diagnosis "HIT" is that HIT is not always HIT. Cases of "pseudo-HIT" have been regularly mentioned in the literature for more than twenty years. In a real, classic HIT, the patient develops a deficiency of platelets after administration of heparin. Sometimes the patient has not received heparin before, so it is not really possible to speak of a "classic HIT". Nevertheless, the distinction is important for determining the correct anticoagulation policy. The administration of heparin could make the situation worse: by activating more platelets, more thrombin is produced, resulting in blood clots and the risk of an embolism.
Heparin-induced thrombocytopenia (HIT) is caused by the activation of platelets in response to Immunoglobulin G (IgG) antibodies. The IgG antibodies recognize Platelet Factor 4 (PF4) complexes, which bind to heparin or negatively charged polymers, "polyanions". The chemokine Platelet Factor 4 (also known as CXCL4) is released during the activation of platelets. HIT Immunoglobulin Antibodies (IgG Ab) activate platelets. Only IgG antibodies can bind to FcgRII receptors on platelets. The Fab portion of HIT-IgG antibodies binds to FP4 heparin and the Fc portion of HIT-IgG binds to the FcRII receptor on the platelets (Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and resultant platelet activation, Blood: Hemostasis, Thrombosis and Vascular Biology Vol 96, Number 1, Jul 1, 2000).
Sensitization: recognition of antigens after previous infections
The anti-PF4 / heparin complex immune response is common in the surgical context: anti-PF4 / H antibodies are measured within 1 to 2 weeks after surgery in 75% of patients undergoing cardiac surgery.
The unusual thing about HIT is that patients produce anti-PF4/H-IgG antibodies within 4 days of a first heparin administration. Thus, there must be pre-immunization to PF4/heparin (Arepally, Nothing typical about HIT, Blood: Inside Blood Vol. 113, Issue 20, 14 May 2009).
This can be illustrated by mouth bacteria. A very old, perhaps rudimentary, mechanism of humans is to overreact with anti-PF4-H antibodies to bacterial infections. PF4 binds to aerobic mouth bacteria, generating the same antigens as PF4/Heparin complexes. Previous gum infections ensure that PF4 is recognized by HIT antibodies. Gingivitis evokes anti-PF4/H antibodies that ensure recognition, "sensitization" during a subsequent infection or surgery. Antigens against PF4 / Heparin complexes naturally occurring in humans are also able to recognize a wide spectrum of bacteria.
When HIT is suspected, administration of high doses of heparin is not recommended for the following reason. Unfractionated heparin (UFH) can bind to PF4/H complexes. The risk is that a PF4 / HIT antigen will develop. By contrast, polysaccharide anticoagulants such as Fondaparinux do tend to evoke anti-PF4/H antibodies, but not to bind them to PF4 complexes.
Greinacher & Warkentin, 2009
A 2009 study by Greinacher (the professor who recently demonstrated the link between the COVID vaccines and thrombotic thrombocytopenia) shows that the immune response to PF4/heparin complexes differs from "classic" immune responses in that it is not a typical primary immune response, initially producing IgM antibodies, followed by a later immune response with IgG. Unlike a typical primary immune response, a high level of IgG is already observed by day 6. The reaction with antibodies decreases rapidly even when heparin is administered to cases that can be typified as "HIT". This makes a typical secondary immune response unlikely.
Several explanations are put forward. The development of antibodies against PF4/heparin complexes may be the result of an immune response that is not dependent on T cells. In that case, B cells would be stimulated by PF4/heparin-antigen complexes. This occurs in responses to viruses that have a repetitive pattern (of epitopes). Repetitive patterns evoke a B-cell response without activation of T-memory cells. The immune response can be evoked by previous exposure of PF to glycosaminoglycans, long sugar chains found in connective tissue, cartilage and bone. These chains are normally broken down to prevent the accumulation of glycosaminoglycans. Another factor that contributes to immunization has been mentioned above: major surgical procedures. During major medical surgery, platelets are activated, which ensure the development of long complexes of PF4/heparin. In response to long complexes of PF4/H, B-cell responses are also evoked, independent of T-memory cells.
Marginal B cells: B cells of the "no active memory" profile
However, some form of "memory" must be involved in the formation of antibodies to PF4/H. Neonates do not develop anti-PF4/H complex antibodies after heparin administration. This means that immunization by heparin is low in newborns. Unlike the "trained" immune system, the newborn's immune system is still naive. One explanation is that "marginal" B cells, B cells without active memories, are stimulated by the clustering of PF4 in response to, for example, inflammation or major surgery. The marginal B cells have no active memory, but are activated by PF4/H clusters and an inflammatory response. This type of B cell, without active memories, becomes involved in the development of IgG antibodies within a short time, with the marginal B cells also becoming inactive again within a short time (Greinacher, Warkentin et al., The temporal profile of the anti -PF4/heparin immune response, Blood: Thrombosis and Haemostasis Vol 113, Issue 20, May 14, 2009).
Anti-PF4/Heparin antibodies disappear in the course of 3 months, because no memory B cells with PF4/H specificity are produced. Because they have no active memory, marginal B cells need a second stimulus to stimulate IgG-type PF4 / H antibodies. Reference to the study on gingivitis and the later appearance of PF4/Heparin antibodies by a second stimulus confirms this (Association with natural anti-platelet factor 4/heparin antibodies with periodontal disease, Blood: Platelets and Thrombopoiesis Vol. 118, Issue 5 , August 4, 2011).
