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Thrombotic thrombocytopenic purpura in pregnancy
Thrombotic
thrombocytopenic
purpura in pregnancy JAMES ANDREW Wathington,
A.
O’LEARY, A.
M.D.
MARCHETTI.
M.D.
D. c,:
THROMBOTIC thrombocytopenic purpura is a hemorrhagic disorder which frequently is diagnosed late in the course of the disease and almost always ends in the death of the patient. Although thrombotic thrombocytopenic purpura is becoming less rare on the medical pavilioq” it is still unusually rare in pregnancy even though the highest incidence is found among young women. The cause for the high mortality is inherent in the disease itself.!’ plus the late recognition of the entity because of its rarity.“’ The primary purpose of this paper is to report the fourth case of this disorder in pregnancy and to add another entity in the differential diagnosis of bleeding in pre‘:‘nancy. In addition, the position of thromhotic thrombocytopenic purpura among thrx hemorrhagic disorders will he discussed and the clinical signs, symptoms, and treatment briefly reviewed.
ages’? but occurs more frequently among women in the childbearing age.? There is no apparent racial predilection. Two forms have been described, the acute form which is highly fatal and with which we arc concerned, and a more chronic forl;n which lasts for months’ (Fig. 1 ‘. Classification
Wintrohe”” has divided the purpuras into thrombocytopenic and nonthrombocytopenic. The thrombocytopenic group has two large subdivisions; the first is the familiar idiopathic thrombocytopenic purpura, which is characterized by petechiae and ecchymoses, the absence of hemolytic anemia and fever, and a good response to cortisone 01 ACTH. The second subdivision is the symptomatic thrombocytopenic purpura, meaning secondary to, or complicating, another disease in which thrombotic thrombocytopenic purpura and other purpuras secondary to infections a.nd chemical and physical qents are to be found. Although classified as a symptomatic purpura? it arises dt ll02’0 and is not truly 3 symptomatic purpura (Table I\.
Definition
Thrombotic thrombocytopenic purpura was first described in 1925 by Moschowitz LiS ‘%an acute febrile pleiochromic anemia with hyalinr thrombosis of the terminal arterioles and capillaries.““l. ,I’ It is a syndrome consisting of three basic elements’“‘: thrombocytopenia with purpura, severe hemolytic anemia. and grave cerebral manifestations.‘. 3o It involves both sexes and all From the Depmtment Gynecology, Hospital.
Georgetown
of Obstetrics Uniuer.tit)
Pathology
An understanding of the basic pathology, histopathology, and pathogenesis will lead to a better appreciation of the clinical manifestations of Moschowitz’s”” disease. The pathognomonic lesion and striking feature are the platelet thrombi in the terminal artrrioles and capillaries involving
and
214
Thrombotic
many organs. I42 I67 25 The most frequently involved are the brain, heart, adrenal cortex, kidney, liver, spleen, and lymph nodeslo, 29 There are many theories advanced to explain the etiology of the thrombi >19, ‘I, 45, 58 but at present the exact cause is still obscure.22, 26, 43 It is generally held that the platelets are secondarily deposited on a damaged endothelium3g, 48 with partial occlusion of the vessel; hence, only minimal parenchymal necrosis.” 23 The fact tha.t the primary lesion is in the vessel wall has led many to classify thrombotic thrombocytopenic purpura as a collagen disease 15, 37. 40 Four basic elements are involved in the pathogenesis of thrombotic throbocytopenic purpura: the vessel wall, platelets, megakaryocytes, and red cells. Adelson and associateP have best described the current concept of the pathogenesis as “an immunohematologic disorder” involving the above elements. The antibody or antibodies which are responsible have not as yet been isolated.5G The increased destruction and decreased production of platelets have been clearly proved. Clinical
picture
The onset is acute and usually without a proved cause. I2 The prodromas are many, involve various organ systems, and are not usually appreciated until the full-blown picture is established*O (Table II). The clinical course is acute with sudden onset of fever, weakness, pallor, mild jaundice, and hemorrhagic manifestations3s ’ The basic triad of the symptomatology soon becomes apparent, namely, purpura, hemolytic anemia, and acute illness with cerebral manifestations. The thrombocytopenia may be mild but is usually severe with petechial hemorrhages primarily seen on the arms and legs, although mucous membrane hemorrhages may also be 0bserved.l’ Some patients have had platelet counts of zero. The hemolytic anemia is accompanied by hepatosplenomegaly, icterus, and marked pallor.“3
thrombocytopenic
purpura
215
The central nervous system thrombi result in both mental and neurological changes which may be so mild as to go unnoticed. The signs which are generally present are restlessness, irritability, confusion, and stupor or coma. 33 Neurologically, one finds abnormal reflexes, ataxia, aphasia, and partial motor paralysis, but these are usually only temporary. ‘2 65 Reisfield48 was impressed by the intermittent and transient nature of these signs and attributed them to partial vessel thrombosis (Table III). laboratory
findings
White blood cell counts are not helpful but frequently may show a leukemoid reaction.
