Practice Guidelines of the Spanish Society of Cardiology for the management of cardiac disease in pregnancy

Maternal adaptation to pregnancy includes reproductive hormone interaction plasma, volume changes with an increase in total body water, vascular alterations with a decrease in systemic resistance and modifications associated with hypercoagulability. These explain, in part, the appearance of signs and symptoms, even in a normal pregnant woman, that are difficult to distinguish from those occurring in heart disease and why some cardiac abnormalities are not well tolerated during pregnancy. Cardiovascular abnormalities are considered the first non-obstetric cause of morbidity and mortality during pregnancy. Rheumatic and congenital heart diseases are currently the most frequent cardiopathy found in women of childbearing age, followed by hypertension, coronary artery disease and arrhythmia. Although pregnancy is well tolerated by most women with heart disease, there are some cardiovascular abnormalities which place the mother and the infant at extremely high risk: patients with congestive heart failure and severe cardiac dysfunction, pulmonary hypertension, cyanotic congenital heart disease, Marfan's syndrome, severe obstructive lesions of the left side of the heart, patients with prosthetic cardiac valves and antecedents of peripartum cardiomyopathy should be encouraged to avoid pregnancy and the interruption of pregnancy may be advisable in cases with great risk of disability or death. The most severe cardiopathies significantly increase the risk of fetal loss and the presence of a congenital cardiac abnormality in either parent increases the risk of congenital cardiac disease in the fetus. Medical care must be initiated early, prior to conception and women with cardiopathy should be informed of the possible risks of pregnancy to both the mother and fetus.     

De novo hemolytic uremic syndrome in a kidney-pancreas recipient in the postoperative period

Among the numeruos adverse side effects of tacrolimus (TAC), de novo thrombotic microangiopathy stands out as an infrecuente but severe complication. Renal dysfunction is the only alteration that should lead to suspicion of thrombotic microangiopathy, because the clinical features of intravascular hemolysis are not always found. The definitive diagnosis can usually be made with kidney biopsy. Patientes with TAC induced thrombotic microangiopathy usually promptly recover after treatment withdrawal or reduction in the dose of TAC and a short course of plasma therapy, but the risk of rejection increases. Switching from TAC to cyclosporine has also been tried with resolution of the hemolysis but thrombotic microangiopathy has been noted with both and this condition may later recur. We present a 29-year-old man who received a kidney-pancreas transplant for end-stage diabetic nephropathy. After initial induction with basiliximab, the immunosuppression consisted of prednisone, tacrolimus and mycophenolate mofetil. Twenty four days posttransplantation his renal function declined with a peak creatine level of 2.35 mg/dl. Laboratory studies showed thrombocytopenia and features of intravascular hemolysis. TAC associated hemolytic uremic syndrome was suspected and drug was immediately stopped and converted to sirolimus. Also he was treated with plasma infusion. The allograft biopsy showed focal glomerular and arteriolar acute thrombosis without evidence of rejection. Our experience demostrate that switching from tacrolimus to sirolimus could be an adecuate strategy for patients who develop FK506-associated de novo thrombotic microangiopathy without increase risk of acute rejection.     

Glycoprotein IIb-IIIa and RGD(S) are not important for fibronectin- dependent platelet adhesion under flow conditions

Previous studies have indicated that activated blood platelets interact with fibronectin through binding of fibronectin to the glycoprotein IIb- IIIa complex (GPIIb-IIIa). The cell attachment site of fibronectin with its crucial arg-gly-asp(-ser) [RGD(S)]sequence is involved in these bindings. We studied the importance of these interactions for the fibronectin dependence of platelet adhesion under flow conditions. An RGDS-containing hexapeptide (GRGDSP) was compared with a nonreactive control peptide (GRGESP). The GRGDSP-peptide inhibited thrombin-induced aggregation and adhesion under static conditions at 0.1 mmol/L. This concentration had no effect on platelet adhesion to nonfibrillar collagen type I in flow. GRGDSP at 1 mmol/L had a significant inhibitory effect at 1,500 s-1, but not at the lower shear rates of 800 and 300 s-1 where platelet adhesion is also fibronectin dependent. On the matrix of cultured human umbilical vein endothelial cells, 1 mmol/L GRGDSP had no effect on platelet adhesion. The relation between GPIIb- IIIa and fibronectin dependence was investigated with platelets of a patient with Glanzmann's thrombasthenia and monoclonal antibodies to GPIIb-IIIa using endothelial cell matrix (ECM) as a surface. Platelets of normal controls or a patient with Glanzmann's thrombasthenia showed a similar inhibition of adhesion in the presence of fibronectin-free plasma after the ECMs had been preincubated with antifibronectin F(ab')2 fragments. Incubation of platelets with anti-GPIIb-IIIa showed inhibition of platelet adhesion at high shear rates. Dependence on fibronectin for platelet adhesion was still observed even though separate experiments had shown that these anti-GPIIb-IIIa antibodies could block binding of radiolabeled fibronectin to thrombin-activated platelets. These data suggest the existence of another binding system for the interaction of platelets with fibronectin that may only appear when fibronectin is present on a surface.     

