Amelioration of endothelial abnormalities by prednisone in experimental thrombocytopenia in the rabbit.

Experimental thrombocytopenia results in endothelial alterations associated with bleeding. In this study prednisone was shown to prevent or reverse these changes, which supports the clinical inference that adrenocorticosteroids decrease capillary fragility in thrombocytopenia. Rabbits (3-4 kg), intraperitoneally injected with busulfan, developed 98-99% reductions in platelet count and hemorrhaged profusely. Orally administered prednisone (0.2 mg/kg or 1.0 mg/kg daily) reduced bleeding despite persistent thrombocytopenia. Tongue biopsies obtained after 3 days of prednisone treatment were examined by electron microscopy. Normal rabbits served as controls. 25 consecutive capillaries or venules from each of four animals in the control group and each of five experimental groups were examined for fenestrations, "thin spots" (<800 A thick), and mean wall thickness as determined by planimetry. Vessels from control animals had no thin spots or fenestrations, and the mean vessel wall thickness was 4,254+/-105 A SEM. The 100 vessels from the thrombocytopenic animals had a mean vessel wall thickness of 2,081+/-218 A (P < 0.001), and 42 had thin spots of fenestrations. After administration of the smaller dosage of prednisone, the mean vessel wall thickness increased to 3,556+/-40 A (P < 0.001), and only nine vessels had thin spots or fenestrations. With the larger dosage, only six vessels had thin spots or fenestrations and the mean vessel wall thickness of this group increased to 3,704+/-206 A (P < 0.005). All preparations demonstrated normal endothelial junctions. The data are consistent with the hypothesis that the bleeding of thrombocytopenia is caused by altered capillary and venule endothelium and that diminished bleeding observed with prednisone administration results from amelioration of these endothelial changes.

To bleed or not to bleed? Is that the question for the PTT?

The activated partial thromboplastin time (PTT) is the grandchild of the Lee-White whole blood clot time (WBCT). Both tests were developed to assist the diagnostic process for patients who exhibited features consistent with hemophilia, i.e., the pretest probability was extremely high. Probably <0.1%-1.0% of PTTs ordered in current medical practice fit that indication with the most common indication now being routine admission order; i.e., a pretest probability that is extremely low. The question asked of the PTT has evolved from 'why does this patient bleed?' to 'will this patient bleed?' As the PTT was never intended to answer that question, one must be careful regarding interpretation of results of that test. As many situations not related to hemorrhage are associated with perturbations of the PTT, a prolonged PTT is not strongly predictive of hemorrhage nor does a normal PTT provide shelter against hemorrhagic risk.

Spontaneous intra-abdominal hemorrhage in hemophilia.

Intra-abdominal hemorrhage in patients with hemophilia is uncommon but represents a major cause of death in hemophiliacs. The manifestations are protean and may mimic other intra-abdominal processes. We present seven episodes of hemophilic intra-abdominal hemorrhage in which the initial diagnoses were incorrect in five of the seven cases. The mean time from seeking medical assistance to correct diagnoses was two days (range, zero to five days). Computed tomography proved useful, particularly when the diagnosis was uncertain or needed to be differentiated from other possibilities, such as aneurysm, tumor, or abscess. Delay in diagnosis and diagnostic and therapeutic misadventures can be minimized only by a knowledge of the nature of such hemorrhage.

Acquired hemophilia. A natural history study of 16 patients with factor VIII inhibitors receiving little or no therapy.

Rarely, a patient develops an antibody against factor VIII coagulant activity. The resultant hemorrhagic diathesis is clinically distinct from inherited hemophilia, being characterized by few hemarthroses but frequent skin and other soft-tissue hematomas. Hematuria may be troublesome. These patients represent therapeutic challenges. This study is one institution's results with 16 such patients followed up over an average of 31 months (range, four to 120 months; median, 19 months). It describes the largest group from a single institution receiving essentially no immunosuppressive agents, yet has one of the better overall results. Two patients experienced fatal hemorrhage and five patients underwent spontaneous remission. Long-term survival is not incompatible with persistence of the inhibitor. We conclude that this hemorrhagic diathesis is clinically distinct, less fatal than usually perceived, and may undergo spontaneous remission. Clearly, there is no mandate for any particular therapeutic regimen, such as immunosuppression, in the attempt to rid the patient of the antibody.

