Kathleen Selleng

Heparin‐induced thrombocytopenia: a prospective study on the incidence, platelet‐activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes

Summary.  Introduction: Platelet‐activating antiplatelet factor 4/heparin (anti‐PF4/heparin) antibodies are the major cause of heparin‐induced thrombocytopenia (HIT). However, the relative utility of functional (platelet activation) vs. antigen [enzyme‐immunoassay (EIA)] assays, and the significance of assay discrepancies remain unresolved.Methods: Consecutive patient sera (n = 1650) referred for diagnostic HIT testing were screened prospectively by both the heparin‐induced platelet activation (HIPA) test and anti‐PF4/heparin EIA – including individual classes (IgG, IgA, IgM) – with clinical correlations studied. Platelet microparticle and annexin‐V‐binding properties of the sera were also investigated.Results: Only 205 (12.4%) sera tested positive in either the HIPA and/or EIA: 95 (46.3%) were positive in both, 109 (53.1%) were only EIA‐positive, and, notably, only one serum was HIPA‐positive/EIA‐negative. Of 185 EIA‐positive sera, only 17.6% had detectable IgM and/or IgA without detectable IgG. Among sera positive for EIA IgG, optical density values were higher when the sera were HIPA‐positive (1.117 vs. 0.768; P < 0.0001), with widely overlapping values. Two HIPA‐positive but EIA‐IgG‐negative sera became HIPA‐negative following IgG depletion, suggesting platelet‐activating antibodies against non‐PF4‐dependent antigens. Clinical correlations showed that HIPA‐negative/EIA‐positive patients did not develop thrombosis and had reasons other than HIT to explain thrombocytopenia. IgM/A antibodies did not increase microparticle penetration, but increased annexin‐V binding.Conclusions: The anti‐PF4/heparin EIA has high (∼99%) sensitivity for HIT. However, only about half of EIA‐positive patients are likely to have HIT. Anti‐PF4/heparin antibodies of IgM/A class and non‐PF4‐dependent antigens have only a minor role in HIT.

Heparin-induced thrombocytopenia in intensive care patients

Objective:To summarize new information on frequency of heparin-induced thrombocytopenia (HIT) in patients treated in intensive care units (ICU), developments in the interpretation of assays for detecting anti-PF4/heparin antibodies, and treatment of HIT patients. Study Selection:All data on the frequency of laboratory-confirmed HIT in ICU patients were included; for laboratory testing of HIT and treatment of patients, this review focuses on recent data that became available in 2005 and 2006. Data Extraction and Synthesis:HIT is a potentially life-threatening adverse effect of heparin treatment caused by platelet-activating antibodies of immunoglobulin G class usually recognizing complexes of platelet factor 4 and heparin. HIT is more often caused by unfractionated heparin than low-molecular-weight heparin and is more common in postsurgical than in medical patients. In the ICU setting, HIT is uncommon (0.3–0.5%), whereas thrombocytopenia from other causes is very common (30–50%). For laboratory diagnosis of HIT antibodies, both antigen assays and functional (platelet activation) assays are available. Both tests are very sensitive (high negative predictive value) but specificity is problematic, especially for the antigen assays, which also detect nonpathogenic immunoglobulin M and immunoglobulin A class antibodies. Detection of immunoglobulin M or immunoglobulin A antibodies could potentially lead to adverse events such as bleeding if a false diagnosis of HIT prompts replacement of heparin by an alternative anticoagulant. For treatment of HIT, three alternative anticoagulants are approved: the direct thrombin inhibitors, lepirudin and argatroban, and the heparinoid, danaparoid (not approved in the United States). Recent data indicate that the approved dosing regimens of the direct thrombin inhibitors are too high, especially in ICU patients. Conclusions:HIT affects <1% of ICU patients even though 30–50% develop thrombocytopenia. The choice of the optimal alternative anticoagulant depends on patient characteristics. Many ICU patients require lower doses of alternative anticoagulant than those recommended by the manufacturer.

Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial

BACKGROUND In May 2011, an outbreak of Shiga toxin-producing enterohaemorrhagic E coli O104:H4 in northern Germany led to a high proportion of patients developing post-enteritis haemolytic uraemic syndrome and thrombotic microangiopathy that were unresponsive to therapeutic plasma exchange or complement-blocking antibody (eculizumab). Some patients needed ventilatory support due to severe neurological complications, which arose 1 week after onset of enteritis, suggesting an antibody-mediated mechanism. Therefore, we aimed to assess immunoadsorption as rescue therapy. METHODS In our prospective non-controlled trial, we enrolled patients with severe neurological symptoms and confirmed recent E coli O104:H4 infection without other acute bacterial infection or raised procalcitonin concentrations. We did IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days, followed by IgG replacement (0·5 g/kg intravenous IgG). We calculated a composite neurological symptom score (lowest score was best) every day and assessed changes before and after immunoadsorption. FINDINGS We enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8·0 days (range 5-12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8·0 days (range 5-15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3·0 (SD 1·1, p=0·038), and improved to 1·0 (1·2, p=0·0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery. INTERPRETATION Antibodies are probably involved in the pathogenesis of severe neurological symptoms in patients with E coli O104:H4-induced haemolytic uraemic syndrome. Immunoadsorption can safely be used to rapidly ameliorate these severe neurological complications. FUNDING Greifswald University and Hannover Medical School.

Reversal of anticoagulants: an overview of current developments

Several new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50 % less intracranial bleeding than VKAs. Nevertheless, they are still associated with bleeding complications. Bleeding can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. This review summarises the current options and strategies in development to antagonise anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors.

Thrombocytopenia in the Intensive Care Unit Patient

The many comorbidities in the severely ill patient also make thrombocytopenia very common (∼40%) in intensive care unit patients. The risk of bleeding is high with severe thrombocytopenia and is enhanced in intensive care patients with mild or moderately low platelet counts when additional factors are present that interfere with normal hemostatic mechanisms (eg, platelet function defects, hyperfibrinolysis, invasive procedures, or catheters). Even if not associated with bleeding, low platelet counts often influence patient management and may prompt physicians to withhold or delay necessary invasive interventions, reduce the intensity of anticoagulation, order prophylactic platelet transfusion, or change anticoagulants due to fear of heparin-induced thrombocytopenia. One approach to identify potential causes of thrombocytopenia that require specific interventions is to consider the dynamics of platelet count changes. The relative decrease in platelet counts within the first 3 to 4 days after major surgery is informative about the magnitude of the trauma or blood loss, whereas the dynamic of the platelet count course thereafter shows whether or not the physiologic compensatory mechanisms are working. A slow and gradual fall in platelet counts developing over 5 to 7 days is more likely to be caused by consumptive coagulopathy or bone marrow failure, whereas any abrupt decrease (within 1-2 days) in platelet counts manifesting after an initial increase in platelet counts approximately 1 to 2 weeks after surgery strongly suggests immunologic causes, including heparin-induced thrombocytopenia, other drug-induced immune thrombocytopenia, and posttransfusion purpura.

Heparin‐induced thrombocytopenia in patients requiring prolonged intensive care unit treatment after cardiopulmonary bypass

