Heparin-induced Thrombocytopenia Type Research Articles

Outcomes of heparin-induced thrombocytopenia type II in aneurysmal subarachnoid hemorrhage patients: A US nationwide analysis.

Despite the widespread use of heparin during and following endovascular procedures in the management of aneurysmal subarachnoid hemorrhage (SAH) patients, limited research has explored the incidence and impact of heparin-induced thrombocytopenia (HIT) on SAH. Descriptive statistics, multivariate regressions, and propensity score-matching were employed to compare clinical characteristics, comorbidities, interventions, complications, and outcomes of HIT in SAH patients identified within the US National Inpatient Sample database from 2010 to 2019. Among 76 387 SAH patients from 2010 to 2019, 166 (0.22%) developed HIT. HIT was identified as a significant predictor of prolonged length of stay (OR 6.799, 95% CI 3.985 to 11.6, P<0.01) and poor functional outcomes (OR 2.541, 95% CI 1.628 to 3.966, P<0.01) after adjusting for relevant factors. HIT incidence was higher in patients with elevated SAH severity scores (1.42 vs 1.06, P<0.01), younger patients (58.04 vs 61.39 years, P=0.01), overweight individuals (0.4% vs 0.2%, P<0.01), those on long-term anticoagulants (10.84% vs 5.72%, P<0.01), or with a cerebrospinal fluid drainage device (external ventricular drain, ventriculoperitoneal shunt; P<0.01). HIT patients showed increased rates of endovascular coiling, ventricular drain placement, shunt placement, deep vein thrombosis, urinary tract infection, acute kidney injury, pulmonary embolism, venous sinus thrombosis, pneumonia, and cerebral vasospasm (all P<0.01). SAH patients with HIT exhibited various comorbidities and increased rates of complications, which may contribute to extended hospital stays. This nationwide study aids clinical suspicion and highlights HIT's impact on SAH patients.

Recurrent Venous Thromboembolism in Patients on Anticoagulation: An Update Based on the Revised AWMF S2k Guideline.

In the recently updated German S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," a new chapter was incorporated about recurrent venous thromboembolism (VTE) in patients on anticoagulation treatment. Despite the high efficacy of anticoagulation in most patients, approximately 2% experience a recurrent VTE event while receiving anticoagulant drugs. The proper diagnosis of the recurrent VTE is important and possible only with the knowledge of localization and thrombus burden of the primary VTE event. Possible reasons for recurrent VTE events in patients on anticoagulation are non-adherence to medication, sub-therapeutic drug levels due to resorption disorders or drug interactions, or concomitant disease with high thrombogenicity. Cancer is the most common underlying disease, but it is important to investigate and understand possible other causes whenever a breakthrough VTE event occurs. This results in the recommendation that in patients with VTE recurrence on therapeutic anticoagulation, in particular, the presence of malignant disease, antiphospholipid syndrome, and rare diseases like paroxysmal nocturnal hemoglobinuria or Behçet's disease should be considered. For VTE recurrence during heparin therapy, heparin-induced thrombocytopenia type II needs to be ruled out, even if platelet counts are within the normal range. Although the mechanisms of recurrence on anticoagulation can be evaluated in a certain degree, clinical evidence for the management of recurrent VTE in anticoagulated patients is minimal and mainly based on expert opinion. Switching anticoagulant medication and intensifying anticoagulant treatment are possible options.

Novel Knowledge about Molecular Mechanisms of Heparin-Induced Thrombocytopenia Type II and Treatment Targets.

