Platelet Factor 4 (PF4), also known as CXCL4, is a CXC chemokine crucial for hemostasis, inflammation, and immune responses. Under physiological conditions PF4 assembles into asymmetric tetramers (31.2kDa) that are dimers of dimers with highly flexible N-terminal regions. PF4 tetramers play a central role in prothrombotic autoimmune conditions, such as heparin-induced thrombocytopenia (HIT), as well as vaccine-induced immune thrombocytopenia and thrombosis (VITT). Here, we report the resonance assignments of 1H, 15N, and 13C nuclei for wild-type asymmetric PF4 tetramers using TROSY-based triple resonance NMR experiments. We also used Nz-exchange spectroscopy to identify peaks split by slow-exchange between two distinct conformational states caused by the asymmetry of PF4 tetramers. Our NMR assignments establish a foundation for future investigations into the structural dynamics and functional mechanisms of PF4 as well as its pathological role in anti-PF4 disorders.

Heparin-induced thrombocytopenia (HIT) is a life-threatening immunologic reaction to heparin exposure that is associated with substantial morbidity and mortality. Limited research is available on host-dependent risk factors, such as age, gender, and ethnicity. This study aims to characterize any association between age, gender, ethnicity, and mortality in HIT patients to better identify patient populations at increased risk. This is a retrospective case control analysis of all-cause mortality in 72,935 patients with a diagnosis of HIT between 2016 and 2020. Adult patients with HIT were selected using the ICD-10 code D75.82 (HIT) for inclusion and evaluated by demographic, clinical, and hospital characteristics. Odds ratios were calculated for continuous variables using 95% confidence intervals. Multivariable logistic regression was used to ascertain the odds of binary clinical outcomes relative to patient and hospital characteristics as well as the odds of clinical outcomes over time. Our analysis indicates that hospitalized patients with HIT are at 5 times higher odds of mortality than those without HIT (OR: 5.42, 95% CI: 5.15-5.71, p < 0.001). Our data also indicates significantly higher odds of HIT-associated mortality based on patient age, gender, and ethnicity. By age, HIT patients at the highest risk of mortality were found to be between ages 46 and 60 (odds ratio (OR): 2.60, 95% CI: 1.58-4.25, p < 0.001). By gender, females with HIT are at significantly lower odds of mortality compared to males (OR: 0.90, 95% CI: 0.82-0.99, p < 0.001). By ethnicity, Hispanic patients are at the highest risk of mortality (OR: 1.52, 95% CI: 1.31-1.77, p < 0.001), followed by Black patients (OR: 1.45, 95% CI: 1.27-1.66, p < 0.001), and then Asian patients (OR: 1.31, 95% CI: 1.00-1.72, p = 0.05). HIT remains a clinical diagnosis based on quantitative criteria such as thrombocytopenia relative to baseline and timing of platelet decline but does not take into consideration other clinical variables that may stratify patients by increased risk. This study elucidates the relationship between host-dependent risk factors such as age, gender, and ethnicity on the risk of all-cause mortality associated with HIT.

Background: Heparin-induced thrombocytopenia (HIT) is an acquired prothrombotic state from anti-heparin platelet-factor 4 (PF4) mediated activation of platelets. Anti-PF4 assay is used to screen for HIT due to high sensitivity and negative predictive value. Case Report: We present a 74-year-old male that had clinical HIT with false negative anti-PF4 and subsequently positive serotonin release assay (SRA). Delay in cessation of heparin led to recurrent limb thrombosis in the setting of multiple revascularization attempts with a poor outcome. Conclusion: We re-emphasize the importance of clinical presentation in management of patients with suspected HIT.

