The role of thrombospondin-1 in the pathogenesis of antiphospholipid syndrome.

OBJECTIVE: Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by recurrent thrombosis and/or pregnancy morbidity, in the presence of antibodies to ß2 glycoprotein-I (ß2GPI), prothrombin or Lupus anticoagulant (LA). Anti-ß2GPI antibodies recognize complexes of ß2GPI dimers with CXCL4 chemokine and activate platelets. Thrombospondin 1 (TSP-1) is secreted by platelets and exhibits prothrombotic and proinflammatory properties. Therefore, we investigated its implication in APS. METHODS: Plasma from APS patients (n = 100), Systemic Lupus Erythematosus (SLE) (n = 27) and healthy donors (HD) (n = 50) was analyzed for TSP-1, IL-1ß, IL-17A and free active TGF-ß1 by ELISA. Human Umbilical Vein Endothelial Cells (HUVECs) and HD monocytes were treated with total HD-IgG or anti-ß2GPI, ß2GPI and CXCL4 and CD4+ T-cells were stimulated by monocyte supernatants. TSP-1, IL-1ß, IL-17A TGF-ß1 levels were quantified by ELISA and Real-Time PCR. RESULTS: Higher plasma levels of TSP-1 and TGF-ß1, which positively correlated each other, were observed in APS but not HDs or SLE patients. Patients with arterial thrombotic events or those undergoing a clinical event had the highest TSP-1 levels. These patients also had detectable IL-1ß, IL-17A in their plasma. HD-derived monocytes and HUVECs stimulated with anti-ß2GPI-IgG-ß2GPI-CXCL4 secreted the highest TSP-1 and IL-1ß levels. Supernatants from anti-ß2GPI-ß2GPI-CXCL4 treated monocytes induced IL-17A expression from CD4+ T-cells. Transcript levels followed a similar pattern. CONCLUSIONS: TSP-1 is probably implicated in the pathogenesis of APS. In vitro cell treatments along with high TSP-1 levels in plasma of APS patients suggest that high TSP-1 levels could mark a prothrombotic state and an underlying inflammatory process.

Severe Transitory Neonatal Neutropenia Associated with Maternal Autoimmune or Idiopathic Neutropenia.

PURPOSE: Neonatal immune neutropenia is observed in rare cases in newborns from mothers with idiopathic or autoimmune neutropenia, secondary to passive transfer of maternal granulocyte auto-antibodies. METHODS: We performed a literature review and report four supplementary cases from the French registry of neutropenia. RESULTS: Only 14 cases (11 mothers, 14 newborns) have been reported. Granulocyte aggregation (GAT) and granulocyte indirect immunofluorescence test (GIFT) are the recommended laboratory procedures for antibody detection. Monoclonal antibody-specific immobilization of granulocyte antigens (MAIGA)-confirmed antibody specificity. Antibody detection in newborns is not generally possible owing to extreme neutropenia. In half of the cases autoantibodies against neutrophils (AAN) were positive in maternal sera (7 out of 11). In some newborns tested, IgG+ AAN were also positive, with disappearance in parallel of spontaneous neutrophil count improvement. No correlation between maternal type of AAN and titer and neonatal neutropenia can be established. Neutropenia resolved spontaneously between 2 weeks and 4 months. Infections in newborns were observed in 43% of cases, with no deaths reported. Granulocyte colony-stimulating factor (G-CSF) was administered to some newborns (5 out of 14) in the case of infections. Low-dose G-CSF administered to childbearing women during pregnancy could be proposed to prevent neutropenia in newborns. CONCLUSIONS: From the few cases reported so far it is impossible to draw any conclusions regarding frequency, risk factors, and outcome, but the overall prognosis for newborns seems good. Because it can be associated with potentially severe neonatal infections, autoimmune neutropenia in childbearing mothers should be closely monitored in collaboration with gynecologists and pediatricians.

High-throughput, non-invasive prenatal testing for fetal Rhesus D genotype to guide antenatal prophylaxis with anti-D immunoglobulin: a cost-effectiveness analysis.