Summary.  Background: The diagnosis of heparin‐induced thrombocytopenia (HIT) is problematic in postcardiac surgery (CS) intensive care unit (ICU) patients, as there are multiple potential explanations for thrombocytopenia and the presence of anti‐platelet factor 4/heparin antibodies is not highly specific for HIT. Two platelet count profiles for HIT – a 40% or greater fall in platelet count beginning on or after day 5 (pattern 1) and persisting thrombocytopenia (< 100 × 109 L–1) beyond day 7 (pattern 2) – have been described in post‐CS patients. Methods and results: We examined the platelet count profiles of 329 consecutive post‐CS patients who required ICU treatment beyond 7 days. Although 70 patients (21.3%) developed thrombocytopenia (57.1% pattern 1, 42.9% pattern 2), the overall incidence of HIT was only 1.8% [6/329; 95% confidence interval (95% CI) 0.7–3.9%] in these ICU patients, with more HIT patients showing a pattern 2 than a pattern 1 platelet count decrease (four vs. two patients). Notably, pattern 2 patients with HIT also showed a new proportional fall of > 30% in platelet count between postoperative days 5 and 10. Among the remaining 2242 post‐CS patients without a prolonged ICU stay, only three (0.1%; 95% CI 0.03–0.4%) developed symptomatic HIT (OR 0.07; 95% CI 0.01–0.3; P = 0.0002 vs. ICU patients), all presenting with pattern 1. Conclusions: Among post‐CS ICU patients, a postoperative platelet count fall between days 5 and 10 increases diagnostic specificity for HIT, irrespective of whether this platelet count fall occurs after postoperative platelet count recovery (pattern 1) or is superimposed upon persisting postoperative thrombocytopenia (pattern 2). A prospective study is required in order to validate the findings of this retrospective analysis.

Management of anticoagulation in patients with subacute heparin-induced thrombocytopenia scheduled for heart transplantation

Anticoagulation management of patients with recent heparin-induced thrombocytopenia (HIT) requiring cardiopulmonary bypass (CPB) surgery is a serious challenge, and especially difficult in patients requiring urgent heart transplantation. As nonheparin anticoagulants during CPB bear a high risk of major bleeding, these patients are at risk of being taken off the transplant list. Short-term use of unfractionated heparin (UFH) for CPB, with restriction of UFH to the surgery itself, is safe and effective in patients with a history of HIT who test negative for antiplatelet factor 4 (PF4)/heparin antibodies. We present evidence that it is safe to expand the concept of UFH reexposure to patients with subacute HIT (ie, those patients with recent HIT in whom the platelet count has recovered but in whom anti-PF4/heparin IgG antibodies remain detectable) requiring heart transplantation, if they test negative by a sensitive functional assay using washed platelets. This can be lifesaving in patients with end-stage heart failure.

Studies of the anti-platelet factor 4/heparin immune response: adapting the enzyme-linked immunosorbent spot assay for detection of memory B cells against complex antigens.

BACKGROUND: The anti–platelet factor 4 (PF4)/heparin immune response, which underlies heparin‐induced thrombocytopenia (HIT), has several atypical features: relatively rapid onset even without previous heparin exposure, lack of immune anamnesis, and transience of antibody production.

Errors in patient specimen collection: application of statistical process control

BACKGROUND: Errors in the collection and labeling of blood samples for pretransfusion testing increase the risk of transfusion‐associated patient morbidity and mortality. Statistical process control (SPC) is a recognized method to monitor the performance of a critical process. An easy‐to‐use SPC method was tested to determine its feasibility as a tool for monitoring quality in transfusion medicine.

Heparin-Induced Thrombocytopenia in Intensive Care Patients

Heparin-induced thrombocytopenia (HIT) is a serious, prothrombotic, immune-mediated complication of heparin therapy that can cause limb- and life-threatening thromboembolic events. Prompt diagnosis and therapeutic dose anticoagulation by an alternative anticoagulant are crucial to improve clinical outcome. In critically ill patients, the diagnosis of HIT is difficult due to the high incidence of thrombocytopenia, often caused by reasons other than HIT, and the high incidence of clinically irrelevant, non-platelet-activating anti-PF4-heparin antibodies. Also, treatment of HIT is problematic in these patients. No antidote is available for any of the alternative anticoagulants, and their half-lives are often prolonged in the presence of renal or hepatic insufficiency. This increases the risk of bleeding complications and mandates careful balancing of both risks, thrombosis and bleeding. Therefore, accurate diagnosis of HIT and individual choice of alternative anticoagulant are important for the adequate management of critically ill HIT patients.