Coronavirus disease 2019 (COVID-19) vaccination reduced morbimortality rates due to severe acute respiratory syndrome coronavirus 2 infection worldwide. However, various complications have been reported, including hematologic disorders.

We conducted a systematic review to synthesize and analyze the current available evidence on the development of hematological disorders associated with COVID-19 vaccination.

A total of 227 patients were reported in the papers that were selected to be included. There was a slight predominance of females (n=114, 50.22%) compared to males (n=113, 49.78%), and the calculated mean age was 54.86±18.94 years. The most frequently reported hematological disorders were Immune thrombocytopenic purpura (n=58, 25.55%), followed by thrombotic thrombocytopenic purpura (n=38, 16.74%). The less frequently recorded cases were acquired factor XIII/13 deficiency (n=2, 0.88%) and pernicious anemia (n=2, 0.88%). Messenger RNA (mRNA)-based COVID-19 vaccines, including Pfizer BioNTech 162b2 (n=106, 46.70%), Moderna mRNA 127-3 (n = 42, 18.50%), and the Bivalent vaccine (n = 1, 0.44%), were the most prevalent (n=150, 66.08%). Most cases developed after the first dose (n=120, 52.86%). In most cases, patient outcomes were favorable (n=175, 77.09%), but there were significant mortality cases (n=23, 10.13%).

Our findings suggest close monitoring of patients who receive the first dose with mRNA technology vaccines, regardless of sex, especially in adults, as they appear more vulnerable to developing hematologic disorders.

PROSPERO Identifier: CRD42023452589.

Intravenous immunoglobulin (IVIG), first developed for the treatment of patients with antibody deficiencies, is now widely used in clinical practice, especially in hematological and immune system diseases, and its application in hematological oncology chemotherapy, cellular immunotherapy and hematopoietic stem cell transplantation (HSCT) is becoming more and more common. The Chinese Collaborative Group for Infection Immunology and Microecology Research Translation Collaborative Group organized relevant experts to discuss and propose the "Chinese expert consensus on the application of intravenous immunoglobulin in hematological diseases," which was formulated based on the progress of research on the application of IVIG in blood diseases, and provides a basis for the standardization of the use of IVIG in hematologic disorders.

Bullous pemphigoid (BP) represents an autoimmune blistering disorder that may coexist with acquired hemophilia A (AHA), a rare autoimmune condition arising from the formation of circulating autoantibodies directed against factor VIII (FVIII). The underlying pathomechanisms of BP-AHA remain elusive. This study conducted a retrospective analysis of data from 196 BP patients admitted to our hospital. We have collected serum samples from a recently admitted BP-AHA patient and healthy controls to isolate, screen and identify the potential FVIII inhibitors. The expression and function of lipopolysaccharide-binding protein (LBP) in BP-AHA were further validated by a series of biochemical experiments. The retrospective analysis showed that the activated partial thromboplastin time (APTT) values of seven patients exceeded 33.8 s (normal value) in 196 BP patients. FVIII: C (%) and FVIII inhibitors in the plasma of partial prolonged-APTT patients were significantly altered compared with control group or non-prolonged-APTT group. LBP was identified as a potential inhibitory protein of FVIII. Consistently, a notable alteration in LBP expression was observed in the plasma of BP patients with prolonged-APTT. Moreover, the amount of LBP bound to FVIII in the BP-AHA patient was notably higher than that in control group, which was also markedly reversed after treatment. In vitro experiments finally confirmed that exogenous LBP directly bound to FVIII and significantly inhibited FVIII activity. In conclusion, the incidence of AHA in BP patients may be substantially underestimated, which needs more vigilance towards indicators such as APTT, LBP, and FVIII. LBP emerges as an inhibitory protein of FVIII, indicating the potential involvement in the progression of BP-AHA.

Acquired hemophilia A (AHA) is a rare and potentially severe bleeding disorder caused by circulating autoantibodies against factor VIII (FVIII). In approximately 50% of the patients, the condition is associated with autoimmune diseases, cancers, medication use, pregnancy, and the post-partum period. Bullous pemphigoid (BP) is a chronic autoimmune subepidermal blistering disease associated with tissue-bound and circulating autoantibodies against BP antigens 180 (BP180) and 230 (BP230). AHA-associated BP has a high mortality rate; hence, the understanding of this disease must improve.