Heparin-induced thrombocytopenia type II (HIT II), as stated in the literature, occurs in about 3% of all patients and in 0.1-5% of surgical patients. Thrombosis develops in 20-64% of patients with HIT. The mortality rate in HIT II has not decreased using non-heparin treatment with anticoagulants such as argatroban and lepirudin. An improved understanding of the pathophysiology of HIT may help identify targeted therapies to prevent thrombosis without subjecting patients to the risk of intense anticoagulation. The review will summarize the current knowledge about the pathogenesis of HIT II, potential new therapeutic targets related to it, and new treatments being developed. HIT II pathogenesis involves multi-step immune-mediated pathways dependent on the ratio of PF4/heparin and platelet, monocyte, neutrophil, and endothelium activation. For years, only platelets were known to take part in HIT II development. A few years ago, specific receptors and signal-induced pathways in monocytes, neutrophils and endothelium were revealed. It had been shown that the cells that had become active realised different newly formed compounds (platelet-released TF, TNFα, NAP2, CXCL-7, ENA-78, platelet-derived microparticles; monocytes-TF-MPs; neutrophils-NETs), leading to additional cell activation and consequently thrombin generation, resulting in thrombosis. Knowledge about FcγIIa receptors on platelets, monocytes, neutrophils and FcγIIIa on endothelium, chemokine (CXCR-2), and PSGL-1 receptors on neutrophils could allow for the development of a new non-anticoagulant treatment for HIT II. IgG degradation, Syk kinase and NETosis inhibition are in the field of developing new treatment possibilities too. Accordingly, IdeS and DNases-related pathways should be investigated for better understanding of HIT pathogenesis and the possibilities of being the HIT II treatment targets.

A Difficult Task: Determining Oral Anticoagulation Efficacy (OAC) in Patients with HIT Type II

Since 1937, heparin has remained the anticoagulant of choice for a wide variety of clinical scenarios. There remains a relatively high prevalence of heparin-induced thrombocytopenia (HIT), an immune-mediated syndrome in which antibodies (most frequently IgG) bind to a complex of heparin and platelet factor IV, resulting in platelet destruction and the release of prothrombotic platelet derived microparticles. Serious complications include thrombocytopenia (usually occurring between 6-12 days after initiating therapy) and thrombosis. The risk of thrombosis in patients with HIT is estimated at 30% and mortality rates have been reported as high as 20-30%. In cases of HIT type II when patients require continuous anticoagulation, such as following implantation of mechanical heart valves, alternative anticoagulants such as direct thrombin inhibitors can be used. The difficulty of using drugs such as argatroban for bridging therapy to warfarin is that they have been found to elevate both the aPTT as well as INR. Therefore, is it difficult to assess whether patients will maintain therapeutic INRs when argatroban is held and they are continued on warfarin monotherapy. The standard treatment regimen calls for argatroban to be started until INR reaches some therapeutic level at which time argatroban is held and INR is rechecked 4-6 hours later. The risk of major bleeding associated with supra-therapeutic INR's is substantial, and as such patients should be continued on bridging therapy to the lowest INR level that is still found to be therapeutic once argatroban is held. Previous research has examined the efficacy of transitioning from argatroban to warfarin in patients with HIT type II. This case report reviews the care of a patient following a diagnosis of HIT, the methods used to measure the efficacy of oral anticoagulation (OAC), and the complications that arose with management. The patient is a 51-year-old woman who received a mechanical mitral valve replacement for mitral valve regurgitation. Two weeks later, she returned to the hospital with lower extremity swelling. On admit, the patient's INR was sub-therapeutic at 1.2. Enoxaparin was initiated with plans to bridge to warfarin until the INR reached 2.5-3.5. Within four days of enoxaparin initiation, platelets decreased from 238,000/uL to 114,000/uL. On day four, a new non-occlusive right internal jugular thrombus was found. A serotonin release assay (SRA) and HIT antibody with reflex were ordered. While labs were in process, enoxaparin was held and argatroban initiated. The PTT was checked and found to be 62.6 seconds, and it was determined that the patient was adequately anticoagulated. A 4-T score of 6 indicated a ~64% probability of HIT with the patient requiring indefinite anticoagulation due to the mechanical mitral valve. When the patient's INR reached 2.5 argatroban was held, however the following INR was found to be subtherapeutic at 1.3. Argatroban was restarted with plans to continue argatroban therapy until INR>4, at which time argatroban was to be held and INR rechecked in 4-6 hrs. If the INR remained therapeutic off argatroban then it was determined that the patient was appropriately anticoagulated. When the INR reached 4.9 and argatroban was held, the recheck 5 hours later was 3.1. Using this algorithm, the patient ultimately achieved a therapeutic INR with platelet counts of >300,000/uL at time of discharge without any major bleeding events or other serious complications. For patients in whom HIT is diagnosed, immediate discontinuation of heparin infusions and elimination of heparin from all flushes and ports is a necessity as the first step of treatment. Argatroban may be used as a bridging agent, but OAC efficacy cannot be monitored solely using the parameter of INR due to argatroban's INR-elevating effect. By trending the aPTT to monitor anticoagulation status and only utilizing the INR once argatroban therapy was removed, we ensured that the patient had achieved OAC efficacy prior to discharge. In our patient an INR of 5 did not result in any major bleeding incident; however, by initially discontinuing prematurely at an INR of 2.5, the patient's hospital stay was extended. The chromogenic factor X assay has shown some accuracy in predicting INR free of argatroban influence by measuring the amount of vitamin x, but further studies are warranted to establish an optimal method by which to convert patients from argatroban to warfarin. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Importance of gradual induction in oral anticoagulation therapy in a patient with heparin-induced thrombocytopenia with a left ventricular assist device: a case report

