Cutaneous Bleeding Research Articles

Late puerperal thrombohemorrhagic complications in a patient with antiphospholipid syndrome

In this study, we present a case of late-puerperal onset of thrombohemorrhagic complications in a 33-yr-old woman with known antiphospholipid syndrome (APS) and heterozygosity for factor V Leiden gene mutation. Antithrombotic prophylaxis with low-molecular-weight (LMW) heparin was given since the 12th gestational week. Pregnancy and cesarean delivery were uncomplicated. Five weeks postpartum, the patient developed a severe hemorrhagic diathesis with marked thrombocytopenia accompanied by vaginal, nasal and cutaneous bleeding. A variety of autoimmune phenomena were also detected, partly at clinical presentation and partly later on, despite ongoing steroid treatment. Platelet counts recovered to normal values within a few weeks secondary to high-dose steroids and intravenous immunoglobulin administration. An ultrasound of both legs, performed because of persistent complaint of moderate calf pain, revealed bilateral deep venous thromboses (DVT). The clinical and biochemical findings were not consistent with thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT) or the 'hemolysis, elevated liver enzymes and low platelet syndrome' (HELLP). The diagnostic criteria for systemic lupus erythematosus (SLE) were not fulfilled either. The complex of thrombohemorrhagic complications and autoimmune phenomena seen in this case is unusual and not previously described in the late puerperal stage of APS-related pregnancies.

Effects of human mast cell tryptase on the kinetics of blood clotting

Mast cells have been associated with bleeding in a variety of disorders. In cutaneous mastocytosis, for example, gastrointestinal and cutaneous bleeding has been attributed to the heparin released by mast cells [1]. Skin mast cells have also been shown to prolong the bleeding time and to inhibit thrombin generation [2]. The clinical association between mast cells, bleeding, and fibrinolysis has led some investigators to propose recently that mast cells may play a physiologic role in promoting a profibrinolytic and antithrombotic state within injured tissues [3].

Characterization of a piscirickettsiosis-like disease in Hawaiian tilapia.

In 1994, tilapia (Oreochromis mossambicus and Sarotherodon melanotheron) in wild and farmed populations on Oahu, Hawaii, USA, began to die of an unknown disease that was similar but not identical to piscirickettsiosis in salmonids. Only tilapia were affected. Diseased tilapia often swam erratically and had trouble staying at depth. Scattered cutaneous haemorrhage and exophthalmia were often noted. In many cases, fish were found dead with no clinical signs. Gills exhibited epithelial hyperplasia with severe multifocal consolidation of secondary lamellae. Multiple granulomas were observed in the gills, spleen, kidney, choroid gland and testes, but not in the liver. Tilapia mortalities occurred only during the cooler months (October to April) of the year and were not recorded during the warmer months (May to September). The mortalities declined with each successive year, after the 1994 outbreak, and currently losses are sporadic. Oxytetracycline-medicated feed reduced mortality. Cytologic examination of blood smears revealed moderate to large numbers of Gram-negative, pleomorphic, intracellular bacteria in rare circulating monocytes. Histologically, some predilection for nervous tissue and brain was observed. When viewed with transmission electron microscopy, pleomorphic coccoid bacteria, measuring 0.56 +/- 0.14 x 0.7 +/- 0.20 microm, occurred free in the cytoplasm and within phagolysosomes. The organisms had a double cell wall, no defined nucleus and variable electron-dense and -lucent areas. Unlike Piscirickettsia salmonis, the agent of piscirickettsiosis, the Hawaiian tilapia Piscirickettsia-like organism (HTPLO) does not form craterform lesions in the liver and is active above 20 degrees C. HTPLO can be transmitted horizontally by cohabitation, and cold stress induces the syndrome in juvenile tilapia from farms where the disease is endemic.

Relationship between bleeding time test and postextraction bleeding in a healthy control population.

We sought to determine whether cutaneous bleeding time (BT) is related to bleeding outcome measures after a single tooth extraction. This was a prospective clinical pilot study of 30 subjects. Cutaneous BT was evaluated before a single tooth extraction. After extraction, an oral BT was determined. Subjects were contacted 3 to 7 hours and 2 days after extraction to assess further postoperative bleeding. The mean cutaneous BT was 5.9 minutes (range 1.5-10.0 minutes). The mean oral BT was 7.5 minutes (range 0-20 minutes). Cutaneous BT did not correlate with oral BT or any of our measures of postoperative bleeding. However, the oral BT correlated with the number of hours of bleeding after surgery (R(s) = 0.54, P =.03). The time necessary to perform the extraction correlated with the extraction site bleeding 3 to 7 hours after surgery (R(s) = 0.67, P =.0006). Cutaneous BT did not correlate with measures of postoperative bleeding in the present study, but oral BT immediately after extraction correlated with the duration of subsequent postoperative bleeding.