A 69-year-old man presented with erythema, blisters, blood blisters, and crusts accompanied by severe pruritus for more than 20 days, and ecchymosis and swelling on his left upper arm for 3 days. Pathological examination revealed a subepidermal blister that contained eosinophils. Laboratory tests showed that the BP180 autoantibody levels had increased, isolated activated partial thromboplastin time was notably prolonged (115.6 s), and coagulation FVIII activity was extremely low (< 1.0%). Furthermore, the FVIII inhibitor titer had greatly increased (59.2 Bethesda units). Therefore, the patient was diagnosed as having BP associated with AHA, prescribed 0.05% topical halometasone cream, and transferred to a higher-level hospital for effective treatment; however, he died after 2 days.

AHA associated BP is rare, dangerous, and has a high mortality rate. Therefore, its timely diagnosis and effective treatment are necessary.

Tissue factor pathway inhibitor (TFPI) regulates tissue factor-triggered coagulation. Humans and mice express transcripts encoding for multidistributed (endothelial, platelet, and plasma) 3-Kunitz domain TFPIα and endothelial membrane-anchored 2-Kunitz TFPIβ. Mice express a third transcript, γ, that encodes plasma lipoprotein-associated 2-Kunitz TFPI. In humans, proteolysis of α and/or β produces plasma lipoprotein-associated 2-Kunitz TFPI at lower levels. In clinical trials, monoclonal antibodies that target all TFPI isoforms extend coagulation and correct bleeding in hemophilic patients but with some thrombosis risks.

To determine the impact of TFPI isoform-specific deletions on promoting clotting in hemophilic mice.

Engineered TFPI isoform-specific, hemophilic (factor VIII-null) mice were evaluated for clotting.

Mice expressing any single TFPI isoform were healthy. Thrombin generation assays identified TFPIγ as the dominant anticoagulation isoform in mouse plasma. Hemostasis was assessed by serial bleeding times from a tail vein laceration. Repeatedly, after a clot forms, it was manually disrupted; the number of clots/disruptions occurring over a 15-minute period were reported. C57BL/6 and hemophilic mice clot on average 25.6 vs 5.4 times, respectively. On a hemophilia background, TFPIβ or TFPIγ-specific deletion improved clotting to 14.6 and 15.2 times, respectively (P < .0001). TFPIα-specific deletion was without impact, clotting 5.1 times. Heterozygous deletion of TFPIβ was effective, clotting 11.8 times (P < .0001). Heterozygous deletion of TFPIα or TFPIγ alone was ineffective, clotting 3.0 and 6.1 times, respectively, but heterozygous TFPIαγ deletion improved clotting to 11.2 times (P < .001).

In hemophilic mice, endothelial TFPIβ and plasma γ-derived 2-Kunitz TFPI individually contribute more to bleeding than total TFPIα.

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the development of antibodies against factor VIII. AHA has previously been reported in association with malignancy and autoimmune disorders, but rarely with liver disease. A prolonged activated partial thromboplastin time is the initial laboratory manifestation of this condition but may be challenging to interpret in the setting of abnormal markers of coagulation typically seen in cirrhosis. We present a case of AHA in a patient with decompensated cirrhosis resulting in refractory bleeding and highlight the complexities of interpreting abnormal coagulation factors in patients with cirrhosis.

Acquired hemophilia A (AHA) is a rare hemorrhagic autoimmune disorder characterized by autoantibodies against coagulation factor VIII (FVIII). In approximately half of the cases AHA does not recognize any cause (idiopathic form), while in the other cases it may be triggered by autoimmune disorders, cancers, drugs, infections, or pregnancy. Besides treating the underlying disorder, specific AHA treatment includes management of bleeding, if necessary, and inhibitor eradication.

This narrative review summarizes the main epidemiological, clinical, laboratory, and therapeutic characteristics of AHA. In particular, it is focused on the current therapeutic options for the inhibitor eradication, also showing the latest findings on the innovative therapies. A literature search strategy was performed, without temporal limits, through Medline and PubMed electronic databases.

Various first-line and second-line immunosuppressive agents are currently available for the management of AHA. Among the latter, the anti-CD20 monoclonal antibody rituximab has been the object of intense research during the last years from investigators as innovative promising eradicating therapy for AHA. Preliminary data from the studies support the use of this drug as a first-line option for newly diagnosed AHA cases.