BackgroundWe encountered a case of a patient with heparin-induced thrombocytopenia (HIT) who developed multiple thromboses following implantable left ventricular assist device (iLVAD) implantation. We herein report this case along with a literature-based discussion on the timing of warfarin initiation for such patients.Case presentationA 15-year-old boy was rushed to our hospital due to cardiogenic shock associated with multiple organ dysfunction. A detailed examination, including cardiac catheterization and right heart biopsy, provided a diagnosis of dilated cardiomyopathy, for which an iLVAD placement as a bridge to cardiac transplantation was scheduled after the transplant workup. Three days before the surgery, the patient’s platelet count decreased drastically from 110,000 to 40,000/µL, suggesting HIT, and his blood sample was sent to a specialized laboratory outside our hospital. The HIT antibody test came back positive during the iLVAD implantation using heparin. Thus, we chose argatroban over heparin for postoperative anticoagulation therapy, which was initiated 6 h after the surgery. The day after surgery, the patient was successfully weaned off mechanical ventilation and extubated. Oral anticoagulation therapy with warfarin was also initiated; however, on postoperative day 2, contrast-enhanced computed tomography revealed multiple thrombi in the left iliac artery, right iliac vein, and right jugular vein. We suspected hypercoagulation associated with the initiation of warfarin, prompting us to suspend warfarin and continue anticoagulation therapy with argatroban alone. On postoperative day 8, the patient’s platelet count increased to 130,000/µL despite not reaching the normal range and showed two consecutive increases; therefore, we resumed oral warfarin, concerning the efficacy of argatroban as an anticoagulant for iLVAD. Thromboembolism did not recur; the patient was discharged 50 days after the operation and is currently awaiting heart transplantation.ConclusionsWe encountered a case of HIT type II in which multiple thromboses occurred following iLVAD implantation. If HIT antibodies are detected, it is crucial to initiate argatroban monotherapy and wait to start oral anticoagulation therapy with warfarin until platelet count has improved.

An institutional report of heparin induced thrombocytopenia type II in aneurysmal subarachnoid hemorrhage patients.

Heparin induced thrombocytopenia Type II (HIT-II) is a dangerous thromboembolic complication of heparin therapy. The current literature on incidence and outcomes of HIT-II in aneurysmal subarachnoid hemorrhage (aSAH) patients remains sparse. We report our institution's incidence and outcomes of HIT-II in aSAH patients. We performed a retrospective cohort study at an academic medical center between June 2014 and July 2018. All patients had aSAH confirmed by digital subtraction angiography. Diagnosis of HIT-II was determined by positive results on both heparin PF4-platelet antibody ELISA (anti-PF4) and serotonin release assay (SRA). 204 patients met inclusion criteria. Seven patients (7/204, 3.5%) underwent laboratory testing, three of whom met clinical criteria. HIT-II incidence was confirmed in two of these seven patients (2/204, 0.98%), who had high BMI and T4 scores. Our institution's report of HIT-II incidence in aSAH patients is lower than previously reported in this population and more closely parallels HIT-II incidence in the general and surgical ICU setting. Widely-accepted American College of Chest Physicians (ACCP) clinical diagnostic criteria in conjunction with anti-PF4 and SRA testing is the gold standard of clinical diagnosis of HIT-II in aSAH patients.