Altered megakaryocyte-platelet-haemostatic axis in patients with acute stroke

Platelet function is accentuated in acute ischaemic stroke (IS) and may also be altered in haemorrhagic stroke. Whether these changes are a direct reaction to the stroke or are secondary to changes in megakaryocytes (MKs) is unknown. To determine whether MKs are altered in acute stroke we studied 24 patients (18 with ischaemic stroke, six with haemorrhagic stroke) within 3 days of symptom onset, and 14 matched controls. MK ploidy (DNA content, N ), size (forward scatter, FSC, arbitrary units), granularity (side scatter, SSC, arbitrary units) and glycoprotein (GP) IIIa expression (arbitrary units) were assessed by flow cytometry. Platelet size (MPV, fl), platelet count (PC, 2 109/l), circulating reticulated platelets (%), and cutaneous bleeding time (s) were also measured. MK ploidy 22.5 (2.7) vs. 20.6 (1.7) (2 p = 0.014); FSC 629 (51) vs. 594 (41) (2 p = 0.025); and SSC 843 (88) vs. 776 (76) (2 p = 0.020) were each increased, whereas bleeding time 318 (102) vs. 401 (94) (2 p = 0.050) was decreased in patients with acute stroke as compared with controls. Trends to increased MK GP IIIa expression and reticulated platelets were also apparent. In a post hoc analysis, the increase in MK ploidy was most prominent in patients with a prior history of hypertension. Ischaemic stroke was associated with non-significant increases in MK ploidy, size, and granularity. However, MK parameters were different in acute haemorrhagic stroke as compared with controls: MK ploidy 23.0 (1.8) vs. 20.6 (1.7) (2 p = 0.018); MK FSC 637 (21) vs. 594 (41) (2 p = 0.050); MK SSC 872 (41) vs. 776 (76) (2 p = 0.020), changes which could be related to the high prevalence of hypertension (83%) in this group. These results demonstrate that pro-thrombotic changes in the megakaryocyte-platelet-haemostatic axis (MPHA) are present in acute stroke. Although megakaryocyte changes are likely, in part, to be secondary to the stroke, they could also precede the stroke and therefore explain some of the increased platelet function observed in acute stroke.

Proliferative vasculopathy and cutaneous hemorrhages in porcine neonates infected with the porcine reproductive and respiratory syndrome virus.

Severe cutaneous hemorrhages with dermal and subcutaneous capillary angioplasia were seen in aborted and stillborn piglets, concurrently with an acute outbreak of porcine reproductive and respiratory syndrome virus (PRRSV) abortions. Histologically, the lesions consisted of angioblastic endothelial cells and immature capillary vascular structures coursing through the edematous myxomatous dermis and subcutis. Proliferating capillaries often were surrounded by large and foamy macrophages that stained positively for PRRSV by immunohistochemistry. The sudden appearance of these vascular lesions during the PRRSV outbreak and their abrupt disappearance after the abortion storm, along with the immunohistochemical localization of PRRSV-positive macrophages adjacent to the proliferating capillaries, suggest that PRRSV likely played a role in the development of these unusual lesions.

Effects of Agents, Used to Treat Bleeding Disorders, on Bleeding Time Prolonged by a Very High Dose of a Direct Thrombin Inhibitor in Anesthesized Rats and Rabbits

