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Products but Not Thromboxane Pathogenesis of Thrombocythaemia

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Products but Not Thromboxane Pathogenesis of Thrombocythaemia View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Research Paper Mediators of Inflammation 2, 385-389 (1993) FLUID of artificial blisters from erythromelalgic skin areas Prostaglandin cyclooxygenase in primary thrombocythaemia contained a high amount of products but not thromboxane prostaglandin-E-like activity. Dazoxiben did not alleviate the erythromelalgia in patients with primary thrombo- Az are involved in the cythaemia despite complete inhibition of platelet mal- pathogenesis of ondialdehyde and thromboxane B2 synthesis and no in- hibition of prostaglandin-E-like material. During a 10-day ewthromelalgia in dazoxiben treatment period, persistent erythromelalgia th rombocythaem ia was associated with a significant shortened mean platelet life span of 3.2 days. During subsequent treatment with low dose acetylsalicylic acid daily complete relief of ery- J. J. Michiels1"cA and F. J. Zijlstraz thromelalgia was associated with inhibition of platelet prostaglandin endoperoxide production and correction of platelet mean life span to normal, 7.9 days. These observa- tions indicate that prostaglandin E2, or another prostaglan- 1Department of Haematology, University Hospital din endoperoxide metabolite, is involved in the patho- Dijkzigt Molewaterplein 40, 3015 G D, and genesisof erythromelalgia. The presented study does not 2Institute of Pharmacology, Erasmus give one single clue as to the origin (platelet, vessel wall or University Medical School, Rotterdam, the other) of the prostanoid, but very likely originates from Netherlands platelets because a very low dose of acetylsalicylic acid (250 to 500 mg every other day), which irreversibly inhibits ca Corresponding Author platelet cyclooxygenase, is highly effective in the preven- tion of erythromelalgia in thrombocythaemia. Key words: Aspirin, Cyclooxygenase, Dazoxyben, Erythro- melalgia, Platelets, Prostaglandins, Thrombocythaemia, Thromboxane Introduction activity in fluid from artificial blisters from areas was Sub- Erythromelalgia is characterized by warm, red, erythromelalgic investigated. sequently the authors evaluated the effects of congested extremities and painful burning sensa- dazoxiben, a selective inhibitor of thromboxane tions. In what appears to be the antithesis of synthetase activity, on Raynaud's disease, warmth intensifies the dis- erythromelalgia, platelet kinetics and prostaglandin synthesis in with comfort and cold provides relief. Acroparesthesias patients primary thrombocythaemia. Evidence is presented e.g. tingling, pins and needles sensations, and numbness in the toes and fingers usually precede the disabling and burning distress. Erythromelalgia THROMBOCYTHAEMIA VERA may lead to painful acrocyanosis and peripheral PERIPHERAL GANGRENE INFLAMMATORY gangrene. ACROCYANOSIS SYMPTOMS In previous studies we demonstrated that erythromelalgia is causally related to thrombo- OCCLUSIVE PROSTAGLANDINS PLATELET ACTIVATION OF THROMBI IN COAGU LATION ETC. cythaemia and results from platelet mediated ARTERIOLES inflammation and microvascular changes (Fig. 1).1-3 The histopathological vascular changes are confined to arterioles and characterized by aspecific inflam- mation, fibromuscular intimal proliferation and occlusive thrombi in the absence of pre-existing vascular disease. 4 Both clinical signs and vascular lesions completely disappear by treatment with the PLATELET DERIVED platelet inhibiting drugs acetylsalicylic acid (ASA) GROWTH FACTOR and indomethacin, which inhibits platelet ag- gregation by inactivation of platelet cyclooxygenase FIBROMUSCuLAR INTIMAL PROLIFERATION activity. OF ARTERIOLES To obtain more information of the pathophysio- FIG. 1. Pathophysiologic pathways in the genesis of platelet-mediated logic mechanism of erythromelalgia, prostaglandin erythromelalgia and acrocyanotic ischaemia in thrombocythaemia. 993 Rapid Communications of Oxford Ltd Mediators of Inflammation. Vol 2. 1993 385 j. j. Michiels and F. J. Zijlstra that platelet prostaglandin E2 or another prosta- Platelet survival studies were performed with glandin endoperoxide metabolite is involved in the sodium 51Cr-chromate labelled autologous plate- pathogenesis of erythromelalgia in primary throm- lets. 1 The mean survival of platelets was calculated bocythaemia. according to the multiple hit model, as re- commended by the International Committee for 2 Methods Standardization in Haematology. Clinical and haematological data were obtained Results routinely. Thermography was carried out with a Bofors Mark II (Karls Koga, Sweden) camera, that Clinical and haematological data of three patients registers the skin temperature indirectly. The skin with primary