OBJECTIVE: To evaluate the cost-effectiveness of high-throughput, non-invasive prenatal testing (HT-NIPT) for fetal Rhesus D (RhD) genotype to guide antenatal prophylaxis with anti-D immunoglobulin compared with routine antenatal anti-D immunoglobulin prophylaxis (RAADP). DESIGN: Cost-effectiveness decision-analytic modelling. SETTING: Primary care. PARTICIPANTS: A simulated population of 100 000 RhD-negative women not known to be sensitised to the RhD antigen. METHODS: A decision tree model was used to characterise the antenatal care pathway in England and the long-term consequences of sensitisation events. The diagnostic accuracy of HT-NIPT was derived from a systematic review and bivariate meta-analysis; estimates of other inputs were derived from relevant literature sources and databases. Women in whom the HT-NIPT was positive or inconclusive continued to receive RAADP, whereas women with a negative result received none. Five alternative strategies in which the use of HT-NIPT may affect the existing postpartum care pathway were considered. MAIN OUTCOME MEASURES: Costs expressed in 2015GBP and impact on health outcomes expressed in terms of quality-adjusted life-years over a lifetime. RESULTS: The results suggested that HT-NIPT appears cost saving but also less effective than current practice, irrespective of the postpartum strategy evaluated. A postpartum strategy in which inconclusive test results are distinguished from positive results performed best. HT-NIPT is only cost-effective when the overall test cost is £26.60 or less. CONCLUSIONS: HT-NIPT would reduce unnecessary treatment with routine anti-D immunoglobulin and is cost saving when compared with current practice. The extent of any savings and cost-effectiveness is sensitive to the overall test cost. TWEETABLE ABSTRACT: HT-NIPT is cost saving compared with providing anti-D to all RhD-negative pregnant women.

Persistent neonatal thrombocytopenia can be caused by IgA antiplatelet antibodies in breast milk of immune thrombocytopenic mothers.

Immune thrombocytopenia (ITP) in pregnant women can cause neonatal thrombocytopenia by transport of antiplatelet autoantibodies across the placenta. Usually, an infant's platelet count normalizes within 2 months. We observed neonatal thrombocytopenia that persisted more than 4 months and disappeared following discontinuation of breastfeeding. The aim of our study was to discern whether breast milk of ITP mothers contained antiplatelet antibodies causing persistent thrombocytopenia. We collected milk samples from 3 groups of women: ITP group, 7 women who had ITP during pregnancy; R-ITP group, 6 women who recovered from ITP before pregnancy; and 9 healthy controls. We found increased levels of antiplatelet antibodies of the immunoglobulin A type in the milk of ITP patients compared with the other 2 groups. Similar increase was demonstrated for antibodies binding to αIIbß3 expressed in cultured cells. Thus, transfer of antiplatelet antibodies from ITP mothers by breastfeeding can be associated with persistent neonatal thrombocytopenia.

Red blood cell alloimmunization in pregnancy during the years 1996-2015 in Iceland: a nation-wide population study.

BACKGROUND: Red blood cell (RBC) alloimmunization during pregnancy is still a major problem. Historically, anti-D antibodies are most likely to cause severe hemolysis, but other antibodies are also important. In Iceland, postnatal RhIg prophylaxis was implemented in 1969, universal RBC antibody screening was implemented in 1978, but antenatal RhIg prophylaxis is not yet routine. STUDY DESIGN AND METHODS: This nation-wide population study gathered data on alloimmunized pregnancies in Iceland between 1996 and 2015. Blood bank alloimmunization data were linked to Icelandic Medical Birth Registry data. RBC antibodies were classified as either clinically significant or clinically nonsignificant. RESULTS: In total, 912 positive antibody screens from 87,437 births were identified (1.04% prevalence). The most frequent antibodies were anti-M (19.4%), anti-E (19.0%), and anti-D (12.5%). Anti-D prevalence among D-negative mothers was 1.1%. Icelandic Medical Birth Registry data were available for 881 (96.6%) pregnancies. In the clinically significant group (n = 474), anti-E (27%) and anti-D (20%) were most common, whereas anti-M was most frequent (53%) in the clinically nonsignificant group (n = 407). Mothers in the clinically significant group were older, more often multigravidae, had more abortions and stillbirths, and had shorter gestational length. Newborns in the clinically significant group were less healthy, had lower weight and Apgar scores, and required more treatment. Among specificities in the clinically significant group, anti-D antibodies were most strongly associated with severe hemolysis. CONCLUSION: In this study, the prevalence of alloimmunization was similar to that in previous reports. Of all clinically significant antibodies, anti-D was most strongly associated with severe hemolysis, requiring phototherapy or exchange transfusions. Our data emphasize the importance of implementing an antenatal prophylactic RhIg program in Iceland in the near future.

