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Background: Acquired von Willebrand syndrome (AVWS) has been associated with monoclonal gammopathy of undetermined significance (MGUS), with limited data on its management., Methods: We conducted a systematic literature search in Medline (Ovid), Embase, and Scopus up to September 11, 2019, for studies reporting on the management of AVWS associated with MGUS (AVWS-MGUS). Data on patient characteristics, laboratory parameters at presentation, and clinical and laboratory outcomes were extracted., Objectives: To describe the clinical presentation and outcomes of different therapeutic approaches., Results: Seventy-five studies were included in the final review, for a total of 137 patients. Most patients had von Willebrand factor ristocetin cofactor activity <30 IU/dL (86.6%) and factor VIII levels <50 IU/dL (91.8%). Bleeding severity ranged from no bleeding (16.1%) to minor bleeding (46.4%) and major bleeding (37.5%). The overall clinical success rates for 1-deamino-8-D-arginine vasopressin (DDAVP), factor replacement therapy, and intravenous immunoglobulin (IVIG) were 43.8%, 33.3%, and 85.4%, respectively. The laboratory response rates for DDAVP, factor replacement therapy, and IVIG were 39.0%, 62.9%, and 88.6%, respectively. Several other treatments were also reported in small numbers, out of which myeloma-directed therapies, plasma exchange, recombinant factor VIIa, and antifibrinolytics appeared most successful, while immunosuppressive agents were largely ineffective., Conclusion: IVIG appears to be an effective treatment for AVWS-MGUS bleeding, conferring a high clinical success rate with measurable laboratory outcomes; albeit temporary. DDAVP and factor replacement therapy may be partially successful in controlling minor bleeds, but not major bleeds. Other less commonly used agents may be effective in certain cases, although data are limited., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Despite increasing use of targeted therapies to treat cancer, anemia remains a common complication of cancer therapy. Physician concerns about the safety of intravenous (IV) iron products and erythropoiesis-stimulating agents (ESAs) have resulted in many patients with cancer receiving no or suboptimal anemia therapy. In this article, we present 4 patient cases that illustrate both common and complex clinical scenarios. We first present a review of erythropoiesis and then describe our approach to cancer-associated anemia by identifying the contributing causes before selecting specific treatments. We summarize clinical trial data affirming the safety and efficacy of currently available IV iron products used to treat cancer-associated anemia and illustrate how we use commonly available laboratory tests to assess iron status during routine patient management. We compare adverse event rates associated with IV iron vs red cell transfusion and discuss using first-line IV iron monotherapy to treat anemic patients with cancer, which decreases the need for ESAs. A possible mechanism behind ESA-induced tumor progression is discussed. Finally, we review the potential of novel therapies such as ascorbic acid, prolyl hydroxylase inhibitors, activin traps, hepcidin, and bone morphogenetic protein antagonists in treating cancer-associated anemia., (© 2020 by The American Society of Hematology.)

Purpose: To identify the molecular cause in five unrelated families with a distinct autosomal dominant ocular systemic disorder we called ROSAH syndrome due to clinical features of retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache., Methods: Independent discovery exome and genome sequencing in families 1, 2, and 3, and confirmation in families 4 and 5. Expression of wild-type messenger RNA and protein in human and mouse tissues and cell lines. Ciliary assays in fibroblasts from affected and unaffected family members., Results: We found the heterozygous missense variant in the ɑ-kinase gene, ALPK1, (c.710C>T, [p.Thr237Met]), segregated with disease in all five families. All patients shared the ROSAH phenotype with additional low-grade ocular inflammation, pancytopenia, recurrent infections, and mild renal impairment in some. ALPK1 was notably expressed in retina, retinal pigment epithelium, and optic nerve, with immunofluorescence indicating localization to the basal body of the connecting cilium of the photoreceptors, and presence in the sweat glands. Immunocytofluorescence revealed expression at the centrioles and spindle poles during metaphase, and at the base of the primary cilium. Affected family member fibroblasts demonstrated defective ciliogenesis., Conclusion: Heterozygosity for ALPK1, p.Thr237Met leads to ROSAH syndrome, an autosomal dominant ocular systemic disorder.