Autoantibody formation in the alloimmunized red blood cell recipient: clinical and laboratory implications.

Alloimmunization to erythrocyte antigens is a well-characterized complication in heavily transfused patients. Less well recognized, however, is the frequency of autoantibody formation in these previously alloimmunized patients. The autoantibodies are heterogeneous and of variable clinical significance. We describe the clinical history, laboratory evaluation, diagnosis, and treatment in 4 patients who developed autoantibodies in temporal association with alloantibody formation. In one case, the autoantibody found on routine screening had no clinical significance. In another case, the autoantibody made accurate blood typing and subsequent transfusion exceedingly difficult. Two patients experienced hemolysis as a consequence of the autoantibody. The management of both patients included supportive measures, while one patient required glucocorticosteroids and red blood cell transfusion. We review the published literature concerning autoimmunization in the transfused alloimmunized host. The spectrum of clinical consequences is important for the general practitioner to recognize, as these complications may occur during routine blood transfusions.

A randomized multicenter trial of crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States.

BACKGROUND: Current therapy for crotaline snakebite includes antivenin (Crotalidae) polyvalent, an antivenom with numerous adverse effects. We compared the efficacy and safety of 2 dosing regimens with a new antivenom, Crotalinae polyvalent immune Fab (Fab AV). METHODS: A single dose of Fab AV alone (as-needed [PRN] group) was compared with an initial dose plus repeated treatments during 18 hours (scheduled group) in a multicenter randomized trial. The study included patients with minimal or moderate envenomation by a crotaline snake within the preceding 6 hours, aged 10 years or older, in whom worsening of the envenomation syndrome was observed before Fab AV treatment. After treatment with Fab AV to achieve initial control, patients were randomized to the scheduled or PRN treatment group. Scheduled group patients received additional doses of Fab AV every 6 hours for 3 doses. The PRN group received no planned additional doses of antivenom. RESULTS: The mean severity score of the 31 patients decreased from 4.35 to 2.39 points (P<.001); there was no difference between scheduled and PRN groups. No patient in the scheduled group received unplanned Fab AV doses, but 8 of 16 patients in the PRN group received unplanned doses (P =.002). Acute reactions occurred in 6 patients (19%), and serum sickness occurred in 6 (23%) of 26 patients who returned for follow-up. CONCLUSIONS: In the first randomized trial of antivenom in the United States, Fab AV effectively terminated venom effects. Since the unplanned use of Fab AV in the PRN group was common, the treatment regimen may require more than 1 initial dose.

Clinical observations of human bone marrow macrophages.

Although human bone marrow is usually obtained to examine precursors of formed elements of blood, important diagnostic information can be gleaned from study of macrophages. These cells are usually unnoticed. Macrophages may be involved in a number of different pathophysiologic mechanisms which are pointed out in this clinical and pictorial study. Inherited enzymatic deficiencies usually result in "storage cells" as exemplified by Gaucher disease. Relative deficiencies may be acquired if phagocytic activity overcomes normal enzymatic mechanisms.

Surgery in hemophilia and related disorders. A prospective study of 100 consecutive procedures.

Surgery is safe in hemophiliacs. The current problem of blood product-transmitted AIDS has recently dampened an unqualified stance, but the dangers of not performing indicated nonelective surgery outweigh the possibility of inflicting AIDS. Successful surgery in hemophiliacs first requires determination of the type of hemophilia involved. If an inhibitor is present, the procedure needs careful re-evaluation, but in general, surgical indications should be those of the general population and routine procedures should be followed. We find it helpful to have nursing personnel aware from the onset that these patients and their medications require certain precautions, especially with respect to pain medication. Unfortunately, too few medical personnel realize how many pain compounds contain aspirin. In addition, we usually prescribe intramuscular injection of medication. Factor levels must be monitored. A less-than-expected yield of factor following infusion is an excellent screen for clinically significant inhibitors. Patients also vary with respect to factor replacement and the half-life of infused factors. Kasper et al found no difference in half-life of infused factor with respect to whether the patient was in a nonoperative or postoperative status; they did not find evidence that factor was consumed during the hemostatic stress of the surgery and that a given patient's response in a nonoperative setting was predictive of his response in the postoperative period. The internist should be available so that any hemostatic problems experienced by the surgeon can be promptly addressed.

Factor XIII.