Heparin is the standard anticoagulant for structural cardiac procedures, including left atrial appendage occlusion (LAAO). However, alternative agents are needed in patients with contraindications such as heparin-induced thrombocytopenia (HIT). Data on the use of argatroban, a direct thrombin inhibitor, for procedural anticoagulation during LAAO are extremely limited. We describe a 67-year-old man with chronic atrial fibrillation, end-stage renal disease on hemodialysis, and a history of HIT type II who underwent LAAO with a Watchman device under general anesthesia. Due to his renal failure and high risk of recurrent HIT, argatroban was selected for intraoperative anticoagulation. A reduced initial bolus of argatroban achieved supratherapeutic activated clotting time (ACT), and when the infusion was started, ACT levels again exceeded the target range, highlighting the need for close monitoring. The procedure was completed without thromboembolic or hemorrhagic complications. This case demonstrates the effective use of argatroban as an intraoperative anticoagulant in LAAO for patients with HIT and renal impairment. A lower initial bolus and infusion rate may be sufficient with vigilant ACT monitoring to avoid complications of prolonged anticoagulation.

Anti-platelet factor 4 (PF4) disorders, including heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), and emerging disorders such as VITT-like monoclonal gammopathy of thrombotic significance (MGTS), are monoclonal antibody-mediated and characterized by thrombocytopenia and thrombosis. Understanding the cellular and molecular mechanisms among these anti-PF4 disorders can help explain the variability in clinical presentations. Recent work demonstrated that beyond platelets, immune and vascular cells serve a critical role in driving thrombosis and the severity of clinical outcomes. Neutrophils drive thrombosis via NETosis, monocytes release tissue factor-rich microparticles, and endothelial cells provide adhesive and immunogenic surfaces that sustain thromboinflammation. Thus, our understanding of the pathogenesis of anti-PF4 disorders is defined by complex interactions and effector functions of multiple cellular contributors working in parallel to create a highly prothrombotic environment. A deeper understanding of these intercellular pathways will shed light on the role of innate immune cells, in addition to platelets, in creating variable clinical outcomes between anti-PF4 disorders and reveal novel therapeutic targets. This expands our understanding of unifying mechanisms between these disorders and informs future strategies to improve diagnosis and treatment.

When pregnancy, HIT, and stroke collide: Navigating complex thrombotic care in a community-based setting

Anti-PF4 antibodies are a potential mediator of antisense oligonucleotide (ASO)-induced thrombocytopenia.

Heparin-induced thrombocytopenia after percutaneous coronary intervention complicated by hemothorax and pulmonary thromboembolism: The scylla and charybdis of hematology

Labile heparin response in a pre-operative cardiac surgery patient: Unmasking predisposition for post-operative coagulopathy

Bleeding and thrombotic events in patients with heparin-induced thrombocytopenia: a two-decade single-center experience in Thailand

Outcomes associated with mitigating venous thromboembolism risk in pregnant patients with sickle cell disease

Evolving catastrophic antiphospholipid syndrome with intracerebral hemorrhage: Treatment with plasma exchange and rituximab

Ecarin-based coagulation monitoring of argatroban in patients with heparin-induced thrombocytopenia: a prospective observational study.