Increased macrophage colony-stimulating factor levels in immune thrombocytopenic purpura

Thrombocytopenia is a dose-limiting toxicity of macrophage colony- stimulating factor (M-CSF) in preclinical and initial phase I trials. Modulation of macrophage-mediated platelet destruction in immune thrombocytopenic purpura (ITP) may be affected by M-CSF activity. In this study, plasma levels of M-CSF were determined by a sensitive radioimmunoassay in 23 patients with ITP. These were compared with control levels measured in 24 healthy subjects. M-CSF levels were significantly higher in the ITP patients than in the control subjects (218 v 179, P < .02); however, there was a great deal of overlap. The highest M-CSF levels (median = 299 U/mL) were observed in three patients with Evan's syndrome. Patients with severe ITP (platelets < 25,000/microL) had intermediate M-CSF levels (median = 231 U/mL) and those with mild thrombocytopenia (> 25,000/microL) had normal levels (median = 173 U/mL). Sixteen patients were treated with corticosteroids: 10 responded and 6 did not. Median M-CSF levels were higher in those who failed to respond compared with responders (272 v 202, P < .05). These findings suggest M-CSF may influence macrophage- mediated platelet destruction in ITP.     

Proteoglycan synthesis by hematopoietic progenitor cells

The synthesis of proteoglycans (PG) by hematopoietic stromal cells has been reported. But PG synthesis by hematopoietic progenitor cells has not been explored. We have studied synthesis, cellular distribution, and molecular characteristics of PG by a cloned interleukin-3 (IL-3)- dependent hematopoietic progenitor cell line, FDCP-1, which is cloned from murine long-term marrow cultures. Under appropriate conditions the cell can differentiate into granulocytes and macrophages, and therefore, can be considered CFU-GM equivalent. The pattern of PG synthesis was studied by 35SO4 labeling. FDCP-1 cells actively synthesize PG, which are distributed in the intracellular, membrane- associated (MP), and extracellular pools. After purification of the 35S- labeled material by ion-exchange and gel filtration techniques, a single chondroitin sulfate-PG (CIS-PG) was observed to be present in the three studied pools. By Sepharose CL-4B chromatography, this PG has a Kav of 0.47, which after alkaline treatment is shifted to a Kav of 0.67. This indicates the proteoglycan nature of the 35SO4-labeled material. The MP CIS-PG is not stable. It is released to the culture medium where it is subsequently processed. However, in the presence of hematopoietic stromal cells D2X, the stability of MP proteoglycan of FDCP-1 cells is enhanced, suggesting that the synthesis of PG by progenitor cells and its accumulation in the membrane may have a role in the interaction between progenitor and stromal cells.     

Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(- )-inhibitor complexes in sepsis

Considerable evidence indicates that activation of the contact system of intrinsic coagulation plays a role in the pathogenesis of septic shock. To monitor contact activation in patients with sepsis, we developed highly sensitive radioimmunoassays (RIAs) for factor XIIa-Cl(- )-inhibitor (Cl(-)-Inh) and kallikrein-Cl(-)-Inh complexes using a monoclonal antibody (MoAb Kok 12) that binds to a neodeterminant exposed on both complexed and cleaved Cl(-)-Inh. Plasma samples were serially collected from 48 patients admitted to the intensive care unit because of severe sepsis. Forty percent of patients on at least one occasion had increased levels of plasma factor XIIa-Cl(-)-Inh (greater than 5 x 10(-4) U/mL) and kallikrein-Cl(-)-Inh (greater than 25 x 10(- 4) U/mL), that correlated at a molar ratio of approximately 1:3. Levels of factor XII antigen in plasma and both the highest as well as the levels on admission of plasma factor XIIa-Cl(-)-Inh in 23 patients with septic shock were lower than in 25 normotensive patients (P = .015: factor XII on admission; P = .04: highest factor XIIa-Cl(-)-Inh; P = .01: factor XIIa-Cl(-)-Inh on admission). No significant differences in plasma kallikrein-Cl(-)-Inh or prekallikrein antigen were found between these patients' groups. Elevated Cl(-)-Inh complex levels were measured less frequently in serial samples from patients with septic shock than in those from patients without shock (P less than .0001). Based on these results, we conclude that plasma Cl(-)-Inh complex levels during sepsis may not properly reflect the extent of contact activation.     