Background: Portal vein thrombosis (PVT) is a serious problem with a high morbidity and mortality, often exceeding 40% of affected patients. Recently, PVT has been reported in patients after laparoscopic sleeve gastrectomy (LSG). The frequency is surprisingly high compared with other abdominal operations., Objective: We present a series of 5 patients with PVT after LSG. The treatment was not restricted simply to anticoagulation alone, but was determined by the extent of disease. A distinction is made among nonocclusive, high-grade nonocclusive, and occlusive PVT. We present evidence that systemic anticoagulation is insufficient in occlusive thrombosis and may also be insufficient in high-grade nonocclusive disease., Setting: Single private institution, United States., Methods: We present a retrospective analysis of 646 patients who underwent LSG between 2012 and 2015. In all patients, the diagnosis was established with an abdominal computed tomography (CT) scan as well as duplex ultrasound of the portal venous system. All patients received systemic anticoagulation. Depending on the extent of disease, thrombolytic therapy and portal vein thrombectomy were utilized. All patients received long-term anticoagulation., Results: Four patients with PVT were identified. A fifth patient with PVT after LSG was referred from another center. The mean age of all patients was 49 years. One patient had a history of deep vein thrombosis (DVT). No complications were identified intraoperatively or during the hospital stay, and all patients were discharged by postoperative day 2. The patients presented with PVT at an average of 20 days (range: 10-35) post-LSG. The CT scan was positive for PVT in all patients. In stable noncirrhotic patients with nonocclusive disease, we administered therapeutic anticoagulation. One patient with high-grade, nonocclusive PVT received anticoagulation alone. Patients with occlusive disease were treated with operative thrombectomy including intraoperative and postoperative thrombolysis (tissue plasminogen activator) with subsequent therapeutic anticoagulation, followed by oral warfarin or a factor Xa inhibitor. There was 1 death from multisystem organ failure in the patient who was referred from another institution with occlusive disease, initially managed only with an anticoagulation infusion., Conclusions: We maintain that portal vein patency is essential to normal gastrointestinal physiology and should be the treatment goal in all patients with PVT. In these patients, the therapeutic option should be guided by the extent of the thrombosis. In view of currently available approaches, we propose that operative portal vein thrombectomy, in conjunction with fibrinolysis and anticoagulation, offers the best long-term success in patients with occlusive PVT., (Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa., Objectives: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF)., Methods: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability., Results: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity., Conclusions: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered., (© 2015 International Society on Thrombosis and Haemostasis.)

Background: Enhanced tissue factor (TF) expression mediates many disease processes. Recently, four completely concordant polymorphisms were detected in the 5'-UTR of the TF gene. Three were single base changes and one was an 18-bp insertion/deletion at -1208., Objectives: This study was undertaken to determine if the I-allele or the D-allele would associate with elevated TF expression in human umbilical vein endothelial cells (HUVEC)., Methods: HUVEC were genotyped by polymerase chain reaction for 18-bp insert status. TF expression was induced by interleukin (IL)-1 or phorbol 12-myristate 13-acetate (PMA). Total TF activity was determined by a one-stage clotting assay and surface TF activity by a chromogenic assay. Protein binding differences between the I- and D-alleles were examined by gel shift assays., Results: IL-1- or PMA-induced total TF activity in D-allele HUVEC was increased 2.0-2.5-fold above that seen in II HUVEC. Surface clotting activity in D-allele cells was 1.3-1.7-fold greater than in II-allele cultures. Experiments with consensus site mutation oligos suggested that the 18-bp insert creates GATA and CCAAT-enhancer binding protein (C/EBP) transcription factor recognition sites., Conclusions: The D-allele is associated with enhanced TF activity in HUVEC. The differences in TF expression between the alleles may be due to variant transcription factor binding in the -1208 region. Further studies are warranted to investigate whether the D-allele is associated with increased incidence of pathological processes that involve TF.

It is now possible to identify a predisposing thrombophilic condition for venous thrombosis in well over half of the cases. Certain thrombophilia diagnoses have a major impact on anticoagulant therapy, and hence it is incumbent upon physicians to understand how to diagnose and manage these conditions. This chapter covers the genetics and epidemiology of the inherited thrombophilias and provides a useful, common-sense approach to the laboratory evaluation of a patient with venous thrombosis.