thrombocythaemia at the time of surface temperature was compared with a reference study are summarized in Table 1. Thermographic source of fixed temperature. documentation of erythromelalgia in the left upper Artificial dermal blisters were produced by a leg and the sole of the right foot in Case 1 is shown suction blister device according to Kristella, 6 which in Fig. 2. The skin surface temperature exceeded was connected to the central suction unit of the 31C at places of red painful erythromelalgic hot hospital. The suction pressure was adjusted to 100 mmHg. The suction cups were cleaned with Table 1. Pertinent data at time of study 70% alcohol and placed on the skin. Within a few minutes the pressure was decreased slowly to Case Age Sex Platelets [Presenting symptoms] --200 mmHg. Blisters of 3 mm developed after 1 x 109/I) to 2 h. Blisters were aspirated using a thin needle and 45 M 750 Disabling burning pain and red syringe. swelling of right forefoot sole and Prostaglandin-like material was extracted from burning painful red spots in the blister fluid according to the method of Unger et skin of the left upper leg as shown in 2 al.7 After the direct extracts in saline Fig. resuspending 2 73 M 1715 Burning pain and redness in toes (NaC1 0.9%), PGE-like material was assayed against and forefoot sole authentic PGE2 (Upjohn Co., Kalamazoo, USA) on 3 65 M 930 Burning pain in red-bluish big toe, the rat forefoot sole and lateral edge of the isolated stomach strip, using the oil-bath right foot technique of Ferreira and de Souza Costa. 8 Both standard and test prostaglandins were injected in 10/1 volumes directly into the Krebs' solution 9 Temperature B superfusing the tissue. All values for PGE-like 33 material were expressed as ng/ml blister fluid. I-- 32 Malondialdehyde production by arachidonic 30-31 28-29 stimulated platelets in platelet-rich plasma was 26-27 measured according to Smith et al. 1 Plasma EC3 24-25 thromboxane B2 (TxB2) and prostaglandin E. (PGE2) were measured in 10 ml peripheral venous blood samples collected under resting conditions in polypropylene tubes, containing 20/1 of heparin (500/,/ml thromboliquine, Organon, the Nether- lands) and 50 #1 indomethacin (0.1 mg/ml in 0.1 M phosphate buffer, pH 8.0). Blood samples were centrifuged immediately at 1400 x g for 10 min and the plasma stored at -20C until assay. Two ml of plasma was applied to a Sep-Pak C18 cartridge (Water Ass). The prostaglandin-like compounds were eluted with 2 ml of absolute ethanol, and 200/,1 aliquots dried under a stream of nitrogen at 40C in a radioimmunoassay tube, then redissolved in assay buffer. Antibody for TxB2 and PGE2 were obtained from L'Institute Pasteur (Paris, France), 3H-TxB2 and 3H-PGE2 from New England Nuclear FIG. 2. Thermographic documentation of erythromelalgia in Case 1. (A) The skin surface temperature of painful red congested areas in the skin (Boston, USA) and standards of TxB2 and PGE2 of the left upper leg and in the right forefoot sole exceed 31 C compared from Sigma. Normal values for TxB2 and PGE2 with that of the corresponding contralateral skin. (B) Complete relief of were obtained erythromelalgia 2 days after treatment with acetylsalicylic acid (500 mg from blood samples taken from per day) is associated with disappearance of hot spots on isothermo- controls (aged 22-78 years) on two occasions. grams. 386 Mediators of Inflammation. Vol 2.1993 Prostaglandin cyclooxygenase products in thrombocythaemia Table 2. Prostaglandin E-like (PGE) activity in fluid of artificial Table 3. The effect of dazoxiben (200 mg every 6 h blisters from skin areas with and without erythromelalgia in for 5 days) on platelet malondialdehyde (MDA) Patient with primary thrombocythaemia as shown in Fig. synthesis in Patient 2 who suffered from primary thrombocythaemia and erythromelalgia Volume of blister fluid PGE Erythromelalgia (ml) (ng/ml) Day MDA (nmol/109 platelets) 1.19 5.40 Present Pretreatment value 2 h 4 h 1.29 6.53 Present 1.02 0.80 Absent 14.3 3.5 1.35 0.99 Absent* 2 1.98 4.81 3 1.25 5.09 *Erythromelalgic skin area during treatment with acetylsalicylic 4 1.98 4.43 acid for 2 weeks. 5 1.89 5.51 spots, which completely disappeared by curative *Time lapse after intake of dazoxiben. treatment with aspirin. Prostaglandin measurements in fluid of artificial (500 mg) lasted 3 to 4 days, but from one oral dose blisters from erythromelalgic areas in the left upper of indomethacin (75mg) less than 24h. The leg in Patient 1 with primary thrombocythaemia analgesic effect of these drugs is in accordance with are shown in Table 2. PGE-like activities in blister the length of inhibition of platelet malondialdehyde fluid from skin areas with active erythromelalgia (MDA) production by arachidonic acid stimulated measured on two different occasions are evidently' platelets in platelet-rich
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