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PubMed1987

Correction of hypoprothrombinemia by immunosuppressive treatment of the lupus anticoagulant-hypoprothrombinemia syndrome.

A 66-year-old man with the lupus anticoagulant-hypoprothrombinemia syndrome was treated with cyclophosphamide and prednisone to correct a factor II deficiency prior to elective major surgery. Whereas the lupus anticoagulant activity persisted, functional factor II levels normalized and he underwent surgery without a bleeding diathesis. Immunosuppressive therapy may temporarily normalize factor II levels in patients with the lupus anticoagulant-hypoprothrombinemia syndrome and reduce the risk of excessive hemorrhage. The disparate response of the lupus anticoagulant and hypoprothrombinemia to immunosuppression suggests that the lupus anticoagulant did not directly cause the hypoprothrombinemia.

Aged↗

PubMed1983

A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome.

Antibodies that bind prothrombin without neutralizing its coagulant activity were demonstrated in the plasma of two patients with the acquired hypoprothrombinemia-lupus anticoagulant syndrome. The first patient's plasma contained less than 1% prothrombin activity and no detectable prothrombin antigen. The second patient's plasma contained about 6% of both prothrombin activity and antigen. Neither patient's plasma neutralized the prothrombin coagulant activity of normal plasma or of purified prothrombin added in vitro. Nevertheless, double immunodiffusion studies and binding experiments utilizing 125I-prothrombin demonstrated the presence of prothrombin antibodies in each patient's plasma. A Scatchard analysis of the binding data obtained with different concentrations of 125I-prothrombin and the first patient's plasma indicated the presence of a high affinity antibody, apparent Kd approximately 10(-10)M, and a lower affinity antibody, apparent Kd approximately 10(-9)M. Studies utilizing purified cleavage products of prothrombin suggested that the antibodies were directed against an epitope or epitopes located on the carboxyl-terminal, latent thrombin segment of the prothrombin molecule. We postulate that the acquired hypoprothrombinemia in these two patients and in other reported patients with the acquired hypoprothrombinemia-lupus anticoagulant syndrome stems from rapid clearance from the circulation of prothrombin antigen-antibody complexes.

Antibodies↗

PubMed1988

Vitamin K-reversible hypoprothrombinemia in rats. I. Sex differences in the development of hypoprothrombinemia and the effects of beta-lactam antibiotics.

Male and female rats were fed an ordinary diet which contained about 500 ng vitamin K/g or a vitamin K-deficient diet containing less than 5 ng vitamin K/g. Hypoprothrombinemic changes such as prolongation of the prothrombin time (PT) and activated partial thromboplastin time (APTT) were detected in male rats within 4-6 days after feeding of the vitamin K deficient diet. Blood clotting factor VII and descarboxy prothrombin (PIVKA) levels changed rapidly, with maximum alteration at 2-4 days. Similar changes in factor VII and PIVKA levels were observed in female rats, but they appeared only after feeding of the K deficient diet for a long period. PT and APTT in female rats showed slight or no alteration even after 10 day feeding of the K-deficient diet. These results indicate that male rats are more susceptible to vitamin K deficiency than female rats. Administration of latamoxef led to a dose-dependent development of hypoprothrombinemia in vitamin K-deficient female rats. The hypoprothrombinemia in vitamin K-deficient female rats was caused by beta-lactam antibiotics with N-methyltetrazolethiol, thiadiazolethiol and methyl-thiadiazolethiol as the 3'-position substituent of the cephem nucleus.

Animals↗

PubMed1987

Determinants of antibiotic-associated hypoprothrombinemia.

Hypoprothrombinemia is a relatively uncommon event in the hospitalized patient. When it does occur, it often is associated with surgery, dietary vitamin K deficiency, renal dysfunction, malignancy, and broad-spectrum antibiotic therapy. Several mechanisms have been proposed to account for antibiotic-associated hypoprothrombinemia, including eradication of gastrointestinal bacteria, direct inhibition of vitamin K-dependent coagulation, and indirect inhibition of coagulation. The anecdotal reports and comparative studies of antibiotic-associated hypoprothrombinemia were reviewed; these usually implicated broad-spectrum or the use of several antibiotics. The increased frequency of hypoprothrombinemia associated with moxalactam and cefoperazone also raises questions about the role of their N-methylthiotetrazole (NMTT) side chains. The hypoprothrombinemia associated with NMTT antibiotics does not occur in healthy volunteers and is rare in patients without complicating conditions. Although NMTT inhibits vitamin K-dependent carboxylation in vitro, the parent cephalosporins do not. It is not clear whether NMTT-containing antibiotics liberate sufficient amounts of NMTT in vivo to antagonize clotting in patients. Thus, although moxalactam, and possibly cefoperazone, may in some cases be responsible for increases in prothrombin time, most important question for further study is whether the newer NMTT-containing antibiotics pose a risk of hypoprothrombinemia that is greater than that of antibiotics lacking this side chain.