Abstract Background Thrombotic microangiopathy (TMA) is a rare but devastating complication of systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). It typically responds poorly to standard immunosuppression. Eculizumab, a recombinant monoclonal antibody C5 inhibitor, is now known to be efficacious for primary complement-mediated TMA due to genetic mutations in the complement pathway, or atypical haemolytic uraemic syndrome (aHUS). Its use is less established in secondary TMA such as that associated with SLE, but case report data have indicated benefit particularly in resistant cases. Since complement activation plays a key role in the pathogenesis of TMA secondary to SLE, it is thought that a therapy targeting the complement pathway could be effective. Case Report We present a case of a 35-year-old South Indian female with the most severe and refractory form of SLE, with background antiphospholipid syndrome (APS) and extensive history of thrombosis. She was strongly positive for lupus anticoagulant, anti-cardiolipin antibodies and anti beta2 glycoprotein 1 antibodies. She had multi-organ involvement of SLE with bilateral lupus related retinochoroiditis, tendinopathies, renal involvement, and unilateral sensorineural hearing loss. During a hospital admission, she became thrombocytopenic and blood film was consistent with microangiopathy. Thrombocytopenia screen including heparin induced thrombocytopenia (HIT) IgG ELISA test was negative; ADAMST13 assay was within normal range. A bone marrow biopsy showed bone marrow necrosis and marrow vessel thrombosis. Given her presentation, the initial proposed diagnosis was catastrophic antiphospholipid syndrome (CAPS) therefore she was treated with plasma exchange, intravenous immunoglobulin (IVIG), high dose steroids as well as continuation of anticoagulation with platelet support. However, thrombocytopenia and microangiopathy persisted despite treatment which was unusual for true CAPS. Therefore, this prompted urgent need for a kidney biopsy. The kidney biopsy confirmed presence of intra-capillary thrombus formation and red cell fragmentation consistent with acute thrombotic microangiopathy. Following this, eculizumab was commenced. She responded to treatment briefly with some resolution of thrombocytopenia for 6 months. However, her symptoms persisted and she had no renal recovery. Discussion Our patient with treatment-resistant SLE was treated with eculizumab for secondary TMA. Unfortunately, the response was not as hoped, and she remained thrombocytopenic with no real evidence of sustained renal or platelet recovery. The evidence is not clear on the benefit of C5-inhibitors in secondary TMA, and the existing literature tends to pull together a heterogenous group with various underlying aetiology; this may explain the differing results. The exact mechanism of TMA in SLE is not fully understood which can make it difficult to predict the type of patients who may or may not respond to eculizumab. Some cases of TMA in SLE/APS may be driven by direct endothelial damage or immune complex deposition; in which case the use of eculizumab which targets complement cascade would be deemed ineffective. Our patient was started on eculizumab after her kidney biopsy confirmed the diagnosis of TMA secondary to SLE. This meant there was a delay in starting treatment, as tissue diagnosis was confounded by thrombocytopenia and deranged coagulation screen. This does beg the question whether the overall outcome would have been more favourable if eculizumab was commenced at presentation without any delay. Conclusion Recommendations for the treatment of SLE and APS-related TMA are currently solely based on case reports and expert opinions. Plasma exchange and /or IVIG are used only in severe and refractory forms. Despite several reported cases of successful outcomes with eculizumab under similar circumstances we present a case that has not shown meaningful benefit.

Thrombocytopenia is defined as a platelet count below 150 000/μL. It increases the risk of bleeding, often due to an existing underlying condition. A meticulous diagnostic evaluation is needed so that specific treatment can be initiated and complications avoided. This review is based on clinical studies up to June 2025 that were retrieved by a selective search with pertinent key words in the MEDLINE/PubMed database, and on current guidelines. Thrombocytopenia often arises in association with pregnancy (7-10 %), immune-mediated diseases such as idiopathic thrombocytopenic purpura (ITP), certain drugs (e.g., heparin-induced thrombocytopenia [HIT] in as many as 1% of patients treated with unfractionated heparin), infections, and systemic and hematologic diseases. The diagnostic evaluation is by an algorithm involving the clinical history, a complete blood count, and other, specific tests. Emergencies such as thrombotic microangiopathy (TMA) and disseminated intravascular coagulation require rapid therapeutic intervention. The treatment depends on the cause and severity of thrombocytopenia; it can include the discontinuation of precipitating drugs, the use of immunosuppressive drugs or thrombopoietin receptor agonists in immune-mediated cases, and specific measures against infection, TMA, or malignant diseases. Prophylactic platelet transfusion can be considered if the platelet count drops below 10 000-20 000/μL, or below 50 000/μL before an intervention or operation, but not in cases of ITP or thrombotic thrombocytopenic purpura (TTP). The treatment depends on the clinical manifestations, platelet count, and underlying cause.

Antibody-mediated multicellular pathophysiology of heparin-induced thrombocytopenia and vaccine-induced thrombotic thrombocytopenia: the dynamic roles of platelets, neutrophils, endothelial cells, and monocytes.