The role of complement activation in thrombosis and hemolytic anemias.

OBJECTIVE: The objective of this study was to describe complement activation in hemostatic and pathologic states of coagulation and in the acquired and congenital hemolytic anemias. METHODS AND RESULTS: We review published and emerging data on the involvement of the classic, alternative and lectin-based complement pathways in coagulation and the hemolytic anemias. The alternative pathway in particular is always "on," at low levels, and is particularly sensitive to hyper-activation in a variety of physiologic and pathologic states including infection, autoimmune disorders, thrombosis and pregnancy, requiring tight control predicated on a variety of soluble and membrane bound regulatory proteins. In acquired hemolytic anemias such as paroxysmal nocturnal hemoglobinuria (PNH) and cold agglutinin disease (CAD), the complement system directly induces red blood cell injury, resulting in intravascular and extravascular hemolysis. In congenital hemolytic anemias such as sickle cell disease and ß-thalassemia, the complement system may also contribute to thrombosis and vascular disease. Complement activation may also lead to a storage lesion in red blood cells prior to transfusion. CONCLUSION: Complement pathways are activated in hemolytic anemias and are closely linked with thrombosis. In acquired disorders such as PNH and possibly CAD, inhibition of the alternative complement pathway improves clinical outcomes and reduces thrombosis risk. Whether complement inhibition has a similar role in congenital hemolytic anemias apart from the atypical hemolytic-uremic (aHUS)-type thrombotic microangiopathies remains to be determined.

Short duplication within the RHCE gene associated with an in cis deleted RHD causing a Rhnull amorph phenotype in an immunized pregnant woman with anti-Rh29.

BACKGROUND: The rare amorph Rhnull phenotype is caused by silent alleles at the RH locus and usually arises in consanguineous families. To date, only five molecular backgrounds have been identified in five unrelated families. Subjects with Rhnull red blood cells (RBCs) readily produce alloantibodies to high-prevalence Rh antigens. STUDY DESIGN AND METHODS: RBCs from a pregnant woman (G5P3) from Libya, with a positive indirect antiglobulin test were phenotyped by hemagglutination. RHD and RHCE genes were analyzed at the genomic level and mutation inheritance pattern was assessed in the patient's family. RESULTS: Hemagglutination testing showed a D-C-E-c-e- phenotype in the proposita associated with the presence of a high titer anti-Rh29 (4096). Molecular analysis revealed a deletion of RHD and presence of a novel RHCE allele with a 7-bp duplication in Exon 7. This duplication is predicted to introduce a frameshift after His350, a new C-terminal sequence, and a premature stop codon resulting in shortened predicted protein with only 402 amino acids. The mutated allele was found at homozygous state in the proposita and heterozygous state in her parents and one brother. CONCLUSION: This report describes a novel RHCE mutation causing the loss of RhCE antigen expression in association with RHD deletion, leading to an amorph Rhnull phenotype.

Recurrent miscarriage: causes, evaluation and management.

Recurrent miscarriage is frustrating for the physician and a heartbreaking experience for the patient. Approximately 5% of couples trying to conceive have two consecutive miscarriages. Despite a thorough study of patients, the aetiology of this common obstetric complication is unknown in 50% of cases. Known causes include abnormal chromosomes, endocrinological disorders and uterine abnormalities. Although antiphospholipid antibodies have been demonstrated in miscarriages, the role played by alloimmune mechanisms remains unclear. New immunological approaches such as natural killer cells, regulatory T cells, tumour necrosis factor α, cell-derived microparticles, leptin, certain glycoproteins and cytokines should be considered. The management of thyroid diseases and immunological disorders is continuously evolving. Several genetic diagnostic procedures such as parental karyotyping and preimplantation genetic screening should probably not be used routinely. Antiphopholipid syndrome and some recurrent miscarriage-related endocrinological disorders can be effectively treated. Finally, new therapeutic approaches and the pleiotropic effects of old ones have led to improved fetal-maternal outcomes.

The role of alloantibodies against human platelet antigen-15 in multiply platelet transfused patients.