Animals↗

PubMed1997

Hypoprothrombinemia associated with cefmetazole.

OBJECTIVE: To report a case of hypoprothrombinemia associated with the use of cefmetazole sodium, define patients at risk for this adverse effect, and identify options to prevent this problem. CASE SUMMARY: A malnourished patient with endstage renal disease received cefmetazole following a below-the-knee amputation of the right leg. Three days later, a prothrombin time (PT) and an international normalized ratio (INR) were obtained and were markedly elevated from baseline; however, the patient had no clinical symptoms of bleeding. Cefmetazole was discontinued. Vitamin K and fresh frozen plasma were administered. The PT and INR normalized within 24 hours and remained normal throughout the remainder of hospitalization. DISCUSSION: The incidence of hypoprothrombinemia associated with cefmetazole reported in the literature is conflicting and not consistent. There are three proposed mechanisms of cephalosporin-associated hypoprothrombinemia, two of which involve the N-methylthiotetrazole (NMTT) chain. The most plausible mechanism is NMTT inhibition of vitamin K epoxide reductase in the liver. Patients at an increased risk for this adverse event include those with low vitamin K stores, specifically patients who are malnourished, with low albumin concentrations and poor food intake. The elderly and patients with liver or renal dysfunction are examples of populations at risk. CONCLUSIONS: Hypoprothrombinemia may occur with cephalosporins and is especially problematic with those containing an NMTT side chain. Clinicians need to identify patients at risk for developing antibiotic-associated hypoprothrombinemia, monitor them closely, and give vitamin K as prophylaxis accordingly.

Anti-Bacterial Agents↗

PubMed1988

Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status.

The mechanism of cephalosporin-induced hypoprothrombinemia has been investigated in hospitalized patients, with respect to cephalosporin structure, vitamin K metabolism, and vitamin K status. Cephalosporins containing side chains of N-methylthiotetrazole (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or methyl-thiadiazole (cefazolin) all caused the transient plasma appearance of vitamin K1 2,3-epoxide in response to a 10-mg intravenous dose of vitamin K1, whereas two cephalosporins without a heterocyclic side chain (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin K1 2,3-epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprocoumon. Patients eating normally had plasma vitamin K1 concentrations (176 to 1184 pg/mL) that were within the normal range (150 to 1550 pg/mL) and their clotting tests remained consistently normal for all antibiotics tested. Patients on total parenteral nutrition had lower plasma vitamin K1 concentrations (50 to 790 pg/mL) but normal clotting before starting antibiotic therapy. Of 19 parenterally fed patients, all seven treated with latamoxef developed hypoprothrombinemia, PIVKA-II and a decrease of protein C within four days whereas 12 patients treated with cefotaxime or cefoxitin showed no clotting changes. Latamoxef-associated hypoprothrombinemia was readily reversible by 1 mg of vitamin K1 given intravenously, but hypoprothrombinemia and sub-normal plasma vitamin K1 could recur within two to three days. The data suggest that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lower nutritional-vitamin K status predisposes to hypoprothrombinemia.

Adult↗

PubMed1985

Effect of sex hormones on hypoprothrombinemia induced by N-methyltetrazolethiol in rats.