Objective: The indications for heparin use during pregnancy are expanding; however, heparin is associated with serious adverse effects including heparin-induced thrombocytopenia. Low-molecular-weight heparin is expensive but is associated with less frequent occurrences of heparin-induced thrombocytopenia in the nonpregnant population. However, the incidence of heparin-induced thrombocytopenia during pregnancy is unknown. The purpose of this study was to compare the incidence of heparin-induced thrombocytopenia in pregnant and nonpregnant women., Study Design: This is a retrospective cohort comparison. Pregnant and nonpregnant women were identified by means of diagnosis related group and Current Procedural Terminology code searches at three medical centers in Utah; the incidence of heparin-induced thrombocytopenia in the two groups was compared., Results: There were 10 (4%) cases of thrombocytopenia among 244 heparin-treated pregnant patients and 26 (11%) cases among the 244 nonpregnant controls. There were no cases of heparin-induced thrombocytopenia in the pregnant group, but there were 10 (4%) cases in the control group (P =.0014)., Conclusion: Heparin-induced thrombocytopenia is extremely rare in pregnant women.

Angiogenesis plays a key role in solid tumor growth. The purpose of this work was to study angiogenesis in acute myeloid leukemia (AML). We stained bone marrow samples from 20 adult patients with untreated AML and 20 normal controls using endothelial cell markers (ULEX-E and von Willebrand factor [vWF]). The number of vessels per millimeter length of bone marrow core biopsy specimen was scored by light microscopy. Using ULEX-E staining, AML marrows had (average +/- SEM) 8.3 +/- 3.6 vessels/mm (range, 3.7-19.3), whereas normal marrows had 4.3 +/- 1.8 vessels/mm (range, 1.6-7.9). A similar difference was noted using vWF staining (8.6 +/- 3.0 vessels/mm vs 4. 9 +/- 2.2 vessels/mm in AML vs normal bone marrows, respectively). The differences between the numbers of vessels/mm in AML and normal marrows were highly significant (P <.0001 for both ULEX-E and vWF staining). When analyzed by FAB category, there was no difference in the average number of vessels/mm among the different subgroups of AML. Using reverse transcriptase polymerase chain reaction, we observed that the HL-60 and U937 human AML cell lines and 4 of 4 freshly isolated AML cells from untreated patients expressed mRNA for vascular endothelial growth factor (VEGF). Both cell lines as well as all fresh AML isolates tested expressed VEGF protein. Basic fibroblast growth factor was expressed only in HL-60 cells and in only 3 of 4 fresh AML samples. These observations suggest that angiogenesis may play a role in the pathogenesis of AML. Inhibition of angiogenesis could constitute a novel strategy for the treatment of AML. (Blood. 2000;95:309-313).

In vivo prothrombin activation is thought to occur via a factor Xa/factor V-dependent mechanism. We investigated whether human venous endothelial cells (EC) could be induced to express a prothrombin activator. EC treated with lipopolysaccharide (LPS) or interleukin-1 activated prothrombin in the absence of exogenous factors Xa and V. This activity resided in the membrane fraction of EC and was not inhibited by an antibody to factor V. The apparent Km value was 3.3 +/- 0.3 mumol/L. Comparative studies of thrombin generation using a model system of phospholipid and factors Xa/V versus LPS-treated EC were performed to quantitate the effects of known inhibitors to factor Xa. The factor Xa inhibitor DEGR-chloromethyl ketone and an antibody to factor X inhibited prothrombin activation. However, the EC activator did not hydrolyze a factor Xa chromogenic substrate, and recombinant tick anticoagulant peptide did not suppress activity of the prothrombin activator. The apparent molecular weight of the EC activator was approximately 30 kD. Exogenous factor V enhanced the activity of the EC activator, such that in the presence of factor V, the apparent K(m) value was 1.28 +/- 0.10 mumol/L. Additionally, LPS-treated EC activated exogenous factor V. This activator has several characteristics of a previously described inducible murine monocyte prothrombin activator and may contribute to thrombin generation associated with pathologic stimuli.