Monoclonal and Oligoclonal Anti-PF4 Antibodies Mediate VITT

Background: ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Janssen Johnson & Johnson) vaccines against COVID-19 have been associated with thrombotic thrombocytopenic reactions referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT) characterized by the presence of platelet-activating, anti-PF4 antibodies. While VITT shares key clinical features with a similar but separate entity, Heparin-induced thrombocytopenia (HIT), there appear to be important differences: 1) VITT patients have extremely high thrombosis rates and are very strongly positive in PF4-polyanion ELISAs, and 2) Many patients with VITT frequently present with refractoriness to therapy or have disease recurrence that suggests distinct antibody characteristics due to a strong autoimmune anti-PF4 response.Aims: The goal of this study was to characterize anti-PF4 antibodies in VITT.Methods: Five VITT patients were studied, one after ChAdOx1 nCoV-19 vaccination and four after Ad26.COV2. Reactivity of VITT anti-PF4 antibodies to uncomplexed PF4, PF4-Polyvinyl sulfonate (PVS), and PF4-heparin targets was evaluated, and the platelet-activating ability of these antibodies was examined in the PF4-dependent P-selectin Expression assay (PEA). Anti-PF4 antibodies were isolated from patient blood samples using PF4-treated heparin sepharose beads, and isolated antibodies were subject to mass spectrometric evaluation (Liquid Chromatography Electrospray Ionization Quadrupole time-of-flight mass spectrometry [LC-ESI-QTOF MS]).Results: Antibodies from all VITT patients recognized both uncomplexed and complexed PF4 (Fig. 1A). Interestingly, recognition of PF4 by VITT antibodies was lower if PF4 targets were complexed with polyanions, PVS, or heparin (Fig. 1A). These results contrasted with those obtained in a “classical” HIT patient which showed reactivity to PF4/polyanion complexes, but not to uncomplexed PF4 (Fig 1A). All samples activated platelets in the PEA (data not shown). Mass spectrometric evaluation of anti-PF4 antibodies isolated from VITT patients demonstrated monoclonal anti-PF4 antibodies in three patients, and bi- and tri-clonal antibodies in one patient each (a representative monoclonal antibody anti-PF4 antibody is shown in Fig 1B). Consistent with current dogma, polyclonal anti-PF4/polyanion antibodies were seen in “classical” HIT (Fig 1C). Evaluation of anti-PF4 antibodies in spontaneous HIT, a type of autoimmune HIT seen in pro-inflammatory milieus such as orthopedic surgery and infectious prodromes also demonstrated monoclonal anti-PF4 antibodies (Fig 1D). Eluates from control heparin-sepharose beads did not reveal any immunoglobulins (data not shown).Conclusion: Although development of platelet-activating anti-PF4 antibodies and the thrombotic thrombocytopenia syndrome seen after ChAdOx1 nCoV-19 and Ad26.COV2.S vaccination resembles HIT, these findings demonstrate that clonally restricted anti-PF4 antibodies mediate VITT while polyclonal anti-PF4 antibodies mediate HIT. In addition, we noted clonally-restricted anti-PF4 antibodies in another condition that does not require proximate heparin exposure, spontaneous (“autoimmune”) HIT. In VITT, the strong immune response after vaccine administration may result in the activation of a single or few pre-existing anti-PF4 reactive clones, and development of clonally restricted anti-PF4 antibodies with a similar pathophysiology to Spontaneous HIT. It is also likely that high levels of monoclonal/oligoclonal anti-PF4 antibodies cause the severe thrombotic phenotypes seen in VITT and Spontaneous HIT. The high mortality rate and reports of disease refractoriness to therapy in VITT may warrant consideration of additional therapeutic modalities like rituximab and therapeutic plasma exchange in select cases.Figure Legends: (A): VITT (Patient 1-ChAdOx1 nCoV-19; Patients 2-5, Ad26.COV2.S) patient samples were tested in ELISA against uncomplexed PF4 (white), and PF4 in complex with polyvinyl sulfonate (light grey), or unfractionated heparin (dark gray). (B-D) Mass spectrometric evaluation of anti-PF4 antibodies isolated from VITT (B), HIT (C) and spontaneous HIT patient sera (D). “Relative Intensity” refers to abundance of the Ig light chain relative to the polyclonal background. Numbers above Ig light chain peaks depict mass/charge ratios. NC- Normal control. [Display omitted] DisclosuresMurray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Padmanabhan: Veralox Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Recurrent Early Filter Clotting during Continuous Veno-Venous Hemodialysis with Regional Citrate Anticoagulation is Linked to Systemic Thrombin Generation and Heparin Induced Thrombocytopenia Type II: A Retrospective Analysis