N-Methyltetrazolethiol (NMTT) increased prothrombin time (PT) and decreased plasma factor VII and prothrombin levels only in vitamin K-deficient male rats. In female rats identical treatment with NMTT did not produce hypoprothrombinemia. Conventional and germ-free rats displayed no significant difference in the manifestation of hypoprothrombinemia, but the increase of PT in NMTT-treated vitamin K-deficient rats was greater in the germ-free males. Estradiol administration or castration of male rats retarded manifestation of vitamin K deficient syndromes such as increases of PT and activated partial thromboplastin time (APTT), decreases of plasma factor VII and prothrombin levels, and increases of plasma and liver descarboxyprothrombin (PIVKA) levels, and testosterone injection to the castrated rats restored these changes. In female rats testosterone treatment or castration enhanced the manifestation of hypoprothrombinemia and estradiol treatment to the castrated females retarded it. Gamma-glutamyl-carboxylase activity was increased by vitamin K-deficiency but not inhibited by testosterone or NMTT. These data suggest that estrogen protects the rat against manifestation of hypoprothrombinemia even with NMTT treatment, while androgen enhances vitamin K deficiency, and supplementation of vitamin K prevents its deficiency in NMTT-treated rats.

Animals↗

PubMed1988

Mechanism of thioamide antithyroid drug associated hypoprothrombinemia.

The thioamide class of antithyroid drugs has been associated with the development of hypoprothrombinemia. Two drugs in this class, propylthiouracil and methimazole, resemble the methyltetrazole-thiol leaving group of certain cephalosporin antibiotics. Both were found in vitro to inhibit the vitamin K dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid with 50 per cent inhibitory concentrations of 2 mM for propylthiouracil and 0.1 mM for methimazole. Methimazole was also found to inhibit vitamin K epoxide reductase, an enzyme related to the carboxylation reaction, with a 50 per cent inhibitory concentration of 25 uM. In vivo methimazole, administered twice at a dose of 500 mg/kg to rats on a vitamin K deficient diet produced hypoprothrombinemia. These results suggest that the mechanism of hypoprothrombinemia associated with thioamide antithyroid drugs may be similar to the mechanism of hypoprothrombinemia associated with cephalosporins which contain the methyltetrazole-thiol leaving group.

Amides↗

PubMedDate not supplied

Antibiotic-associated hypoprothrombinemia: a review of prospective studies, 1966-1988.

Many antimicrobial agents have been associated with hypoprothrombinemia. The precise mechanisms are unknown, but alteration in vitamin K status or utilization is involved. The two postulated mechanisms implicate either direct inhibition of biosynthesis of the vitamin K-dependent clotting factors by the N-methylthiotetrazole (NMTT) moiety found in certain antimicrobial agents or eradication of vitamin K-producing intestinal microflora in patients with reduced oral intake of vitamin K. An English-language review of all prospective studies reported between 1966 and 1988 in which serial prothrombin times were monitored in adult patients revealed that the incidence of hypoprothrombinemia varied from 3.7% to 64% with NMTT-containing regimens and from 0% to 24% with non-NMTT-containing regimens. Detailed evaluation of these and other studies suggests that certain risk factors, including malnutrition, hepatic and renal dysfunction, older age, and severity of illness, may be the major determinants of hypoprothrombinemia. The hypothesis that the NMTT side chain is primarily responsible for hypoprothrombinemia may not be justified. We conclude that patients at high risk for coagulopathy should be carefully monitored and that serious consideration should be given to the use of prophylactic vitamin K in such cases.

Anti-Bacterial Agents↗

PubMed1986

Hypoprothrombinemia in patients with cancer receiving cefoperazone and mezlocillin.

Forty-one patients with cancer who were receiving cefoperazone sodium plus mezlocillin sodium were prospectively followed up for the development of abnormal bleeding or hypoprothrombinemia. Ten of 41 patients developed an increased prothrombin time, three with a hemorrhagic episode. Serum transport proteins and serum carotene were measured in 18 patients, six of whom developed hypoprothrombinemia. Low serum prealbumin and low serum carotene levels were associated with the development of hypoprothrombinemia. Patients with cancer are especially predisposed to the development of antibiotic-associated hypoprothrombinemia. This is probably a result of protein-calorie malnutrition and low vitamin K stores.

Carotenoids↗

PubMed1986

Hypoprothrombinemia associated with cefamandole use in a rural teaching hospital.

