Heparin-induced thrombocytopenia (HIT) occurs when patients develop an immune response to platelet factor (PF)4/heparin complexes after surgery.
It is a common adverse effect of heparin and can limit the use of these anticoagulants.
But Norbert Lubenow (Ernst-Mortiz-Arndt-Universität, Greifswald, Germany) and colleagues have identified an important non-drug factor that influences the risk for HIT, “namely the severity of trauma and the requisite need for either major or minor surgery.”
They found that the risk for seroconversion increased nearly eight-fold in 224 patients undergoing major surgery compared with 337 patients receiving minor surgery, irrespective of the type of heparin received.
“An increased release of PF4 during major surgery resulting in more immunogenic complexes is one potential explanation for the enhanced immune response after major trauma,” say the researchers.
“An alternative explanation might be that the surgical trauma by itself, or the inflammation associated with major surgery, modifies the immune system in a way to trigger B-cells specific for PF4-complexes.”
Surgery and other non-heparin factors can also trigger thrombocytopenia in patients following cardiac surgery.
Indeed, research by S. Selling (Ernst-Mortiz-Arndt-Universität, Greifswald, Germany) and colleagues suggests that these non-heparin factors are the main cause of thrombocytopenia in these patients.
Because thrombocytopenia is common following cardiac surgery, HIT is notoriously difficult to diagnose.
Many patients will experience a major decrease in platelet count during the first 72 hours after surgery and develop anti-PF4–heparin antibodies. However, only a minority of these patients will develop HIT, say the researchers. Indeed, in their study of 581 coronary artery bypass graft (CABG) patients, only three developed HIT.
The researchers found that early-onset and persisting thrombocytopenia post-cardiac surgery is rarely due to heparin-induced thrombocytopenia, but rather non-HIT factors, such as the type of surgery, with coinciding heparin-dependent antibody seroconversion.
“In these patients, even in those with positive platelet-activating assay results, maintaining heparin should remain a treatment option, given the low likelihood of HIT in these patients, and the risks of alternative anticoagulants,” report Selling and colleagues.
In contrast, they found that a 50% or greater platelet count decline that begins between days 5 and 10 after cardiac surgery is highly predictive for HIT.
This “should prompt a change in anticoagulation even before the results of antibody tests become available,” they recommend.
Therapeutic approaches for reducing post-cardiac surgery bleeding
Fibrinogen is a key protein in hemostasis and researchers have reported that prophylactic infusion of fibrinogen concentration may reduce postoperative bleeding in patients undergoing coronary artery bypass graft (CABG) surgery.
In their pilot study of 20 CABG patients with pre-operative fibrinogen levels below 3.8 g/L, Martin Karlsson (Sahlgrenska University Hospital, Gothenburg, Sweden) and colleagues found that infusion of 2 g of fibrinogen concentration before surgery reduced postoperative blood loss by 32% compared with no infusion.
Also, postoperative hemoglobin levels were maintained at a higher level and there was no evidence of postoperative hypercoagulability.
Repletion of coagulation factor (F)XIII, which acts as a clot-stabilizing factor by cross-linking fibrin, may be another novel therapeutic approach for reducing blood loss after cardiac surgery.
Plasma levels of FXIII typically drop significantly after cardiac surgery with cardiopulmonary bypass, but a single dose of FXIII administered using a recombinant A-subunit homodimer (rFXIII-A2) after surgery can restore levels to pre-operative levels, say Jerrold Levy (Emory University School of Medicine, Atlanta, Georgia, USA) and colleagues.
They found that 35 IU/Kg was the most effective dose for restoring pre-operative FXIII levels.
The recombinant hemostatic protein was also generally well-tolerated. There were 18 adverse events, but they were all well-recognized complications of cardiac surgery. A relationship between the protein and two adverse events – anaphylactic reaction and soft-tissue necrosis at the site of injection – could not be excluded, however.