1. Activated factor XIII is the enzyme that covalently cross-links fibrin monomers into fibrin polymers and results in increased clot strength and resistance of the clot to fibrinolysis. 2. Small amounts (greater than 1% of normal) of factor XIII are necessary for normal in vitro and in vivo activity. 3. Factor XIII deficiency is a rare autosomal recessive illness in which a hemorrhagic diathesis is caused by the virtual absence of the active a subunit of factor XIII. Approximately 100 cases have been described. 4. The disease in homozygotes is characterized by umbilical stump bleeding, a high incidence of fetal wastage, delayed soft tissue hemorrhage, and a high incidence of intracranial bleeding. The heterozygote is asymptomatic. 5. This paper calls attention to the apparent high incidence of oligospermia and small testes seen in homozygote males. Otherwise secondary sex characterics are normal. 6. Because there is no abnormality in thrombin generation and conversion of fibrinogen to fibrin, route coagulation tests (prothrombin time, partial thromboplastin time, thrombin time, etc.) are normal. Platelet function tests are normal. 7. Clots made from recalcified plasma severely deficient in factor XIII are soluble in 5 M urea or 1% monochloroacetic acid. These screening tests are simple and nearly pathognomonic of the illness. 8. More sophisticated and quantitative tests (e.g., dansylcadaverine incorporation) are available for definitive diagnosis and heterozygote detection. 9. Replacement treatment of the illness is simple, effective, and relatively inexpensive. Due to the long half-life of infused factor XIII and the small amounts necessary for normal hemostasis, prophylaxis is feasible and encouraged.

Are transfusions overrated? Surgical outcome of Jehovah's Witnesses.

Physicians as well as their patients are quite familiar with the ever growing list of complications of transfusion. Blood is usually administered by physicians with the nearly unchallenged view that failure to transfuse would have dire consequences. Evidence supporting that view is very difficult to obtain. Although no controlled trial exists, data are collected from 16 reports of the surgical outcome of a series of patients of the Jehovah's Witness faith who were not given transfusion for operations during which transfusion is typically given. Analysis of these data supports the concept that approximately 0.5% to 1.5% of such operations are complicated by anemia resulting in death. This risk of not transfusing patients must be weighed against the cost, morbidity, and mortality that would be expected to accrue had these patients been transfused. These concepts should be employed whenever one is formulating a risk-benefit ratio for patients for whom transfusion is contemplated.

Thrombotic storm: when thrombosis begets thrombosis.

Patients with hypercoagulability may present with a single thrombosis and subsequently develop progressive thromboses at other sites. With inadequate therapy, the thrombotic process may self-perpetuate, leading to multiple thromboses and even death. Six cases are presented demonstrating key features of what may be termed thrombotic storm: (1) an underlying hypercoagulable disorder; (2) a provocation to initiate thrombosis; (3) rapid development of new thromboses; (4) response to prompt use of thrombolytic agent or anticoagulant therapy; and (5) remarkable good long-term prognosis if the cycle of thrombosis is interrupted. Continued activation of coagulation by fresh thrombosis is hypothesized as the cause of the syndrome, which may explain its control by anticoagulants. Whereas these unusual patients' courses most likely represent only an extreme of hypercoagulability and not a new disorder, their characteristic behavior warrants attention.

Hemorrhagic diathesis in a carrier of hemophilia B.

A carrier of hemophilia B was found to have an unusually low factor IX level of 13 per cent. Her history of previous bleeding and the hospital course following elective dental extractions were consistent with a mild hemorrhagic diathesis. The patient is a member of a rare kindred of hemophiliacs. The mean level of factor IX in 12 carriers in this kindred was 42 per cent, with a range of 13 to 100 per cent. This patient represents the sixth reported case in which a female carrier of factor IX deficiency was symptomatic.

Aeromonas hydrophila bacteremia in ambulatory immunocompromised hosts.

We observed seven episodes of Aeromonas hydrophila septicemia in five patients. All but one patient had an underlying disease resulting in immunosuppression. All episodes occurred in ambulatory patients whose vocation or avocation had recently caused them to contact water or fish. We hypothesize that infection with this gram-negative bacterium is acquired more frequently from the natural habitat of the organism than from nosocomial sources.

Intravenous immunoglobulin administration in the treatment of severe chronic immune thrombocytopenic purpura.