The incidence of hypoprothrombinemia (prothrombin time greater than or equal to 2 s above the highest control) associated with concurrent cefamandole nafate usage in our institution was determined. Of 77 patients receiving cefamandole for no less than 48 hours, serial prothrombin time was monitored in 31 (40.2%). Four (12.9%) of 31 in whom a baseline normal prothrombin time was obtained developed hypoprothrombinemia during cefamandole therapy. An additional three patients for whom baseline prothrombin time was not determined were noted to have hypoprothrombinemia during therapy with cefamandole. Two patients had clinically significant bleeding episodes. The prothrombin time normalized in six of seven patients following administration of fresh frozen plasma, phytonadione therapy, discontinuation of cefamandole, or a combination of the three. This study illustrated that the incidence of hypoprothrombinemia associated with concurrent cefamandole use is relatively high. Serial prothrombin time monitoring is indicated when patients receive cefamandole.

Adult↗

PubMed1994

Case report: the lupus anticoagulant-hypoprothrombinemia syndrome.

The lupus anticoagulant is a well-described in vitro phenomenon that may be associated with arterial and venous thrombotic episodes. The lupus anticoagulant is never accompanied by a hemorrhagic diathesis unless it is associated with a second coagulation abnormality such as thrombocytopenia or hypoprothrombinemia. The lupus anticoagulant-hypoprothrombinemia syndrome is now a well-defined entity that may cause a severe, life-threatening hemorrhagic diathesis. The hypoprothrombinemia in this syndrome is the result of rapid clearance of prothrombin-antiprothrombin antibody complexes by the reticulo-endothelial system. The cause of antiprothrombin antibody formation is unknown. The authors describe a recent experience with a patient with this syndrome who initially had recurrent, life-threatening gastrointestinal bleeding. They were able to demonstrate hypoprothrombinemia and the presence of prothrombin-antiprothrombin antibody immune complexes. The patient was treated with prednisone, with correction of the bleeding disorder; however, the patient had resultant death from thrombosis. A literature review of the past 30 years as it relates to the discovery and treatment of this phenomenon is included.

Adult↗

PubMed1987

Hypoprothrombinemia associated with cefoperazone therapy.

Cefoperazone, a beta-lactam antibiotic with a methylthiotetrazole side chain, has been reported infrequently to cause hypoprothrombinemia and hemorrhage. We retrospectively analyzed the records of 80 patients who had been given this drug for more than 72 hours. Nine patients received vitamin K1 (phytonadione) prophylaxis and had no evidence of hemorrhage. Of the remaining 71 patients, 32 had prothrombin times measured; 14 of them had hypoprothrombinemia. Prothrombin times ranged from 14.8 to 97.3 seconds at a mean of 6.2 days after initiation of therapy. Seven of the 14 patients had clinically significant hemorrhage and five required transfusions. Two patients with clinically evident hemorrhage died during or immediately after cefoperazone therapy. Prothrombin times rapidly returned to normal in all patients treated with phytonadione. We believe hypoprothrombinemia is a more common complication of cefoperazone therapy than is generally acknowledged, and is preventable. Unless clinically contraindicated, we recommend that all patients treated with cefoperazone receive phytonadione prophylaxis.

Aged↗

PubMed1992

Molecular and genetic analysis of a compound heterozygote for dysprothrombinemia of prothrombin Tokushima and hypoprothrombinemia.

The molecular and genetic basis of a compound heterozygote for dys- and hypoprothrombinemia was analyzed. Abnormal nucleotide sequences of the human prothrombin gene were screened by PCR-single-strand conformation polymorphism (PCR-SSCP) with endonuclease digestion and mutated primer-mediated PCR-RFLP. A single nucleotide substitution responsible for dysprothrombinemia of prothrombin Tokushima was detected, as were three polymorphisms. The mutation for hypoprothrombinemia was detected by PCR-single-strand conformation polymorphism (PCR-SSCP) with endonuclease digestion in exon 6, near MboII-RFLP and NcoI-RFLP. Sequencing of PCR-amplified genomic DNA revealed a single base insertion of thymine (T) at position 4177. The resulting frameshift mutation caused both an altered amino acid sequence from codon 114 and a premature termination codon (i.e., TGA) at codon 174 in exon 7. Because exon 7 encodes the kringle 2 domain preceding the thrombin sequence, this frameshift leads to the null prothrombin phenotype. The inheritance of the hypoprothrombinemia gene from the father to the proband was proved by PCR-SSCP with endonuclease digestion and mutated primer-mediated PCR-RFLP.

Amino Acid Sequence↗

PubMed1991

Hypoprothrombinemia and hemorrhage in a surgical patient treated with cefotetan.