Melagatran is the active form of the oral, direct thrombin inhibitor, H 376/95, that is under evaluation in clinical trials for the prevention and treatment of thromboembolism. In this study, a single dose, calculated on body weight basis, of antifibrinolytic treatment, factor VIIa, factor VIII with and without von Willebrand factor (vWF), factor IX, activated (APCC) or nonactivated (PCC) prothrombin complex concentrates was given intravenously to rats and rabbits, in an attempt to reverse the prolonged bleeding time during intensive anticoagulation with melagatran (2 μmol/kg/h). The doses used were at or above human therapeutic doses. The cutaneous tail bleeding time in the rat, as well as the ear incision bleeding time and cuticle bleeding time, and the blood loss in the rabbit were used for evaluation of the hemostatic effects of these agents. In vivo Feiba (APCC) and Prothromplex-T (PCC) shortened the prolonged cutaneous bleeding times in rats ( P<.05); Feiba and Autoplex (APCC) shortened the cutaneous bleeding times in rabbits ( P<.05). In contrast, Prothromplex-T prolonged bleeding times and blood loss in the rabbits ( P<.05). Ex vivo Feiba, Autoplex and NovoSeven (rF VIIa) significantly ( P<.05) shortened the prolonged whole blood clotting time (WBCT). Prothromplex-T significantly prolonged WBCT, activated clotting time (ACT) and activated partial thromboplastin time (APTT). Feiba, Autoplex, and Prothromplex-T increased thrombin generation measured as increased thrombin–antithrombin complex (TAT) formation. In conclusion, APCCs were found to be the most effective agents for reversing bleeding time induced by a very high plasma concentration of melagatran. APCC and recombinant activated factor FVII (rF VIIa) effectively shortened the prolonged WBCT. Thus, stimulating thrombin generation with the use of APCC may counteract the anticoagulant effect observed with a very high dose of a thrombin inhibitor.

Prothrombotic megakaryocyte and platelet changes in hypertension are reversed following treatment: a pilot study

Platelets are formed from, and their function determined by, bone marrow megakaryocytes (MK). Previous studies have found that hypertension is associated with accentuated platelet function and that some antihypertensive drug classes have antiplatelet activity. We measured MK ploidy (DNA content), size, granularity, and expression of the adhesion molecule glycoprotein (GP) IIIa, using flow cytometry and measures of platelet function, in 12 untreated hypertensive patients and 14 normotensive subjects. Eight hypertensive patients were then treated with losartan (50 mg daily), an angiotensin receptor antagonist that lowers blood pressure, and MK and platelet parameters re-measured after 6 weeks. Hypertensive patients had, as compared with matched normotensive subjects: increased MK ploidy (mean - SD) 22.9 - 2.2 N versus 20.8 - 1.6 N (2 P = 0.009); increased platelet size, 10.67 - 1.03fl versus 9.26 - 0.72fl (2 P < 0.001); increased platelet expression of GP IIIa, 108.6 - 22.5 versus 92.0 - 12.3 (2 P = 0.036); and reduced platelet count, (207 - 52) 2 10 9 /l versus (257 - 55) 2 10 9 /l (2 P = 0.026). Losartan significantly reduced MK ploidy, 22.6 - 2.2 N versus 21.4 - 1.9 N (2 P = 0.006); MK size, 607 - 22 versus 579 - 16 (2 P = 0.003); and lengthened cutaneous bleeding time, 424 - 86s versus 563 - 164s (2 P = 0.011), in hypertensive patients. Losartan did not alter MK granularity or GP IIIa expression, or platelet count, size, mass, GP IIIa expression, or aggregation. The data suggest that platelet changes in hypertension may be secondary to changes in MKs, and that anti-hypertensive treatment can alter MKs and the function of platelets they produce. Since antihypertensive therapy reduces the risk of stroke and myocardial infarction, MKs are a novel therapeutic target for the prevention of vascular events.

Altered megakaryocyte–platelet haemostatic axis in hypercholesterolaemia

Hypercholesterolaemia is associated with accentuated platelet function. We assessed in a pilot study whether megakaryocytes (MK), the platelet precursor cell, were altered in subjects with primary hypercholesterolaemia and whether these changes were linked with platelet function. MK and platelet function were assessed in eight untreated patients with primary hypercholesterolaemia (total cholesterol, TC > 7 mmol/l), and 14 control subjects (TC h 7 mmol/l): MK ploidy (DNA content), size, granularity, and expression of the adhesion molecule GP IIIa, and platelet expression of GP IIIa, P selectin and CD 63, and RNA content, were each measured using flow cytometry; mean platelet volume, platelet count, plasma thrombopoietin, and cutaneous bleeding time were also assessed. Hypercholesterolaemic patients had increased MK ploidy, mean (SD) 22.9 N (2.3) vs. 20.8 N (1.6) (2 P =0.021); platelet size, 10.6 fl (1.2) vs. 9.3 fl (0.7) (2 P =0.006); and platelet expression of GP IIIa, 111.3 (18.9) vs. 92.0 (12.3) (2 P =0.010), as compared with matched control subjects. Cutaneous bleeding time tended to be reduced in the hypercholesterolaemic patients, 364 s (136) vs. 483 s (165) (2 P =0.11). No differences in MK size, granularity or GP IIIa expression, or platelet count, mass, RNA content, P selectin or CD 63 expression, or plasma thrombopoietin were seen. The data suggest that aspects of megakaryocytes and platelets are altered in hypercholesterolaemia, as has also been seen in other vascular risk factors states, including hypertension and diabetes mellitus. Furthermore, changes in megakaryocytes may have contributed to the altered platelet function seen here. Further study is now required to assess whether lipid lowering therapy 'normalises' these changes in the megakaryocyte-platelet haemostatic axis.