Objective: Regional Citrate Anticoagulation (RCA) for Continuous Renal Replacement Therapy (CRRT) is widely used and leads to an excellent clottingfree filter survival. Despite strict adherence to protocols, in some cases recurrent early filter-clotting occurs. The aim of this observational study was to evaluate the underlying causes and the efficacy of interventions in patients with early recurrent filter-clotting during RCA. Methods: In a retrospective analysis of a cohort of 1183 patients treated with RCA-CRRT we detected 12 patients with early filter-clotting unrelated to protocol violation or any obvious technical or medical reason. Results: All patients were systemically anticoagulated with low molecular weight or unfractionated heparin for at least 24h before initiation of Continuous Veno-Venous Hemodialysis with RCA (RCA-CVVHD). During RCA, all postfilter ionized calcium concentrations were in the target range (mean 0.33±0.05 mmol/L). At the time of the first clotting event, thrombocyte counts were 168±66/ nL. After the clotting events, the systemic anticoagulation was switched to argatroban in all patients. With systemic anticoagulation using argatroban filter lifetime of RCA-CVVHD increased significantly (p&lt;0.001) and clotting-events decreased from 0.61 to 0.10 per 24h. All patients were tested for HIT and 5/12 (42%) had a positive test for hep-PF4-antibodies. Application of argatroban significantly reduced early filter-clotting both in HIT-positive patients as well as in HIT-negative patients. At the time of the first clotting event, no patient had clinical signs of thrombosis or thromboembolism. However, during follow up a thromboembolic event occurred in three patients. Conclusion: In patients with recurrent early filter-clotting despite strict adherence to the citrate protocol undetected HIT or other causes of thrombin activation may be present. Therefore, patients with recurrent early filter clotting in RCA-CVVHD should be screened for HIT or other conditions that may activate thrombin. A significant improvement of filter run-time can be achieved by systemic administration of a thrombin inhibitor both in patients with and without HIT.

Recurrent Early Filter Clotting during Continuous Veno-Venous Hemodialysis with Regional Citrate Anticoagulation is Linked to Systemic Thrombin Generation and Heparin Induced Thrombocytopenia Type II: A Retrospective Analysis

Objective: Regional Citrate Anticoagulation (RCA) for Continuous Renal Replacement Therapy (CRRT) is widely used and leads to an excellent clottingfree filter survival. Despite strict adherence to protocols, in some cases recurrent early filter-clotting occurs. The aim of this observational study was to evaluate the underlying causes and the efficacy of interventions in patients with early recurrent filter-clotting during RCA. Methods: In a retrospective analysis of a cohort of 1183 patients treated with RCA-CRRT we detected 12 patients with early filter-clotting unrelated to protocol violation or any obvious technical or medical reason. Results: All patients were systemically anticoagulated with low molecular weight or unfractionated heparin for at least 24h before initiation of Continuous Veno-Venous Hemodialysis with RCA (RCA-CVVHD). During RCA, all postfilter ionized calcium concentrations were in the target range (mean 0.33±0.05 mmol/L). At the time of the first clotting event, thrombocyte counts were 168±66/ nL. After the clotting events, the systemic anticoagulation was switched to argatroban in all patients. With systemic anticoagulation using argatroban filter lifetime of RCA-CVVHD increased significantly (p&lt;0.001) and clotting-events decreased from 0.61 to 0.10 per 24h. All patients were tested for HIT and 5/12 (42%) had a positive test for hep-PF4-antibodies. Application of argatroban significantly reduced early filter-clotting both in HIT-positive patients as well as in HIT-negative patients. At the time of the first clotting event, no patient had clinical signs of thrombosis or thromboembolism. However, during follow up a thromboembolic event occurred in three patients. Conclusion: In patients with recurrent early filter-clotting despite strict adherence to the citrate protocol undetected HIT or other causes of thrombin activation may be present. Therefore, patients with recurrent early filter clotting in RCA-CVVHD should be screened for HIT or other conditions that may activate thrombin. A significant improvement of filter run-time can be achieved by systemic administration of a thrombin inhibitor both in patients with and without HIT.