Major blood loss: Optimal fibrinogen dose and role of cryoprecipitate
Fibrinogen replacement is also a key therapeutic approach in severe hemodilution, and D Bollinger (Emory University School of Medicine, Atlanta, Georgia, USA) and team have identified the optimal concentration range needed to optimize clot formation.
They diluted blood samples from six healthy volunteers with saline, keeping hematocrit at 24% using red cell concentrates.
The half maximal effective concentration for fibrinogen replacement was calculated to be 125 mg/dl, suggesting that clot formation is optimized only after increasing fibrinogen concentration to over 200 mg/dl, the researchers report.
“This concentration is twice the level suggested by the current transfusion guidelines,” they note.
Fresh frozen plasma (FFP) is one means of increasing fibrinogen concentration after major blood loss, but 30 ml/kg of FFP is needed to increase fibrinogen by 100 mg/dl, note Bollinger et al. It is therefore extremely difficult to increase fibrinogen concentrations this way without risking volume overload and further dilutional coagulopathy.
Cryoprecipitate is the standard of care when fibrinogen concentrates are not available. They provide concentrated fibrinogen (about 150–250 mg per 10 mL), factor VIII, von Willebrand factor, fibrinogen, fibronectin, factor XIII, and platelet microparticles, but it is not available in a pathogen-inactivated form.
Jeannie Callum and colleagues, from the Sunnybrook Health Sciences Centre and University Health Network in Toronto, Ontario, Canada, discuss the role of this complex product in the management of hemostasis in a recent review.
Currently, cryoprecipitate is most commonly administered in patients who suffer major hemorrhage after cardiac surgery and trauma, they say.
The British Committee for Standards in Haematology, Blood Transfusion Task Force guidelines indicate that cryoprecipitate is appropriate if fibrinogen levels fall below 1.0 g/L in the setting of severe bleeding and/or disseminated intravascular coagulation.
Cryoprecipitate guidelines published in the British Columbia Medical Journal also advise its use for hypodysfibrinogenemia when recombinant or virally inactivated concentrates are not available for von Willebrand disease, hemophilia A, factor XIII deficiency, and thrombolytic-related hemorrhage. It has also been suggested as a reasonable therapeutic option for uremic bleeding.
However, despite its widespread use in different clinical scenarios, Callum et al suggest: “There are insufficient data to determine the clinical setting where this product might be clinically efficacious.”
They highlight some clinical questions regarding the transfusion of cryoprecipitate that remain to be answered, including the dosage of cryoprecipitate needed to replete hypofibringenemia, the impact of pooling on the speed of cryoprecipitate delivery to the patient, the incidence of adverse events reported to national hemovigilance programs, and the possible clinical role of virally inactivated pooled fibrinogen products.
Cryroprecipitate has also been suggested as a possible treatment for patients with severe and persistent disseminated intravascular coagulation (DIC) that does not resolve with FFP replacement.
DIC complicates a range of illnesses, including sepsis and severe infection, trauma, malignancy, and can occur as a result of obstetric complications and vascular abnormalities.
In their guidelines for the British Society for Haematology, M Levi (Academic Medical Centre, Amsterdam, The Netherlands) and colleagues say that DIC should be diagnosed based on an appropriate clinical suspicion supported by relevant laboratory tests.
Moreover, the cornerstone of DIC treatment is treating the underlying condition.
They summarize that transfusion of platelets or plasma should be reserved for patients with DIC who present with bleeding or are at high risk for bleeding and have a platelet count below 50 x 109/L.
Administration of FFP may be useful for such DIC patients if they have prolonged prothrombin time and activated partial thromboplastin time.
However, if FFP transfusion is not possible because of fluid overload, the researchers say that factor concentrates, such as prothrombin complex concentrate can be considered.
Patients with persistent severe hypofibrinogenemia of less than 1 g/L despite FFP replacement may be treated with fibrinogen concentrate or cryoprecipitate.