For 4 days before surgical repair of a diverticulitic colovesical fistula and for 6 days after, a 63-year-old man was treated with 2 g of intravenous cefotetan disodium every 12 hours for associated urosepsis with bacteremia. Postoperatively, the patient followed a diet of intravenous nutrition only. Uneventful convalescence was interrupted by signs of sudden major blood loss, accompanied by prolonged prothrombin time. After stabilization with packed red blood cells, fresh plasma, crystalloids, and parenteral vitamin K, laparotomy revealed a huge intra-abdominal clot, which was evacuated. This case illustrates the risk of unexpected hypoprothrombinemia and hemorrhage in a cefotetan-treated surgical patient who demonstrated none of the usual comorbid conditions generally described in patients with antibiotic-induced hypoprothrombinemia. Like cefamandole nafate, cefoperazone sodium, moxalactam disodium, and other cephalosporins containing the methylthiotetrazole side chain, cefotetan appears to pose an unusual risk of major bleeding.

Cefotetan↗

PubMed1981

Transient hypoproteinemia and hypoprothrombinemia in an infant.

A 7 months old infant with transient hypoproteinemia and hypoprothrombinemia is described. The hypoproteinemia is attributed to protein losing enteropathy, and transient Menetrier's disease is suggested as a possible cause for the protein loss. Assuming that this baby was not vitamin K deficient, and knowing that the mononuclear weight of prothrombin is lower than that of albumin, the hypoprothrombinemia might be due to prothrombin loss into the gut together with albumin

Gastritis↗

PubMed1997

Molecular analysis of a compound heterozygote for hypoprothrombinemia and dysprothrombinemia (-G 7248/7249 and ARG 340 TRP).

Hypoprothrombinemia is an uncommon hereditary coagulation defect characterized by low levels of biologically active prothrombin. Automated fluorescence-based DNA sequence analysis of amplified genomic DNA was used to define prothrombin gene regions from a patient with severe functional hypoprothrombinemia and little detectable prothrombin antigen. Two changes that alter amino acid sequence were observed: a deletion of one nucleotide (-G, 7248/7249) in exon 8 of one allele, causing a frameshift at codon 249/250 that results in premature termination of translation; and a C --> T change resulting in the substitution of tryptophan (TGG) for arginine (CGG) at amino acid 340 in exon 10 of the prothrombin gene. Computer modeling of the thrombin molecule confirmed that arginine 340 is located at the surface of the thrombin molecule, which points to the aqueous solvent. As tryptophan is a highly hydrophobic amino acid, the Arg --> Trp change may be associated with instability of the thrombin molecule.

Adult↗

PubMed1992

Hypoprothrombinemia associated with interleukin-2 therapy: correction with vitamin K.

We noted that patients treated with high-dose interleukin (IL)-2 (600,000 IU/kg every 8 h by intravenous bolus) at our institution frequently developed prolongation of their prothrombin time (PT). We therefore performed a prospective study of coagulation function during IL-2 treatment. Since IL-2 treated individuals are known to develop cholestatic liver dysfunction, we hypothesized that the hypoprothrombinemia was due to deficiency of liver-synthesized clotting factors and could be prevented by vitamin K replacement. Alternating patients served as controls or received prophylactic subcutaneous subcutaneous vitamin K. While the nine control patients did not exhibit a significant increase (mean +/- SD) in PT (13.6 +/- 0.6 s pretreatment, 15.0 +/- 2.2 on day 4, and 15.0 +/- 2.5 on day 7, p = 0.77 by repeated measures analysis), three patients developed marked increases in PT (greater than 18 s). Changes in partial thromboplastin time (PTT) over this interval were also not statistically significant. Factor VII levels decreased in all patients from 106 +/- 22 to 59 +/- 16 and 52 +/- 26% on days 4 and 7 (p = 0.0002). Factor VII levels in four patients dropped below the lower limit of normal. Prophylactic treatment of seven patients with vitamin K on days 1-8 of the IL-2 therapy protocol resulted in diminished changes in PT and factor VII compared to control patients (p = 0.02 and 0.003 respectively). No vitamin K-treated patient developed PT or Factor VII levels significantly outside the normal range. Prophylactic vitamin K can prevent hypoprothrombinemia in patients treated with IL-2. This may be of importance in patients with decreased hepatic vitamin K stores, who may be at risk for bleeding complications.

Blood Coagulation↗