A Case Report of Hematuria in Heparin-Induced Thrombocytopenia: An Unusual Presentation Leading to End Organ Damage

Heparin is commonly used in many clinical scenarios, including venous thromboembolism, acute coronary syndromes, atrial fibrillation, orthopedic surgeries, dialysis, during extracorporeal circulation and peripheral occlusive disease.1 A life-threatening complication following heparin therapy is heparin-induced thrombocytopenia (HIT). Generally, there are two types of HIT. Type 1 HIT is a mild and non-immune disorder that presents early, usually in the first 48 hours after exposure to heparin. It is caused by an interaction between heparin and platelets leading to the formation of platelet aggregates.1,2 Type 2 HIT is an immune-mediated condition which occurs 4-14 days after exposure and sometimes has life-threatening complications.2 HIT has many different manifestations, so it is important to be cautious in a patient who is on heparin for any reason. Here, we are reporting a case of an elderly lady presented with frank hematuria (a rare presentation) later diagnosed as HIT and ultimately had extensive renal vein thrombosis which led to end-organ damage

Use of argatroban in combination with nafamostat mesilate in open-heart surgery for a pediatric patient with heparin-induced thrombocytopenia type II: a case report

BackgroundHeparin-induced thrombocytopenia type II (HIT II) is a rare, immune-mediated complication of heparin therapy and can cause life-threatening thromboembolism. However, perioperative anticoagulation therapy for patients with a complication of HIT II has not been established.Case presentationA 6-year-old boy with tetralogy of Fallot underwent radical intracardiac repair with administration of argatroban at 1 year old due to positive HIT antibody. Reoperation was scheduled for pulmonary valve insufficiency, using argatroban and nafamostat mesilate as anticoagulants. Argatroban has a long onset time and the activated coagulation time (ACT) requires 7–26 h to return to the preadministration level, making hemorrhage control difficult, while half-life of nafamostat mesilate is shorter than that of argatroban. Celite ACT reflects the effects of both argatroban and nafamostat mesilate, but kaolin ACT reflects only the effect of argatroban. Due to the early termination of argatroban administration based on Celite and kaolin ACTs, ACT recovered to ≤ 200 s at 5 h after the end of argatroban administration.ConclusionCelite and kaolin ACTs can be used as markers to obtain close control of the required dose of argatroban in combination with nafamostat mesilate for the management of HIT II patients.

Incidence and outcomes of heparin-induced thrombocytopenia type II in children after correction of congenital heart disease

Incidence and outcomes of heparin-induced thrombocytopenia type II in children after correction of congenital heart disease

Oral Bruton tyrosine kinase inhibitors block activation of the platelet Fc receptor CD32a (FcγRIIA): a new option in HIT?