This retrospective cohort study evaluates the safety and efficacy of replacement therapy with regard to pregnancy outcomes in hemophilia carriers. Hemophilia carriers face elevated bleeding risks during pregnancy, necessitating meticulous management, including replacement therapy with clotting factors. This research examines the records of 64 pregnant hemophilia carriers at King Fahad Medical City, Riyadh, from January 2010 to December 2023, analyzing their demographic details, hemophilia type and severity, replacement therapy specifics, and pregnancy outcomes. The study found that 62.5% of the participants had hemophilia A, with 43.8% categorized as severe. Most subjects (87.5%) received recombinant factor VIII at a median dosage of 30 IU/kg weekly. Adverse pregnancy outcomes included gestational hypertension (15.6%), preterm labor (18.8%), and postpartum hemorrhage (12.5%). The cesarean section rate was 28.1%. Neonatal outcomes were generally favorable, with median birth weights at 3100 g and mean Apgar scores of 8.2 and 9.1 at 1 and 5 min, respectively. Logistic regression analysis revealed no significant association between adverse events and therapy type or dosage, though a trend towards significance was noted with once-weekly administration (p = 0.082). The study concludes that replacement therapy is a viable method for managing hemophilia in pregnant carriers, leading to generally favorable maternal and neonatal outcomes. However, it underscores the importance of individualized treatment plans and close monitoring to effectively manage the risks associated with hemophilia during pregnancy.

To present a case of acquired factor VIII deficiency in the setting of labor and describe the challenges of its diagnosis and treatment.

A 31-year-old woman was diagnosed with acquired factor VIII deficiency while undergoing induction of labor. Her labor and post operative course were complicated by epidural hematoma formation, prolonged postoperative surgical site bleeding, and subcutaneous hematoma. Management included blood products, human Factor VII, rituximab, and a steroid taper.

Acquired factor VIII deficiency can be challenging to diagnose and should be considered in the differential diagnosis in patients with prolonged bleeding accompanied by a prolonged activated partial thromboplastin time (aPTT).

A 74-year-old female was admitted for painless jaundice. Laboratory tests showed hyperbilirubinemia, cholestasis, normal coagulation, and Ca19-9:163U/L. The CT-scan reported dilation of the intrahepatic and extrahepatic bile ducts secondary to a 24mm tumor in the intrapancreatic common bile duct. The magnetic cholangioresonance showed multiple endoluminal polypoid lesions, suggestive of intraductal papillary neoplasm of the bile duct (IPNB). The endoscopic bile duct brushing was non-conclusive.

Acquired bleeding disorders because of an autoimmune phenomenon are rare events. Acquired von Willebrand disease (aVWD) has been estimated as having a prevalence of 400 per million in the general population. Acquired hemophilia A (AHA), the most common of the acquired hemophilias, has an estimated incidence of 1.3-1.5 cases per million per year. Immune checkpoint inhibitors (ICI) targeting PD-1, PD-L1, and CTLA-4 are being used with increasing frequency for hematologic and oncologic disorders. Acquired hemophilias and aVWD have been reported with the use of ICI therapy. We performed a systematic review of the literature to identify cases of acquired bleeding disorders with ICI therapy and contribute our own institution's experience with a case of AHA after pembrolizumab therapy. Six cases of AHA, one case of aVWD, and one case of factor V inhibitor were identified in the literature. Inhibitors were successfully eradicated in five of the eight cases identified. We propose that a centralized registry, possibly through the Scientific and Standardization Subcommittee on Plasma Coagulation Inhibitors through the International Society on Thrombosis and Hemostasis (ISTH), be developed to record treatment and outcomes of this rare ICI complication in order to prognosticate risk and better understand optimal treatment strategies.

Acquired haemophilia (AH) is a serious autoimmune haematological disease caused by the production of auto-antibodies against coagulation factor VIII. In some patients, AH is associated with a concomitant malignancy. In case of surgical intervention, AH poses a high risk of life-threatening bleeding.