Heparin-induced thrombocytopenia (HIT) is a serious complication associated with heparin use in orthopedic surgery. However, its incidence and risk factors in total knee arthroplasty (TKA) and revision TKA (RTKA) remain unclear. This study aimed to evaluate how preoperative comorbidities, hospital characteristics, and patient demographics influence the incidence of HIT in patients who underwent TKA and RTKA. Differences in postoperative complications, mortality, hospital length of stay, HIT-related costs, and changes in HIT risk following revision surgery were examined. This retrospective study examined data from the National Inpatient Sample (NIS) on patients with TKA and RTKA from 2010 to 2019, categorizing them by the incidence of HIT. Demographics (race, sex, and age) and hospital (admission type, insurance, hospital size, teaching status, and region) details were analyzed. Mortality, comorbidities, and perioperative complications were assessed, and logistic regression analyses were performed to identify potential risk factors. Pulmonary circulatory disorders were strongly associated with HIT in both TKA (P < 0.01, OR = 3.43) and RTKA (P < 0.01, OR = 4.13) groups. Teaching hospitals were associated with lower odds of HIT in the TKA group (P = 0.01, OR = 0.62). Risk factors in RTKA included valvular heart disease (OR = 2.50, 95% CI 1.12-5.57). Common complications among HIT cases included deep vein thrombosis, acute myocardial infarction, and acute renal failure. Pulmonary embolism, postoperative pneumonia, procedural pain, and prosthetic joint infection were more common in TKA group, whereas dyspnea was more prevalent in RTKA group. Certain preoperative comorbidities and baseline characteristics are associated with increased HIT risk following TKA. RTKA is associated with higher odds of HIT and a greater incidence of adverse clinical outcomes. These findings may support the need for improved risk stratification and postoperative planning to reduce complications and enhance recovery.

Extracorporeal membrane oxygenation (ECMO), a form of temporary mechanical circulatory support, causes a prothrombotic state due to activation of inflammatory processes via exposure of blood to the circuit. Systemic anticoagulation is recommended to prevent thrombosis. Unfractionated heparin (UFH) and direct thrombin inhibitors (DTIs) are anticoagulant agents that inactivate thrombin; however, UFH requires antithrombin III (ATIII) for its activity, and patients supported by ECMO are at risk for acquired ATIII deficiency. In addition, heparin may cause heparin-induced thrombocytopenia, complicating therapy. Guidelines on anticoagulant use in ECMO reference UFH as a recommended agent with DTIs as an alternative option. Meta-analyses comparing the 2 agents in ECMO have evaluated efficacy and safety; however, discordant results prompt the need for additional research. The objective of this study is to evaluate differences in bleeding and thrombotic events between UFH and bivalirudin for anticoagulation during ECMO support. This study is a retrospective, single-center cohort study conducted at a primary ECMO center and a tertiary academic medical center. Bleeding and systemic thrombosis rates were not different between bivalirudin and UFH (30 vs 33 events, hazard ratio [HR] = 0.89; 95% confidence interval [CI] = 0.55-1.47, P = 0.7; 12 vs 17 events, HR = 0.68; 95% CI = 0.32-1.42, P = 0.3); however, when controlled for covariates, device thrombosis was lower with bivalirudin (30.2% vs 43.4%, P = 0.017). Time in therapeutic range (TTR) was higher with bivalirudin (69.98% vs 55.5%, P < 0.001). When compared to heparin, bivalirudin for anticoagulation in ECMO was associated with a decreased rate of device thrombosis and greater TTR.

Regional citrate anticoagulation (RCA) has gained increasing attention as a superior anticoagulation strategy in pediatric continuous renal replacement therapy (CRRT). Compared to systemic heparin anticoagulation (SHA), RCA offers significant advantages, including prolonged circuit lifespan, reduced clotting rates, and a lower incidence of bleeding complications. While heparin remains widely used due to its availability and ease of administration, its systemic effects, particularly the risk of bleeding and heparin-induced thrombocytopenia, pose considerable challenges in critically ill children. Studies have consistently demonstrated that RCA reduces transfusion requirements and enhances circuit survival without increasing bleeding risk. Despite potential metabolic concerns such as citrate accumulation, metabolic alkalosis, and electrolyte imbalances, these risks can be effectively managed with careful monitoring and protocol adjustments. As pediatric CRRT protocols continue to evolve, RCA is emerging as the preferred first-line anticoagulation method, particularly in patients with high bleeding risk. The growing body of evidence supports its wider clinical application, promising better treatment outcomes and improved survival rates in critically ill pediatric patients requiring CRRT.

Nafamostat Mesilate as an Anticoagulation Strategy for Heparin-Induced Thrombocytopenia