Previously (Part I), I discussed that "HIT" is not always an accurate diagnosis because thrombocytopenia might occur even before heparin is administered. Sometimes there has even been no intervention with heparin at all, but the symptoms give cause to make the diagnosis (in the absence of more precise diagnosis) of HIT. The distinction between "classic" HIT and other forms of HIT or even "Pseudo-HIT" is important for determining the right treatment: should heparin be avoided or does a low dose offer a solution for thrombocytopenia?
Autoimmune HIT (aHIT)
The phenomenon of "autoimmune HIT" ("aHIT") implies that anti-Platelet Factor 4 polyanion antibodies activate platelets without heparin being administered. Although aHIT can occur without prior administration of heparin, the absence of heparin is not a decisive factor in making the diagnosis "aHIT". AHIT also includes: delayed-onset HIT (HIT occurring after short-term administration of heparin or after heparin discontinuation occurs and persists), spontaneous HIT, HIT due to fondaparinux, severe sustained HIT, and heparin flush HIT .
Let me first explain what HIT means. Next, I will discuss the mechanisms that cause thrombocytopenia and thrombosis in HIT. Finally, I discuss the possible treatment options for the different manifestations of HIT.
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. An immune complex composed of antibodies to Platelet Factor 4-Heparin complex binds to platelets and monocytes via the FcgIIA receptor. Subsequently, platelets eventually become overactive and microparticles containing coagulation factors are released. This increases the risk of venous thrombosis (Heparin-induced Thrombocytopenia: Pathophysiology, Diagnosis and Management, Cureus March 2020; 12(3)).
Type I HIT is due to non-immune platelet activation. Type I is usually not serious. Type II HIT is due to platelet activation 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. Whether people actually develop thrombocytopenia after the formation of antibodies against PF4 or PF4/Heparin complexes depends, among other things, on the individual shape and expression of the Fc receptor on the platelets (this differs per person!) and the duration and dose of the administration of heparin.
The development of thrombosis depends, among other things, on the interruption of protein C and treatment with coumarin derivatives (Antibodies to Heparin-Platelet Factor 4 Complex: Pathogenesis, Epidemiology and Management of Heparin-Induced Thrombocytopenia in Hemodialysis, American Journal of Kidney Diseases: In Practice Vol 54, Issue 2, August 1, 2009). Medications such as Histamine2 blockers, vancomycin, penicillin, antipsychotics, antidepressants, and proton pump inhibitors can also contribute to thrombocytopenia.
Electrostatic charge and thrombotic activity
(PF4 = + [positively charged])
Under the influence of chondroitin sulfate and polyphosphate, anti-PF4 antibodies are able to bind PF4, an electrical charge dependent activity in the structure of PF4. Two tetramers of PF4 (tetramer = four parts) must be brought close together to form the HIT antigen. This requires that a neutral charge is reached. This can be done by negatively charged bacteria and other pathogens, but also by DNA and medicines.
PF4 is a positively charged protein that is stored in the platelets. When PF4 is released, it binds to negatively charged glycosamines (GAGs, "sugars") on endothelial cells (ECs). As a result, antithrombin becomes unstable and the condition within the vascular system becomes prothrombotic. PF4/H complexes bind to B immune cells. The complement system is activated. The binding of CD21 takes place and the overactivation of the complement system ensures more generation of thrombin. When HIT antibodies bind to platelets, even more thrombin is released (Heparin-induced thrombocytopenia, Blood: Clinical Platelet Disorders Vol. 129, Issue 21, May 25, 2017).
The Complement System and thrombosis
The negative charge of heparin can activate the contact coagulation cascade, leading to the generation of kallikrein and bradykinin ("leaky vascular tissue"), additional production of nitric oxide and the production of complement factors C3a and C5a (these complement factors provide an inflammatory mechanism) (Antibodies to Heparin-Platelet Factor 4 Complex: Pathogenesis, Epidemiology and Management of Heparin-Induced Thrombocytopenia in Hemodialysis, American Journal of Kidney Diseases: In Practice Vol.54, Issue 2, August 1, 2009).
Treatment options
Given that in cases of aHIT, heparin will be discontinued or either no heparin has been administered at all, the sole discontinuing of treatment with heparin derivatives does not end the clinical picture of aHIT. Administration of Vitamin K antagonists (VKA) is avoided because VKA exacerbate thrombotic activity/hypercoagulation by interfering with protein C. If Vitamin K antagonists have already been administered to a patient with aHIT, Vitamin K should be administered.
For the treatment of aHIT, the following agents may be considered:
1. Preventing the production of thrombin by means of:
- DOACs (rivaroxaban, edoxaban, dabigatran, apixaban);
- Argatroban, bivalirudin, lepirudin;
- Intravenous danaparoid;
- Subcutaneous fondaparinux;
2. Inhibition Of Fc Receptor On Platelets:
- Intravenous Immunoglobulin (IVIG);
3. Interrupting the HIT Antigen:
- Intravenous danaparoid;
4. Factor Xa Inhibition:
- Rivaroxaban
ODSH (2-O, 3-O Desulfated Heparin)
In aHIT, administration of heparin derivatives is not recommended. In a case of "classical HIT", 2-O, 3-O-desulfated heparin (ODSH) can be used. ODSH prevents the formation of PF4/HIT complexes and may be considered in patients requiring heparin. ODSH prevents binding of PF4 to platelets and reduces the binding of anti-PF4/heparin antibodies to PF4/H complexes. At higher concentration, ODSH has the property to disrupt PF4/H complexes. A combination of UFH (unfractioned heparin) or LMWH (Low Molecular Weight Heparin) with ODSH is proposed to prevent HIT (Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban and low sulfated heparin with Platelet Factor 4 and anti -PF4 / heparin antibodies, Blood: Thrombosis and Haemostasis Vol. 119, Issue 5, February 2, 2012).
Fondaparinux
A few cases report that treatment with fondaparinux was insufficient to effectively treat persistent thrombocytopenia or DIC (Disseminated Intravascular Coagulopathy) (Severe and persistent heparin-induced thrombocytopenia despite fondaparinux treatment, American Journal of Hematology Vol. 90, Issue 7, July 2015). In some cases where aHIT was caused by previous heparin administration, a therapeutic dose of fondaparinux was effective to combat HIT (Progressive thrombocytopenia after cardiac surgery in a 67-year-old man, CMAJ Vol. 186, Issue 12, September 2, 2014 ). Fondaparinux administered subcutaneously counteracts the production of thrombin. The tolerable dose of fondaparinux is dependent on renal function, while underdosing is a common problem with fondaparinux.
Argatroban and bivalirudin
Argatroban and bivalirudin administered intravenously counteract thrombin aggregation. As with subcutaneous administration of fondaparinux, there is a risk of underdosing with argatroban and bivalirudin.
Danaparoid
Therapeutic doses of danaparoid can overcome HIT by inhibiting thrombin and by releasing PF4 from the platelets. The PF4 complexes that are the culprit in HIT are thereby interrupted.
DOACs: rivaroxaban, dabigatran and apixaban
Direct Oral Anticoagulants (DOAC) such as rivaroxaban and dabigatran are effective in suppressing hypercoagulation in patients with aHIT. DOACs should also be considered in cases where fondaparinux and argatroban have no effect (Outcomes in Heparin-Induced Thrombocytopenia Managed with Direct Oral Anticoagulants, Blood: 332. Anticoagulation and Antithrombotic Therapy Vol. 134, Issue Supplement_1, November 13, 2019).