Occurrence of a unique protein toxin from the Indian King Cobra ( Ophiophagus hannah) venom

A unique (lethal–cardiotoxic–hemorrhagic) protein toxin (Toxin CM55) was isolated and purified from Indian King Cobra ( Ophiophagus hannah) venom by CM-sephadex ion exchange chromatography and reverse phase HPLC. The purified toxin had an SDS-molecular weight of 22 ± 0.5 kD. UV absorption spectra of Toxin CM55 showed a peak at 280 nm, whereas when excited at 280 nm fluorescence, Toxin CM55 showed an E max at 333.4 nm. Toxin CM55 had an LD 50 of 28.28 μg/20 g (i.v.) in albino mice. The cardiotoxic action of the toxin was established on isolated guinea pig/rabbit heart and guinea pig auricle. In rats, Toxin CM55 caused ECG abnormalities including widened QRS complex and monomorphic ventricular tachycardia suggesting that the possible site of action of Toxin CM55 was the ventricle. Toxin CM55 produced significant vasoconstriction on peripheral blood vessels. It produced significant contraction of isolated guinea pig ileum, rat fundus and rat uterus, which was completely antagonised by methysergide. The toxin was found to release a significant amount of serotonin from rabbit platelets. Toxin CM55 produced cutaneous hemorrhage in albino mice, which was also produced in reserpine and p-chloro phenylalanine pretreated animals. Rabbit antiserum was raised against Toxin CM55, which gave prominent bands in immunogel diffusion and immunoelectrophoresis. The antiserum provided 2 LD 50 protection against Toxin CM55-induced lethality in mice and also neutralised 3 MHD hemorrhagic dose of the toxin.

Dietary Fish Oil Reduces Microvascular Thrombosis in a Porcine Experimental Model

Microvascular thrombosis plays a significant role in the pathophysiology of ischaemic reperfusion injury. A fish oil-supplemented diet containing n-3 polyunsaturated fatty acids (PUFA) reduces thromboxane A 2 (TxA 2) synthesis and, thus, vasoconstriction and platelet aggregation. The aim of this study was to elucidate whether n-3 PUFA in a porcine model of ischaemia and reperfusion injury 1) inhibit accumulation of platelets and fibrinogen in ischaemia-reperfusion injured tissue, 2) prolong the bleeding time, and 3) inhibit TxA 2 synthesis. Nine pigs were fed a standard diet supplemented with 7 g n-3 PUFA/day for 3 weeks. Nine pigs on the standard diet served as controls. Unilateral myocutaneous flaps were exposed to ischaemia for a period of 6 hours. Contralateral flaps were nonischaemic. Tissue contents of radioactive-labelled platelets and fibrinogen were measured after 4 hours of reperfusion. Platelet count, serum TxB 2, and the cutaneous bleeding time were measured before and after 3 weeks of diet. In the fish oil group, the accumulation of platelets was significantly reduced in all the myocutaneous flaps, except in the ischaemic skin part, when compared to control animals. Fibrinogen was significantly reduced in nonischaemic flaps, but not in ischaemic flaps. After the feeding period, the level of TxB 2 was significantly lowered in the fish oil group ( p<0.01). No difference in the bleeding time was observed. Thus, dietary supplementation with n-3 PUFA inhibits the formation of microvasculatory thrombosis in this model.

The buccal mucosal bleeding time.