Tissue factor (TF), a 46-kD glycoprotein receptor for coagulation factors VII and VIIa, is expressed on the surface of endothelial cells in response to a variety of agonists and is thought to play an important role in initiating the thrombosis associated with inflammation during infection, sepsis, and organ transplant rejection. The induction of TF activity by lipopolysaccharide (LPS) is regulated, at least partially, at a transcriptional level and an LPS response element containing two activator protein-1 sites and a nuclear factor-kappa B (NF kappa B)-like site has been localized to the 5' flanking region of the TF gene by transfection studies of TF promoter/reporter gene constructs. We have examined the effect of pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of the NF kappa B pathway on the expression of the endogenous TF gene in human umbilical vein endothelial cells (HUVEC). Preincubation of HUVEC for 60 minutes with PDTC inhibited LPS induction of TF activity on the cell surface in a dose-dependent manner, with 50% inhibition occurring at 10 mumol/L PDTC and 100% inhibition at higher concentrations (> or = 100 mumol/L). Furthermore, PDTC inhibited TF expression in response to tumor necrosis factor-alpha, interleukin-1 beta, and phorbol 12-myristate 13-acetate. The effect of PDTC was at the mRNA level, as seen by the complete abrogation of the large increase in TF mRNA observed in LPS-treated HUVEC. These results suggest that endothelial cell activation by diverse agonists initiates intracellular signaling events that converge upon a common pathway involving NF kappa B and, furthermore, that NF kappa B activation is an obligatory step induction of TF.

Normal human plasma contains procoagulant albumin (PC-Al), an anionic form of albumin that induces tissue factor (TF) activity in human umbilical vein endothelial cells (HUVEC) and monocytes. In this study, we investigated both the interactions between HUVEC and PC-Al and the mechanism by which PC-Al induces TF activity. Binding of PC-Al to HUVEC was specific and reversible. Further studies indicated that membrane-bound PC-Al was not internalized by HUVEC. A potential receptor on HUVEC was suggested by studies in which the capacity of a variety of reagents to inhibit the activity of PC-Al was quantitated. Induction of TF activity by PC-Al was antagonized by dextran sulfate, heparin, fucoidan, and concanavalin A but not by ovalbumin, polyglutamic acid, or polyvinyl sulfate. This competition profile bears similarities to those reported for scavenger receptors that have been identified on both HUVEC and monocytes. Involvement of protein kinase C (PKC) in the PC-Al-induced enhancement of TF activity was suggested by experiments in which staurosporine, an inhibitor of PKC, suppressed the activity of PC-Al. The induction of TF activity by PC-Al was further characterized by using a quantitative polymerase chain reaction assay. Increased TF mRNA was first seen after 1 hour of incubation with PC-Al. Maximal observed expression occurred at 2 hours, but at 5 hours, expression had significantly decreased. Monocytes could also be induced to express TF mRNA after a 2-hour incubation with PC-Al. These results suggest that the functionally relevant binding of PC-Al to HUVEC may be mediated through interactions with a membrane constituent that has some of the properties of a scavenger receptor and that this interaction augments TF activity by enhancing transcription of TF mRNA, at least in part, by a mechanism that is dependent on activation of PKC.

Objective: The hypothesis of our study is that antiphospholipid antibodies predispose to thrombosis by inducing endothelial cell tissue factor expression., Study Design: Monolayers of cultured human umbilical vein endothelial cells were incubated for 8 hours in a medium containing 20% serum obtained either from patients with antiphospholipid antibodies (n = 11) or normal subjects (n = 8). Similar incubations were performed with immunoglobulin G fractions from either patients with antiphospholipid antibodies (n = 3) or normal subjects (n = 3). Endothelial cell tissue factor expression was measured with a tissue factor-specific chromogenic substrate assay. The results were analyzed with a two-tailed t test., Results: The mean endothelial cell tissue factor expression induced by antiphospholipid sera was significantly greater than the controls (p < 0.02). Immunoglobulin experiments indicated that the factor(s) responsible for the induction of tissue factor expression resides in the immunoglobulin G fraction of the sera (p < 0.01)., Conclusions: Endothelial cell tissue factor expression is induced by antiphospholipid sera, with activity residing at least in part in the immunoglobulin fraction. The induction of tissue factor by antiphospholipid sera may play a role in the thrombotic tendency observed in patients with antiphospholipid syndrome.