BACKGROUND: Several studies have documented the role of antibodies against human platelet (PLT) antigen (HPA)-15 in alloimmune-mediated thrombocytopenia including neonatal alloimmune thrombocytopenia, PLT transfusion refractoriness (PTR), and posttransfusion purpura in Caucasian persons. However, the relevance of anti-HPA-15 in PTR among the Japanese population is still unclear. STUDY DESIGN AND METHODS: The sera of 305 multiply PLT transfused (MPT) patients, previously investigated for the presence of human leukocyte antigen (HLA) and HPA antibodies by mixed passive hemagglutination, were reexamined for the presence of HPA-15 alloantibodies, using the monoclonal antibody-specific immobilization of PLT antigens (MAIPA) technique. RESULTS: Among the 305 MPT samples, antibodies against HPA-15 alloantigen was detected in seven (2.3%), two (0.66%) being anti-HPA-15a and five (1.64%) being anti-HPA-15b. Additionally, one case of CD109 panreactive antibody was found (0.33%). Among them, one aplastic anemia patient with blood group O developed multispecific anti-HLA and anti-HPA-15b alloantibody after MPTs. However, transfusion with HLA-matched PLTs of blood group AB did not result in adequate PLT count increment. Analysis of the possible influence of immune anti-A and anti-B by the MAIPA assay resulted negative, indicating that anti-HPA-15b is responsible for the refractory state in this patient. CONCLUSION: In this study, we found alloimmunization against HPA-15a and -15b in Japanese populations and demonstrated the relevance of these antibodies in a patient with PTR.

Anti-Emm in a pregnant patient--case report.

A 23-year-old primigravida of North African origin presented with a positive antibody screen at booking at 15 weeks of gestation. An antibody to a high-frequency antigen (HFA) of unknown identity was detected, which was reactive with the red blood cells of the father. This led to several challenges including antibody identification, clinical monitoring to detect signs of haemolytic disease of the foetus and newborn (HDFN) and compatible blood in case perinatal transfusion was needed. Anti-Emm was identified 2 months post-partum. This is the first published case which describes a pregnant patient with anti-Emm.

Transfusion therapy and alloimmunization in Thalassemia Intermedia: a 10 year experience at a tertiary care university hospital.

BACKGROUND: Thalassemia Intermedia (TI) has a wide clinical profile with many patients requiring only occasional transfusions. To prevent alloimmunization, we adopted a policy of issuing phenotype matched red blood cells in 2009. We examined transfusion indications and alloimmunization rate in TI patients. STUDY DESIGN AND METHODS: Clinical and blood bank records of 37 TI patients were reviewed. RESULTS: 23 Patients required transfusion for pregnancy (26), splenectomy (8) and anemia (11). Since 2009, total of 335 units were transfused with only one antibody developing after transfusing a non-phenotype matched unit. CONCLUSION: The commonest indication for blood transfusion was pregnancy. Providing phenotype matched blood has successfully reduced the rate of alloimmunization.

Assessment of feto-maternal hemorrhage among rhesus D negative pregnant mothers using the kleihauer-betke test (KBT) and flow cytometry (FCM) in Addis Ababa, Ethiopia.

BACKGROUND: This study aimed to assess fetomaternal hemorrhage (FMH) among RhD negative pregnant mothers using two techniques, Kleihauer-Betke (KBT) and Flow cytometry (FCM). To determine if patient-specific doses of prophylactic anti-D warrant further investigation in Ethiopia and wider Africa. METHODS: Hospital- based cross-sectional study was conducted among 75 RhD negative pregnant mothers using convenient sampling technique. RESULT: FMH has been detected in 52% and 60% by KBT and FCM techniques, respectively. The volume of FMH quantified in the majority of the cases (92.5% and 87%) was <10 mL fetal blood while >30 mL in 1.3% (1/75) and 2.7% (2/75) as calculated by KBT and FCM, respectively. The FMH calculated by the two methods have good correlation; r = 0.828 (p = 0.000) for categorized and r = 0.897 (p = 0.000) for continuous values and the agreement between the FCM and KBT was moderate with kappa (κ) value of 0.53 (p = 0.000). CONCLUSION: Most of FMH calculated (<10 mL) could have been neutralized by lower doses which might have lower costs than administering 300 µg dose which is currently in practice in our country for affording mothers. Besides, it also showed that the volume of FMH was >30 mL in 1.3% and 2.7% of the cases as calculated by KBT and FCM, respectively, which need more than 300 µg dose RhIG for neutralization. Further investigation into the cost- effectiveness and scalability of patient- specific dosing of prophylactic anti-D appears warranted.

Hepatitis C virus-associated thrombocytopenia in pregnancy: impact upon multidisciplinary care provision.