289 Steven L. Marks, BVSc, MS, MRCVS, Diplomate ACVIM Bleeding occurs when vascular integrity is disrupted. Hemostasis is accomplished by vascular reaction, formation of a platelet plug, and activation of the coagulation cascade. In general, hemostasis can be divided into primary and secondary systems. The primary hemostasis system relies on the dynamic interaction between the vessel wall, vascular endothelium, and platelets. Exposure of vascular subendothelium triggers activation of von Willebrand’s factor, which links platelets to the site of vessel injury. Once platelets have adhered to the area and form the platelet plug, they assist in activation of the intrinsic pathway of the coagulation cascade or secondary hemostasis. Several commonly used “bleeding times” are utilized in veterinary medicine to evaluate patients for hemostatic disorders. The one-stage prothrombin time (OSPT), activated partial thromboplastin time (APTT), activated clotting time (ACT), and the buccal mucosal bleeding time (BMBT) are parameters that provide the veterinary clinician with critical information about the bleeding or at-risk patient. All of the tests mentioned, other than the BMBT, are used to evaluate secondary hemostasis. The BMBT is used along with the platelet count to evaluate primary hemostasis. The BMBT is a valuable diagnostic tool that is cost effective and easy to use in the general practice setting. The BMBT is used to evaluate hemorrhage from a standardized incision on the oral mucosa. It is performed using a disposable, single-use, spring-loaded lancet [Figure 1]. The procedure is performed with the dog restrained in lateral recumbency. The upper lip is everted and held in place by a length of roll gauze [Figure 2]. The gauze acts to maintain the eversion of the lip and to cause some vascular congestion. The lancet is placed against the buccal mucosa in a vertical direction directly above the maxillary canine tooth. Depressing the trigger [Figure 1] then activates the lancet. The lancet causes a controlled incision, which will readily bleed. Once the incision is made, the time should be noted and monitored. Circular filter paper is used to blot the blood as it drips from the incision. The filter paper should be held approximately 1 to 2 mm away from the incision, using care not to disrupt the clot formation. It is important to not allow the blood to drip into the animal’s mouth, as this may lead to agitation and movement. The end point of this test is when the incision stops bleeding. The published normal range for the BMBT in the dog is less than three minutes. Prolongation of the BMBT can occur with thrombocytopenia, thrombocytopathy, and von Willebrand’s disease. Clinical findings associated with abnormalities of primary hemostasis include superficial cutaneous bleeding, petechiation, ecchymosis, epistaxis, and mucosal bleeding of the gastrointestinal tract and urogenital tract (hematuria). If The Buccal Mucosal Bleeding Time

Platelet fibrinogen in the patients with idiopathic bleeding platelet disorder.

The changes of platelet fibrinogen in patients with obscure cutaneous mucosal bleeding and their relation with disease were evaluated. By using flow cytometry and Western blot, the platelet binding site of fibrinogen and the expression of platelet fibrinogen in 8 cases of obscure bleeding were detected. The results showed that platelet surface binding sites of fibrinogen were 65.38 +/- 3.62 in the resting state and 65.25 +/- 5.78 after activated by adenosine diphosphate, showing no significant difference as compared with control group (P > 0.05). The expression of platelet fibrinogen was obviously decreased in 4 patients and increased in one case as compared with control group. It was concluded that the binding sites of fibrinogen on the platelet surface were normal in the patients with idiopathic bleeding platelet disorder. The abnormal of platelet fibrinogen might be one of hemorrhagic reasons in partial patients.

Antiplatelet and Antithrombotic Effects of Orbofiban, a New Orally Active GPIIb/IIIa Antagonist, in Guinea Pigs

Antiplatelet and antithrombotic effects of orbofiban, a new orally active glycoprotein IIb/IIIa antagonist, were evaluated in guinea pigs. SC-57101A (0.03–1 μM), the hydrochloride salt of the active form of orbofiban, inhibited in vitro ADP- and collagen-induced platelet aggregation in a concentration-dependent manner. Oral administration of orbofiban (3–30 mg/kg) resulted in dose-dependent inhibition of ADP- and collagen-induced platelet aggregation. The inhibition peaked at 1–2 hours postdose and then declined slowly. The agent also showed similar inhibition of platelet aggregation in guinea pigs with dietary-induced hypercholesterolemia. In contrast, the antiaggregatory effects of acetylsalicylic acid differed more widely between normal and hyperlipidemic animals compared to those of orbofiban. Plasma concentration of the active form, measured by a column-switching HPLC method, correlated well with the inhibition of platelet aggregation. Orbofiban (3–100 mg/kg, p.o.) caused dose-dependent inhibition of thrombus formation in an arteriovenous-shunt-thrombosis model. Orbofiban at high doses (⩾30 mg/kg) and acetylsalicylic acid (100 mg/kg) both prolonged cutaneous bleeding time measured by the template method. These results demonstrate that orbofiban is an orally active and potent inhibitor of platelet aggregation with an efficacy that correlates well with the plasma concentration of its active form.