AbstractActivation of the platelet Fc-receptor CD32a (FcγRIIA) is an early and crucial step in the pathogenesis of heparin-induced thrombocytopenia type II (HIT) that has not been therapeutically targeted. Downstream FcγRIIA Bruton tyrosine kinase (BTK) is activated; however, its role in Fc receptor–induced platelet activation is unknown. We explored the potential to prevent FcγRIIA-induced platelet activation by BTK inhibitors (BTKi's) approved (ibrutinib, acalabrutinib) or in clinical trials (zanubrutinib [BGB-3111] and tirabrutinib [ONO/GS-4059]) for B-cell malignancies, or in trials for autoimmune diseases (evobrutinib, fenebrutinib [GDC-0853]). We found that all BTKi's blocked platelet activation in blood after FcγRIIA stimulation by antibody-mediated cross-linking (inducing platelet aggregation and secretion) or anti-CD9 antibody (inducing platelet aggregation only). The concentrations that inhibit 50% (IC50) of FcγRIIA cross-linking–induced platelet aggregation were for the irreversible BTKi's ibrutinib 0.08 µM, zanubrutinib 0.11 µM, acalabrutinib 0.38 µM, tirabrutinib 0.42 µM, evobrutinib 1.13 µM, and for the reversible BTKi fenebrutinib 0.011 µM. IC50 values for ibrutinib and acalabrutinib were four- to fivefold lower than the drug plasma concentrations in patients treated for B-cell malignancies. The BTKi's also suppressed adenosine triphosphate secretion, P-selectin expression, and platelet-neutrophil complex formation after FcγRIIA cross-linking. Moreover, platelet aggregation in donor blood stimulated by sera from HIT patients was blocked by BTKi's. A single oral intake of ibrutinib (280 mg) was sufficient for a rapid and sustained suppression of platelet FcγRIIA activation. Platelet aggregation by adenosine 5′-diphosphate, arachidonic acid, or thrombin receptor-activating peptide was not inhibited. Thus, irreversible and reversible BTKi's potently inhibit platelet activation by FcγRIIA in blood. This new rationale deserves testing in patients with HIT.

Argatroban-refractory, Heparin-induced Thrombocytopenia after Coronary Intervention with Radial Artery Occlusion.

Heparin induced thrombocytopenia (HIT) is serious disorder that occurs in a small percentage of patients following exposure to heparin. HIT can further be classified into two types: HIT type 1 and type 2. Type 2 HIT is a potentially life threatening with clinically significant outcomes. It presents with thrombocytopenia and evidence of thrombus formation in the presence of antibody formation. Additionally, several variations of HIT exist, including delayed onset HIT and refractory HIT, known collectively as autoimmune HIT (aHIT). Here we present a case of delayed onset and refractory HIT in a patient with little heparin exposure, discovered only after cardiac intervention for suspected STEMI. Significant thrombotic events occurred thereafter, including radial artery stenosis and intracardiac thrombus. Treatment with argatroban was ineffective. Significant resolution of thrombocytopenia was seen several weeks after infusion with IVIG, thus depicting further suspicion for refractory HIT. IVIG for aHIT treatment is traditionally chosen only if the disease process is refractory to other anticoagulation efforts due to the potential risk for increasing thrombotic risk with IVIG infusion. Our case illistrate the rare presentation of aHIT and the use if IVIG to successfully treat thrombocytopenia in refractory HIT.

A Case of Surgical Ventricular Restoration with Heparin-Induced Thrombocytopenia Type II

A Case of Surgical Ventricular Restoration with Heparin-Induced Thrombocytopenia Type II

The Use of Cangrelor and Heparin for Anticoagulation in a Patient Requiring Pulmonary Thromboendarterectomy Surgery with Suspected Heparin-Induced Thrombocytopenia

The management of heparin-induced thrombocytopenia (HIT) in the perioperative period for patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) can be a challenging clinical scenario. Once a diagnosis of HIT has been established, heparin products typically are avoided and alternative therapies for anticoagulation are started. Alternative anticoagulation strategies for CPB are limited and often have various pharmacokinetic profiles that may lead to increased perioperative bleeding. Historically the use of a GPIIb/IIIa inhibitor, such as tirofiban, followed by unfractionated heparin (UFH) is the typical alternative for surgeries requiring DHCA in patients with HIT at the authors' institution. This article presents a case in which cangrelor followed by UFH was used in a 20-year-old patient with suspected HIT and chronic thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy surgery requiring CPB and DHCA. Due to the frequency of significant postoperative bleeding encountered when using tirofiban and UFH, it was decided to attempt to block platelet aggregation with significantly shorter-acting cangrelor. The authors hypothesized that cangrelor would reduce the risk of significant bleeding compared with tirofiban because of its favorable pharmacokinetics. Specifically, cangrelor has a short elimination half-life of 3 to 6 minutes, and its elimination is not altered by renal and hepatic impairment. This case report discusses the pathophysiology of HIT, the alternative anticoagulants used for HIT type II in pulmonary thromboendarterectomy, and the potential of cangrelor in conjunction with UFH to be a favorable option for patients in similar clinical scenarios.