OBJECTIVE: Recent studies have implicated hepatitis C virus (HCV) in the pathogenesis of immune thrombocytopenia. In pregnancy-associated immune thrombocytopenia, multidisciplinary management is required due to a potential for bleeding complications. We performed a retrospective review of HCV-infected pregnant women and age-matched controls who were not infected with HCV. METHODS: One hundred and six women with a HCV viral load were identified from 2009 to 2011. RESULTS: Thrombocytopenia was identified in 10.3% of HCV-infected pregnant women and 1.6% of age-matched controls (P<0.001). Mean platelet count during pregnancy was 120 ± 23 × 109/L in HCV-infected women and at delivery was significantly lower in HCV-infected women than in controls (P=0.01). Despite the significant difference in platelet counts, there was no significant difference in estimated blood loss (EBL) at delivery. Regional anaesthesia was performed in 73% of thrombocytopenic HCV-infected women and no complications were recorded. There were no fetal bleeding complications. CONCLUSION: In the first study to date to investigate the impact of HCV on maternal platelet count we demonstrated a significantly higher frequency of thrombocytopenia and a significantly lower platelet count in HCV-infected pregnant women compared with controls. Interestingly, thrombocytopenia had no detectable impact on EBL at delivery.

Comparison of gestational diabetes mellitus rates in women with increased and normal white blood cell counts in early pregnancy.

AIM: To compare the rates of gestational diabetes mellitus (GDM) among Thai or other South-East Asian women with increased and normal peripheral white blood cell (WBC) counts in early pregnancy. The risk of GDM in relation to WBC count was also determined. METHODS: We included singleton pregnant women who sought their first antenatal care in our institution between May 2010 and December 2011. Subjects were 595 gravidas with an increased WBC count while controls were 595 pregnancies with a normal WBC count. Data of pregnant women were collected. The WBC of each woman was obtained from a complete blood count performed in the first trimester. The rates of GDM between both groups were compared. The odds ratio (OR) with 95% confidence interval (CI) of GDM development in the subject group was determined by multivariate analysis. RESULTS: Data on 570 subjects with increased WBC and 575 controls with normal WBC were obtained. The rate of GDM was significantly higher in subjects compared to controls at 13.2% versus 5.2% (P<0.001) with a crude OR of 2.75 (95% CI, 1.77-4.28). By multivariate analysis, the subject group was found at increased risk of GDM compared to the control group, with an adjusted OR of 2.20 (95% CI, 1.39-3.47). CONCLUSION: Thai or other South-East Asian women with an increased WBC count in early pregnancy had a significantly higher rate of GDM than women having a normal WBC count. Our results demonstrate that WBC count is an independent risk factor for GDM.

Unexpected postpartum hemorrhage due to an acquired factor VIII inhibitor.

Unexplained postpartum hemorrhage (PPH) refractory to standard hemostatic measures should trigger a heightened clinical suspicion of an acquired bleeding disorder. When hemostatic medical interventions and surgical procedures fail to control the bleeding, then significant postoperative blood loss, debilitating morbidity, loss of fertility, and death may occur. In the setting of an autoantibody inhibitor to factor VIII (FVIII), control of life-threatening PPH and avoidance of subsequent bleeding episodes depends on a timely and accurate diagnosis, prompt hemostatic treatment and eradication of FVIII inhibitors, and appropriate long-term patient care and management. Acquired postpartum hemophilia due to a FVIII inhibitor is a rare cause of PPH; however, delayed treatment can lead to increased maternal morbidity and mortality. Acquired FVIII inhibitors also pose an emerging bleeding threat to the neonate as a result of possible transplacental transfer of FVIII autoantibodies to the fetus during the last trimester of pregnancy. The purpose of this review is to increase awareness among hematologists and obstetricians/gynecologists regarding the occurrence of FVIII neutralizing autoantibodies as a cause of PPH, and emphasize the importance of collaboration between obstetrician/gynecologists and hematology specialists to optimize the diagnostic evaluation, treatment, and long-term management of women who experience PPH due to an acquired FVIII inhibitor.

Notorious anti-Jk3 in a pregnant woman.