Self-Reported Diagnostic and Management Strategies in Childhood Idiopathic Thrombocytopenic Purpura: Results of a Survey of Practicing Pediatric Hematology/Oncology Specialists

To assess current physician self-reported practices regarding initial management of childhood idiopathic thrombocytopenic purpura (ITP) and to determine physician self-reported willingness to participate in randomized clinical trials comparing different initial management strategies. A questionnaire was mailed in November 1997 to all 720 members of the American Society of Pediatric Hematology/Oncology asking how they would diagnose and manage ITP in children 18 months, 5 years, and 15 years of age who were experiencing either dry purpura (cutaneous hemorrhage only) or wet purpura (active mucous membrane hemorrhage). Specific questions dealt with bone marrow aspiration, hospital admittance, treatment strategy, and specific doses of corticosteroids and intravenous immunoglobulin. The response rate to the questionnaire was 57%. Most respondents indicated they usually perform a bone marrow aspirate when corticosteroids are to be prescribed and administer drug therapy to patients with newly diagnosed ITP with wet or dry purpura. Only 16% of respondents would administer no drug therapy to a child with dry purpura. Intravenous immunoglobulin (IVIG) was preferred to steroids, with anti-D immunoglobulin prescribed less frequently. Hospital admittance often was used for patients with dry purpura and usually recommended for patients with wet purpura. Most respondents expressed willingness to randomize patients with dry purpura to IVIG versus no therapy and those with wet purpura to IVIG versus prednisone as part of a randomized controlled clinical trial. The self-reported care of the patient with ITP was influenced by the severity of presentation (dry versus wet purpura). Most physicians reported they would administer specific drug treatment in both scenarios. This survey illustrates the diverse diagnostic and management strategies currently used in childhood ITP. Because no one therapeutic approach is predominant and a scientific basis for decision making in childhood ITP has not been developed, future randomized trials are warranted. On the basis of these survey results, such trials are desired by most pediatric hematology/oncology specialists.

Differences in some haemostatic variables between fish-eating and non-fish-eating populations

The rare incidence of coronary artery disease in Eskimos has been ascribed to their diet of marine fish rich in n-3 fatty acids, which have an antithrombotic influence on haemostasis. In order to test this hypothesis, a crosssectional study was conducted on 1000 healthy individuals chosen randomly from coastal and inland villages in the state of Andhra Pradesh, India. A total of 500 fish-eating and 500 non-fish-eating age- and sex-matched subjects were selected based on fish-eating habits for parameters related to haemostasis. Mean cutaneous bleeding time and clotting time were decreased with advancing age in men and women of both populations.Women had more prolonged bleeding and clotting times than did men in both population groups. The platelet count was significantly lower in the fish-eating population. The mean bleeding time was observed to be prolonged significantly in men and women of the fish-eating population than that of the non-fish-eating population. However, the clotting time in the fish-eating population was significantly longer in certain age groups than in non-fish-eating population. The results indicate that fish consumption influences haemostatic function relative to a non-fish-eating population.

Cutaneous bleeding related to zinc deficiency in two cases of advanced cancer

One patient with metastatic squamous cell carcinoma of the larynx and one with advanced non-Hodgkin lymphoma, both with poor nutritional status, developed ecchymoses and demonstrated prolonged bleeding time and abnormal aggregation of platelets. On the basis of previous studies, the author measured the level of zinc in the serum and urine of these patients and the effect of zinc supplementation on the clinical symptoms and laboratory findings. Also studied were serum and urine zinc levels in 15 newly diagnosed, untreated cancer patients with no evidence of bleeding. The two patients were found to have very low serum and urine zinc levels, which were 6 and 9 microgram/dL and 28 and 22 microgram/24 hours, respectively, compared with normal average values of 70-150 microgram/dL and 150-1200 microgram/24 hours. The mean values of zinc in the serum and urine of the 15 patients newly diagnosed with cancer were 109.18 microgram/dL and 433.8 microgram/24 hours, respectively. Oral administration of zinc without any additional therapy was rapidly followed by control of bleeding, normalization of bleeding time, and platelet aggregation. Discontinuation of zinc caused the return of bleeding and abnormal laboratory findings, which again were corrected with zinc supplementation. Severe depletion of zinc in two patients with advanced cancer and malnutrition was accompanied by cutaneous bleeding and laboratory findings of platelet dysfunction, both of which were corrected by oral supplementation of zinc and reoccurred on discontinuing therapy. Zinc deficiency should be suspected in patients with advanced cancer demonstrating bleeding when a prolonged bleeding time is the only hemostatic abnormality.