Molecules that induce tissue factor expression by responsive cells such as endothelial cells and monocytes may be important in the regulation of hemostasis and, perhaps, in mediating certain hemostatic disorders. A constituent of normal human plasma capable of inducing tissue factor activity in human endothelial cells and monocytes has been isolated and identified as a derivative of, or modification associated with albumin. Procoagulant albumin caused a concentration-dependent induction of tissue factor expression by human endothelial cells, but bovine endothelial cells were unresponsive. The dose-response curve developed a plateau phase, indicating that the capacity of endothelial cells to respond to the stimulus was finite. The maximum response induced by the procoagulant albumin was similar to that observed for maximally effective concentrations of endotoxin, interleukin-1, and tumor necrosis factor. Time-course studies showed that procoagulant albumin produced peak activity in 4 to 6 hours. Identification of a procoagulant form of albumin in normal human plasma suggests a potential role for this constituent in regulation of hemostasis.

Elevated blood levels of homocysteine are associated with atherosclerosis and thrombotic disease. We previously reported that treatment of cultured endothelial cells with homocysteine increased endogenous factor V activity by activation of the cofactor. Because endothelial cell-associated factor Va would be regulated by the protein C mechanism, the ability of homocysteine-treated arterial and venous endothelial cells to activate protein C was investigated. Both arterial and venous endothelial cells activated protein C; 0.6 mmol/L homocysteine reduced endothelial cell protein C activation by 12%. Maximal inhibition (90%) of protein C activation occurred with 7.5 to 10 mmol/L homocysteine after 6 to 9 hours of incubation. Metabolism of homocysteine was not accelerated by cultured endothelial cells. Investigation of the mechanism(s) by which homocysteine reduced protein C activation indicated that the metabolite did not induce an inhibitor to activated protein C, but in low concentrations acted as a competitive inhibitor to thrombin. These data suggest that perturbation of the vascular endothelial cell protein C mechanism by homocysteine may contribute to the thrombotic tendency seen in patients with elevated blood levels of this metabolite.

Preeclampsia occurs in 7% to 10% of pregnancies and is a leading cause of morbidity for mothers and their infants. Intensive investigation has failed to reveal the cause of the multiple organ dysfunction characteristic of this disorder, which abates completely with delivery. However, several observations suggest that endothelial cell dysfunction is a central pathophysiologic event. We report that serum from preeclamptic women is cytotoxic to endothelial cells in vitro. Consistent with the reversal of the clinical condition after delivery, cytotoxic activity in serum of preeclamptic women is reduced after 24 to 48 hours post partum. In contrast, cytotoxic activity of serum from normal pregnant women increases after delivery.

Previously, we showed that cells derived from nonvascular tissues initiate clotting primarily by markedly increasing the activity of coagulation factor VII. Cells derived from vascular tissue do not normally exhibit this property (tissue factor activity). In this study, we have characterized the relationship between the tissue factor activity of cultured cells derived from normal tissues and the number of receptors they possess for coagulation factor VII. Only cultured nonvascular cells expressed tissue factor activity or possessed receptors for 125I-factor VII. Fetal lung cells, the nonvascular tissue with the largest amount of procoagulant and tissue factor activity, possessed the most receptors for 125I-factor VII (880,000/cell). Bovine corneal endothelial cells, the nonvascular tissue possessing the fewest number of receptors (2,400/cell), had the least amount of procoagulant or tissue factor activity. The affinity of nonvascular cells for 125I-factor VII varied for the cells studied (Kd congruent to 1.3-90 X 10(-10) M). Vascular cells expressed no tissue factor activity, nor did they bind 125I-factor VII. 125I-factor VII and unlabeled factor VII bound to cells had identical procoagulant activities. These results indicate that the ability of cultured cells to initiate coagulation may be regulated in part by the number of receptors they possess for factor VII.