This is a case study of a 23-year-old pregnant Polynesian woman with anti-Jk3 identified in her plasma during her third visit to a hospital. This patient, with a history of mild anemia due to beta-thalassemia minor and two known transfusion of packed red cells came to an emergency room complaining of severe abdominal cramps. Her hemoglobin during her second hospital visit was 7.5 g/dL and her antibody screen was negative. Two units of crossmatch compatible packed cells were transfused with no adverse reaction and she was discharged. Four days post transfusion, she returned to the hospital complaining of back pain and fatigue and she was running a fever (101 degrees F). Her antibody screen was positive, direct antiglobulin testing was also positive and the eluate showed pan-agglutination with a red cell panel. Anti-Jk3 was identified in her plasma by the Red Cross and a delayed transfusion reaction was suspected. As a result, Kidd null crossmatch compatible units were obtained from relatives. The patient was successfully transfused and was discharged with a hemoglobin of 10.1 g/dL. The fetus appeared to be unaffected by the antibody. This case reiterates the hard-to-identify characteristics of Kidd antibodies and highlights the need for medical laboratory personnel to be informed on the prevalence of the Kidd null phenotype among various populations. Educating ethnic populations with rare phenotypes and organizing targeted blood drives may increase inventories of these rare blood phenotypes.

How I manage patients with acquired haemophilia A.

Acquired haemophilia A (AHA) is a potentially life-threatening bleeding disorder occurring in patients without a previous personal or family history of bleeding. Development of immune-mediated autoantibodies against coagulation factor VIII is associated with a wide range of clinical disorders including pregnancy, autoimmune disorders, malignancy, or with no apparent disease. There exists great potential for morbidity and mortality related to acute and recurrent bleeding episodes, making prompt diagnosis and treatment necessary. The two primary goals of treatment focus on cessation of bleeding and eradication of the acquired factor VIII inhibitor. No randomized clinical trials have been conducted regarding treatment, so expert clinical opinion guides therapeutic intervention. This current report provides a profile of patient characteristics, an algorithm for diagnosis, and outlines treatment recommendations based upon current guidelines and clinical experience. As first-line interventions for acute bleeding and inhibitor eradication are generally accepted, we will emphasize discussion of second-line therapeutic options.

Seronegative antiphospholipid syndrome.

APS is an autoimmune disease that leads to arterial and/or venous thrombosis, recurrent pregnancy loss and persistently positive aPLs. Patients with clinical manifestations highly suggestive of APS but persistently negative conventional aPLs are classified as having seronegative APS. Ongoing research has revealed the existence of non-criteria antibodies proposed to be relevant to APS and that can be potentially included in the disease's classification criteria. We present a literature review on the most promising antibodies of this heterogeneous aPL family, which includes antibodies to a zwitterionic phospholipid, namely phosphatidylethanolamine, phospholipid-binding plasma proteins, phospholipid-protein complexes and anionic phospholipids other than cardiolipin. Although these molecules can increase the diagnostic yield of APS, their clinical relevance is still debatable and needs to be confirmed by interlaboratory efforts toward standardizing diagnostic tools, in addition to experimental data and larger longitudinal studies.

Protein Z, an anticoagulant protein with expanding role in reproductive biology.

Protein Z (PZ) is a vitamin K-dependent factor characterized by its homology to other vitamin K-dependent factors (factors VII, IX, and X, protein C and protein S), but lacks any enzymatic activity. Instead, PZ acts as a cofactor for the inhibition of factor Xa through the serpin PZ-dependent protease inhibitor (ZPI). PZ deficiency is associated with a procoagulant state, highlighted by excessive FXa secretion and thrombin production, and is linked with several thrombotic disorders, including arterial vascular and venous thromboembolic diseases. A role for the PZ-ZPI complex in the regulation of physiological pregnancy has been demonstrated, highlighted by the progressive elevation in PZ levels in the first trimester of gestation, which then steadily decline toward delivery. An association between altered plasma PZ concentrations and adverse pregnancy outcomes (recurrent miscarriage, stillbirth, preeclampsia, intrauterine growth restriction, and placental abruption) has been reported. The mechanism by which PZ deficiency leads to adverse pregnancy outcomes is not clear, but it is multifactorial. It may be attributed to the anti-PZ IgG and IgM autoantibodies, which apparently act independently of classical antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-ß2-glycoprotein I antibodies). PZ deficiency has also been reported to be constitutional, and a number of variants in the PROZ (PZ) gene and SERPINA10 (ZPI) gene are linked with specific adverse pregnancy complications. This review summarizes the relationship between adverse pregnancy outcomes and acquired and constitutional PZ-ZPI deficiency, in order to understand whether or not PZ deficiency could be considered as a risk factor for poor pregnancy outcomes.