Antibodies reactive with human T cell leukemia viruses in the serum of hemophiliacs receiving factor VIII concentrate

The third member of the family of T cell leukemia viruses (HTLV III) has been proposed as the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). A high risk of AIDS has been reported among patients with hemophilia, particularly those with factor VIII deficiency who receive commercial clotting factor concentrates. In a prevalence survey conducted between September 1982 and April 1984, initial serum samples from 74% of hemophiliacs who had ever been treated with commercial factor VIII concentrate, 90% of those frequently treated with factor VIII concentrate, and 50% of those treated with both factor VIII and factor IX concentrates had antibodies reactive against antigens of HTLV III, compared with none of the hemophiliacs treated only with factor IX concentrate or volunteer donor plasma or cryoprecipitate. Two of the seropositive patients have developed AIDS-related illnesses, and a third patient died of bacterial pneumonia. One initially seronegative patient developed antibodies against HTLV III during the study and is currently well. The predominant antibody specificities appear directed against p24 and p41, the presumed core and envelope antigens of HTLV III, suggesting that factor VIII concentrate may transmit the p24 and p41 antigens of HTLV III. However, the presence of infectious retroviruses in clotting factor concentrates and the effectiveness of screening and viral neutralization procedures remain to be determined.     

Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo

The vascular endothelium plays an important role in fibrinolysis by producing tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). The monokine tumor necrosis factor (human recombinant TNF) increased the production of PAI by cultured human endothelial cells from umbilical vein (twofold) and from foreskin microvessles (four to eight fold). This was demonstrated by titration of endothelial cell-conditioned medium with t-PA, by reverse fibrin autography, and by immunoprecipitation of [35S]PAI-1 by anti-PAI-1 IgG. TNF also induced a marked increase of PAI-1 messenger RNA (mRNA) in the cells. The stimulation of PAI activity by TNF was seen at 4 U/mL and reached a maximum at 500 U/mL. Human recombinant lymphotoxin and interleukin-1 (alpha and beta) also stimulated the production of PAI activity, while interleukin-6 was ineffective. Separate additions of TNF or interleukin-1 (IL-1) at optimal concentrations (500 U/mL and 5 U/mL, respectively) resulted in a comparable stimulation of PAI production by endothelial cells. The simultaneous addition of both mediators resulted in an additive effect. The effect of TNF could not be prevented by the addition of polymyxin B or by anti-IL-1 antibodies. Therefore, it is unlikely that TNF acts through the induction of IL-1 secretion by endothelial cells. Two hours after a bolus injection of 250,000 U/kg TNF into rats, a fivefold increase in circulating PAI levels was found. In the next ten hours, the levels returned to normal. Blood platelets do not significantly contribute to the increase in circulating PAI, because the number of platelets did not change after TNF injection and the amount of PAI in blood platelets is not sufficient for several hours during an increase in PAI activity. The acute phase reactants, fibrinogen and alpha 2-antiplasmin in rat plasma, were altered little if any two to 24 hours after injection of 250,000 U/kg TNF. In vitro, TNF did not change PAI production by human and rat hepatocytes in primary monolayer culture. Therefore, it is most likely that vascular endothelial cells contribute to the increased amount of circulating PAI induced by TNF in vivo. This increase in PAI activity might decrease fibrinolysis.     

Von Willebrand factor in the vessel wall mediates platelet adherence

A monoclonal antibody directed against the von Willebrand factor moiety (vWF) of factor VIII-von Willebrand factor (FVIII-vWF), which blocks ristocetin-induced platelet aggregation as well as the binding of FVIII- vWF to platelets in the presence of ristocetin, inhibited platelet adherence to human artery subendothelium when present in normal flowing blood. This monoclonal antibody, CLB-RAg 35, inhibited platelet adherence as a function of the shear rate. At wall shear rates below 500 s-1, platelet adherence was not affected, but at higher shear rates platelet adherence was gradually inhibited, reaching an average of 11% of the normal value at 2,500 s-1. Indirect immunofluorescence established the reactivity of CLB-RAg 35 with vWF present in artery subendothelium. Pretreatment of normal vessel walls with this antibody inhibited adherence of platelets in blood from a patient with severe homozygous von Willebrand's disease and in blood from normal individuals. The inhibition was shear-rate dependent and significant at high shear rates (2,500 s-1). By adding increasing amounts of purified FVIII-vWF to normal blood, the inhibition was gradually overcome. These data indicate that vWF present in the vessel wall contributes appreciably to platelet adherence. At high wall shear rates, platelet adherence is mediated virtually completely by both plasma FVIII-vWF and vWF in the vessel wall. At low wall shear rates (below 500 s-1), platelet adherence occurs independent of FVIII-vWF in plasma and vWF in the vessel wall.