Human immunoglobulin was administered intravenously to nine adult patients having severe chronic immune thrombocytopenia purpura. The response in three patients was an increase in the platelet count to greater than 50,000/mm3, a hemostatically adequate level. Response was associated with a pretreatment platelet-associated immunoglobulin level of more than 5,000 molecules per platelet, and successful treatment resulted in a decrease in that level. In those patients with pretreatment platelet-associated immunoglobulin levels less than 5,000 molecules per platelet, there was neither a significant decrease in that level nor an increase in their platelet count. Immunoglobulin infusion may prove useful for selected patients with severe chronic immune thrombocytopenia.

Pseudo-prolongation of the partial thromboplastin time.

A patient with a negative personal and family history for bleeding was being prepared for bronchoscopy when an extremely long activated partial thromboplastin time was detected. Analyses for the contact phase factors were normal. It was determined subsequently that the prolongation was artifactual. The prolongation was due to a peculiar set of circumstances requiring an intrinsically short partial thromboplastin time, a rapid-acting commercial accelerating agent, and a clot-sensing device having a built-in lag phase longer than the resulting partial thromboplastin time. The authors wish to bring to the attention of laboratory personnel this curiosity.

Coagulation and fibrinolysis in estrogen-treated surgically menopausal women.

The short-term effects of different types and doses of estrogen therapy on coagulation and fibrinolysis were studied in 35 surgically menopausal women. Dynamic tests of the coagulation cascade, tests indicative of ongoing, intravascular coagulation, and assessments of coagulation inhibition and fibrinolysis were performed. No clinically abnormal responses were found with the tested regimens--1 and 2 mg of 17 beta-estradiol and 0.625 and 1.25 mg of conjugated equine estrogens. Increased plasminogen antigen and activity were found with the conjugated estrogens but not with the 17 beta-estradiol preparations. The age of the woman had no effect on either the direction or magnitude of response to treatment. Estrogen therapy at the reported doses does not appear to adversely affect the coagulation-fibrinolysis systems of surgically menopausal women. Based on their ability to enhance plasminogen activity, conjugated estrogens may be preferred over the 17 beta-estradiol preparations for this clinical population.

Hemostatic aspects of envenomation by North American snakes.

1. North American poisonous snakes have a wide spectrum of complex venoms. 2. Venom, especially that of the rattlesnakes, may cause a variety of hemostatic abnormalities by directly, yet only partially, cleaving fibrinogen, activating the fibrinolytic system, or activating and clearing platelets through the action of proteolytic enzymes. 3. Because these venoms do not result in the generation of thrombin, the syndrome is distinct from true DIC. Bleeding or thrombosis is rare. 4. As thrombin generation remains intact, hemostasis is largely preserved despite dramatic changes in hemostatic tests. 5. Therapy with heparin, blood, or blood products is rarely indicated. 6. Therapy with antivenin in selected cases is logical and efficacious.

Approach to the bleeding patient.

A broad, open, inquisitive, and semiskeptical mind must be used when approaching the bleeding patient. As in most endeavors in medicine, the history and physical examination provide an important baseline. Key laboratory tests must be quickly ordered and interpreted. Using this data base, one can quickly determine whether the hemorrhagic disorder is congenital or acquired, severe or mild, and progressive or stable. Hemostasis may fail owing to deficiencies of platelets, the plasma coagulation protein system, or endothelial disturbances. A precise diagnosis and appreciation of the tempo of the disorder will guide specific therapy.

Severe myonecrosis in a fatal case of envenomation by the canebrake rattlesnake (Crotalus horridus atricaudatus).

Severe myonecrosis was found at autopsy in a fatal case of envenomation by Crotalus horridus atricaudatus. The degree and extent of rhabdomyolysis were independent of the site of muscle sampling, being no more advanced at the site of envenomation. We conclude that myonecrosis was not enhanced by increased interstitial pressure.

Evolution of our understanding of the pathophysiology of primary mesenteric venous thrombosis.

Mesenteric venous thrombosis is a rare insidious event that is difficult to diagnose. Approximately half the cases in the past were deemed "primary" or "idiopathic." These cases were also frequently associated with a previous history of thromboembolism and a family history positive for thromboembolism. Inherited hypercoagulable disorders, such as deficiency of protein C, protein S, or antithrombin III, will probably explain many "primary" cases. Prompt diagnosis, especially with modern imaging techniques, and prompt anticoagulant therapy decrease mortality.