Cutaneous bleeding related to zinc deficiency in two cases of advanced cancer

BACKGROUND One patient with metastatic squamous cell carcinoma of the larynx and one with advanced non-Hodgkin lymphoma, both with poor nutritional status, developed ecchymoses and demonstrated prolonged bleeding time and abnormal aggregation of platelets. METHODS On the basis of previous studies, the author measured the level of zinc in the serum and urine of these patients and the effect of zinc supplementation on the clinical symptoms and laboratory findings. Also studied were serum and urine zinc levels in 15 newly diagnosed, untreated cancer patients with no evidence of bleeding. RESULTS The two patients were found to have very low serum and urine zinc levels, which were 6 and 9 μg/dL and 28 and 22 μg/24 hours, respectively, compared with normal average values of 70–150 μg/dL and 150–1200 μg/24 hours. The mean values of zinc in the serum and urine of the 15 patients newly diagnosed with cancer were 109.18 μg/dL and 433.8 μg/24 hours, respectively. Oral administration of zinc without any additional therapy was rapidly followed by control of bleeding, normalization of bleeding time, and platelet aggregation. Discontinuation of zinc caused the return of bleeding and abnormal laboratory findings, which again were corrected with zinc supplementation. CONCLUSIONS Severe depletion of zinc in two patients with advanced cancer and malnutrition was accompanied by cutaneous bleeding and laboratory findings of platelet dysfunction, both of which were corrected by oral supplementation of zinc and reoccurred on discontinuing therapy. Zinc deficiency should be suspected in patients with advanced cancer demonstrating bleeding when a prolonged bleeding time is the only hemostatic abnormality. Cancer 1999;86:866–70. © 1999 American Cancer Society.

Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.

beta3 integrins have been implicated in a wide variety of functions, including platelet aggregation and thrombosis (alphaIIbbeta3) and implantation, placentation, angiogenesis, bone remodeling, and tumor progression (alphavbeta3). The human bleeding disorder Glanzmann thrombasthenia (GT) can result from defects in the genes for either the alphaIIb or the beta3 subunit. In order to develop a mouse model of this disease and to further studies of hemostasis, thrombosis, and other suggested roles of beta3 integrins, we have generated a strain of beta3-null mice. The mice are viable and fertile, and show all the cardinal features of GT (defects in platelet aggregation and clot retraction, prolonged bleeding times, and cutaneous and gastrointestinal bleeding). Implantation appears to be unaffected, but placental defects do occur and lead to fetal mortality. Postnatal hemorrhage leads to anemia and reduced survival. These mice will allow analyses of the other suggested functions of beta3 integrins and we report that postnatal neovascularization of the retina appears to be beta3-integrin-independent, contrary to expectations from inhibition experiments.

Acute infectious purpura fulminans: pathogenesis and medical management.

Purpura fulminans (PF) is a potentially disabling and life-threatening disorder characterized by acute onset of progressive cutaneous hemorrhage and necrosis, and disseminated intravascular necrosis. Acute infectious PF occurs most commonly in the setting of meningococcemia due to elaboration of endotoxin. Presence of purpura, particularly when generalized, is an important predictor of a poor outcome following meningococcal infection. Histopathologic hallmarks of acute infectious PF are dermal vascular thrombosis and secondary hemorrhagic necrosis, findings which are identical to those of the Shwartzman reaction. Acute infectious PF and the Shwartzman reaction have a common pathogenesis, involving a disturbance in the balance of anticoagulant and procoagulant activities of endothelial cells. This disturbance, which is triggered by endotoxin, appears to be mediated by cytokines, particularly interleukin-12, interferon-gamma, tumor necrosis factor-alpha, and interleukin-1, leading to the consumption of proteins C and S and antithrombin III. State-of-the-art therapeutic interventions based on recent advances in our understanding of the pathogenesis of acute infectious PF are discussed.