Use of Fondaparinux Off-Label or Approved Anticoagulants for Management of Heparin-Induced Thrombocytopenia

BackgroundLife-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label. ObjectivesThe authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT. MethodsIn a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings. ResultsOf 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed “true“ HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux. ConclusionsFondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238)

Prevalence and Overtesting of True Heparin-Induced Thrombocytopenia in a 591-Bed Tertiary Care, Teaching Hospital.

Heparin-induced thrombocytopenia type II (HIT) is a rare but potentially fatal antibody-mediated reaction to all forms of heparin (unfractionated heparin, low-molecular weight heparin, heparin flushes, and heparin-coated catheters), which can lead to HIT with thrombosis. Two tests commonly used to screen for HIT include the enzyme-linked immunosorbent assay (ELISA) and serotonin release assay (SRA). This is a retrospective chart review study conducted from January 1, 2013, through December 31, 2014, to estimate the rate of true HIT in critical care patients at Winthrop-University Hospital, located in Mineola, New York. Patients are classified as positive for HIT if both ELISA and SRA immunoassays are positive. We reviewed 507 heparin immunoassays, excluding 64 who had an inappropriate ELISA test sent due to no administration of heparin, enoxaparin, or heparin lock flush at this or previous hospital stays at Winthrop. Of the 443 heparin immunoassays, ELISA results were positive for 66 patients (15.1%), and only 11 (2.5%) patients had true cases of HIT with a 95% confidence interval of 1.3% to 4.4%. The 4T score for those with true HIT (median: 5.0) was statistically higher compared to those without true HIT (median: 2.0; P < .001). Despite guidelines in place, overtesting for HIT is still a prevalent issue.

Transjugular local thrombolysis with/without TIPS in patients with acute non-cirrhotic, non-malignant portal vein thrombosis

Background & aimsTherapeutic anticoagulation is the standard treatment in patients with acute non-cirrhotic portal vein thrombosis (PVT). In critically ill patients, anticoagulation only may not suffice to achive rapid and stable recanalization. This study evaluates efficacy and safety of transjugular interventional therapy in acute non-cirrhotic PVT. MethodsThis retrospective study includes 17 consecutive patients with acute noncirrhotic, non-malignant PVT. Main indication for interventional therapy was imminent intestinal infarction (n=10). Treatment consisted of a combination of transjugular thrombectomy, local fibrinolysis and – depending on thrombus resolution – transjugular intrahepatic portosystemic shunt. ResultsRecanalization was successful in 94.1%. One- and two-year secondary PV patency rates were 88.2%. Major complications (n=3) resolved spontaneously in all but one patient (heparin induced thrombocytopenia type 2 with intestinal infarction). Symptoms improved in all patients. However, segmental bowel resection had to be performed in two (11.8%). During a median follow-up of 28.6 months, no patient experienced portal hypertensive complications. Presence of JAK2 V617F mutation predicted both short-term and long-term technical success. ConclusionsTransjugular recanalization is safe and effective in patients with acute non-cirrhotic, non-malignant PVT. It should be considered especially in patients with imminent bowel infarction and low likelihood of recanalization following therapeutic anticoagulation. Patients with JAK2 mutation ought to be followed meticulously.

Heparin-Induced Thrombocytopenia with Thrombosis

Heparin-induced thrombocytopenia type II (HIT II) is an immune-mediated adverse drug reaction to heparin and heparinoid compounds. Unlike other etiologies of thrombocytopenia, HIT II frequently manifests with arterial or venous thromboemboli, leading to significant morbidity and mortality. Diagnosis of HIT II requires a high clinical suspicion, pretest probability scoring, and laboratory confirmation through immunologic and functional assays. Moderate probability for HIT II should be met with discontinuation of the offending agent and initiation of an alternative anticoagulant. Key words: heparin-induced thrombocytopenia, heparin-induced thrombocytopenia with thrombosis, HIT II, HITT