There is increasing evidence that endothelial cell injury and altered endothelial cell function play an important role in the pathogenesis of preeclampsia. Endothelial cell injury can lead to the secretion of potent mitogens by activating platelets and directly through the increased production of peptide growth factors by endothelial cells themselves. This study was undertaken to test the hypotheses that increased secretion of mitogenic factors is a feature of preeclampsia and that this activity could be detected in the serum of preeclamptic women. Paired serum samples were collected in early labor and again at 24 to 48 hours post partum from term patients with preeclampsia (n = 15) and normal pregnant controls (n = 14). A bioassay was used to quantify mitogenic activity in these paired samples by assessing their ability to stimulate the incorporation of tritiated thymidine into deoxyribonucleic acid of confluent, quiescent (GO stage) human fibroblasts in monolayer culture. Mitogenic activity was significantly increased in prepartum, preeclamptic sera compared with normal controls and diminished rapidly postpartum to levels equivalent to normal pre- and postpartum serum. These findings are consistent with endothelial cell injury, a process that we believe plays a central role in the pathophysiology of the preeclamptic syndrome.

The coagulant properties of intact bovine vascular cells (aortic endothelial and smooth muscle cells) and human vascular cells (cutaneous and foreskin microvascular cells, umbilical venous endothelium) grown in vitro were studied. Compared to nonvascular cells (fibroblasts, corneal endothelial cells, fetal lung or intestinal mucosal cells), vascular cells had little procoagulant activity. Radioimmunologic measurement of thrombin in recalcified plasma demonstrated markedly lower concentrations of thrombin in the presence of vascular endothelial and smooth muscle cells compared to corneal endothelial and fetal lung cells. The low thrombin concentrations were not a consequence of thrombin binding to the vascular cells nor were they due to accelerated thrombin inactivation by antithrombin-III or alpha 2-macroglobulin. Neither vascular cells nor the nonvascular cells promoted contact activation of plasma as measured by a sensitive specific assay for kallikrein. Studies with intact cell monolayers and purified factors VIIa and X indicated that while nonvascular cells express tissue factor activity, vascular cells do not exhibit this property. These data suggest that the nonthrombogenic nature of intact vascular cells is due to their failure to initiate contact activation and to express tissue factor activity. In addition, the primary difference in coagulant potential between vascular cells and nonvascular cells is the lack of tissue factor expression by the vascular cells.

Although antibody inhibitors directed against blood coagulation factors are well known, antibody inhibitors directed against thrombin are rare. We describe three postsurgical patients with prosthetic cardiac valves who developed serum autoantibodies reactive with human and bovine thrombin, as demonstrated by coagulation studies and immunoblotting. Despite marked prolongation of the thrombin time in these patients, the inhibitors were not associated with significant clinical bleeding. The mechanism of antithrombin autoantibody formation following surgery in patients with prosthetic cardiac valves remains to be determined.

Despite intense study preeclampsia remains enigmatic and a major cause of maternal and fetal morbidity and mortality. Most investigative efforts have focused on the hypertensive component of this disorder with reduced attention given to other equally important characteristics. Increased sensitivity to pressor agents and activation of the coagulation cascade occur early in the course of preeclampsia, often antedating clinically recognizable disease. Inasmuch as endothelial cell injury reduces the synthesis of vasorelaxing agents, increases the production of vasoconstrictors, impairs synthesis of endogenous anticoagulants, and increases procoagulant production, these cells are likely to be implicated in the pathophysiology of preeclampsia. Indeed, evidence of endothelial cell injury is provided by the most characteristic morphologic lesion of preeclampsia, glomerular endotheliosis. Additional support for this hypothesis is derived from reports that indicate increased levels of circulating fibronectin (which can be released from injured endothelial cells) and increased factor VIII antigen present in the blood of preeclamptic women. More recently, direct evidence of activities that injure endothelial cells in vitro and increase the contractile sensitivity of isolated vessels has been presented. We propose that poorly perfused placental tissue releases a factor(s) into the systemic circulation that injuries endothelial cells. The changes initiated by endothelial cell injury set in motion a dysfunctional cascade of coagulation, vasoconstriction, and intravascular fluid redistribution that results in the clinical syndrome of preeclampsia.