A 60-year-old female patient with multiple recurrences of non-muscle invasive bladder cancer underwent transurethral tumour resection. A severe haematuria developed postoperatively warranting two endoscopic revisions; however, no clear source of bleeding was identified in the bladder. Subsequent haematological examination established a diagnosis of AH. Treatment with factor VIII inhibitor bypass activity and immunosuppressive therapy was initiated immediately. The patient responded well to the therapy and was discharged from the hospital 21 d after the primary surgery. At the 38-mo follow-up, both AH and bladder cancer remained in complete remission.

AH is a rare, life-threatening haematological disease. AH should be considered in patients with persistent severe haematuria or other bleeding symptoms, especially if combined with isolated activated partial thromboplastin time prolongation.

Acquired hemophilia A (AHA) or factor VIII (FVIII) deficiency is caused by autoantibodies targeting FVIII in the blood coagulation pathway; it is a rare condition making it challenging to diagnose. A timely diagnosis is crucial, without which there is a risk of catastrophic bleeding. We report a case of a patient with a history of duodenal arteriovenous malformations, previously on apixaban, who presented with four days of melena. On admission he was found to have a hemoglobin of 5.7 and elevated partial thromboplastin time (PTT), promoting further workup showing FVIII levels of <1%, with a mixing study that failed to correct suggesting the presence of inhibitors against FVIII. Other characteristics of this patient's cases included controlled rheumatoid arthritis without detectable rheumatoid factor or increased erythrocyte sedimentation rate (ESR). The patient was initially treated with prednisone and intravenous immunoglobulins, but an insufficient response prompted the initiation of recombinant factor VII, rituximab, and cyclophosphamide during hospitalization.

We report a case of a patient with recurrent hematomas while on anticoagulation for a pulmonary embolism and a prolonged hospital stay due to a delayed diagnosis for acquired hemophilia A. Acquired hemophilia A is a rare autoimmune bleeding disorder with autoantibodies directed against coagulation factor VIII (FVIII), leading to an acquired FVIII deficiency. A prolonged isolated activated partial thromboplastin time (aPTT) in a bleeding patient warrants workup for acquired hemophilia A. This is specifically challenging in patients with thrombosis on anticoagulation and can lead to significant delays in diagnosis and associated morbidities. The case highlights the need for further awareness of this disease, potential laboratory pitfalls when conducting and interpreting coagulation assays, and the management considerations in a patient with a simultaneous thrombotic and hemorrhagic condition.

Acquired hemophilia A (AHA) is a rare hemorrhagic coagulopathy caused by the presence of autoantibodies that inhibit the activity of factor VIII (FVIII). Its diagnosis requires a high index of suspicion. It should be suspected in the presence of extensive hematomas or intense mucosal bleeding in patients with no history of previous trauma or hemorrhagic symptoms. We present two clinical cases of AHA, with different presentations and therapeutic management based on immunosuppression and hemostatic control through bypass agents such as activated recombinant FVII (rFVIIa; Novoseven®) and activated prothrombin complex concentrate (aPCC; Feiba®). The first case was an idiopathic AHA that presented with extensive subcutaneous hematomas with inhibitor titer >40 Bethesda units/ml (BU/mL), prolonged activated partial thromboplastin time (aPTT), and FVIII of 0.8%. In contrast, the second case involved a patient with a history of autoimmune disease, who presented with epistaxis and inhibitor titer of 10.8 BU/ml and FVIII of 5.3%.

We present a case of a 74-year-old male with a past medical history of polymyalgia rheumatica that presented as a transfer for evaluation of hematomas of the scrotum, left groin, back, and bilateral thighs. Further questioning revealed hematuria and bleeding gums for the past month. The patient complained of left thigh pain without recent fever, chills, chest pain, or shortness of breath. A physical exam showed hematomas of the left groin, scrotum, bilateral thighs, and back with an ecchymotic appearance.  Initial pertinent laboratory workup showed decreased hemoglobin, leukocytosis, and elevated partial thromboplastin time (PTT). Therefore, a decision was made to obtain a CT angiogram of the abdomen and pelvis, which revealed retroperitoneal hematoma. Further diagnostic workup showed a coagulation factor VIII level of zero percent and mixing studies supporting the presence of an acquired factor VIII inhibitor. Therefore, the patient was treated with rituximab and recombinant factor VIIa, with an improvement of factor VIII levels to normal limits within a week.