Table I. Classification condensed
of purpuras Wintrobe’s fourth
from
as editions’
I. Thrombocytopenic purpura A. Idiopathic thrombocytopenic purpura B. Symptomatic thrombocytopenic purpura 1. Secondary to chemical and physical agents 2. Hemopoietic disorders a. Thrombotic thrombocytopenic purpura b. Leukemia c. Anemia d. Hypersplenism 3. Infections 4. Hemangioendothelioma and miscellaneous II. Nonthrombocytopenic purpura A. Allergic-Henoch-Schonlein purpura B. Symptomatic-infections, chemicals, avitaminosis ,and chronic diseases C. Miscellaneous
Table II” Symptom Weakness Headache Anorexia Vomiting Abdominal Fever Hematuria Cough Arthralgia Numbness Intestinal “From
Antes.2
I
and and
fatigue nausea
distress and
bleeding
dysuria
70 65 45 30 20 20 15 10 12 8 7 5
216
O’Leary
and
Marchetti
and frontal headaches of one wec~k’s durati( ,I,. 90 pertinent family history was obtained and \h(* denied any recent ingestion of drugs or c.cu1lac.t
GlXV.9 Cerebral
!4anirestation3
with toxic substances except that to admission, while her husband the kitchen, she inhaled turpcntinc
Furpum
Fig. 1. Triad
of symptomatology
in an acutely
ill
patient.
Platelets are depressed and may be completely absent.3” Blood smears show a normochromic, normocytic anemia with an increase in reticulocytes and spherocytes.2s The red cell surviva1 time is decreased as is the red cell count.;“’
A negative Coombs test is a helpful diagnostic aid since one would expect a positive reaction in view of the acquired hemolytic anemia. 47 This is a good differential point in the diagnosis of thrombotic thrombocytopenic purpura from idiopathic thrombocytopenic purpura with superimposed hemolytic anemia.“4 Prolonged bleeding time and poor clot retraction are common while the clotting time
is normal.“.
Urinalysis cast
formation,
renal
damage
Case
.“’ frequently
shows
hematuria,
and
albuminuria, reflecting secondary to the thrombi.
report
A 36year-old
Negro
woman,
gravida
ix,
para
viii, who had had 1 abortion and whose expected date of confinement was May 8, 1960, was admitted to the Georgetown University Hospital on March 4, 1960, because of severe anemia (hematocrit 20). This was discovered when she was admitted to the emergency room complaining of a sore throat. History on admission disclosed that she had complained of a sore throat, swelling in the neck, fever, chills, black watery diarrhea, and mild cramping abdominal pain for about 3 weeks; however, she had not attended the prenatal clinic at any time. She had also noticed occasional bleeding of the gums with brushing and had one episode of cpistaxis one week previously which was moderately severe. There were generalized
2 weeks prior \vas painting fumes.
Two years previously, at the time of the last pregnancy, she was treated for an iron dcficicmcy anemia secondary to malnutrition, and post partum required a blood transfusion. C)thcrwisr, the past history was ncgativc.. Physical examination showed scv~rc pallor; rectal temperature was lOO.@ F., pulse 120, and blood pressure 110 systolic, 70 diastolic. The sclcrae were mildly icteric and th(a conjunctivae pale. The tonsils were enlarged \jith qucstionable hemorrhage or exudate and t\\ o stnall petechiac \vcre noted in the pharynx. Cervical lymph nodes wvrc palpable and tender. The lungs were clear and there were nu cardiac allnormalities c’xcc‘pt for the tachycnrdia. Al)dominal examination showed the uterus to bc cmlargcd to the size of a 32 weeks’ ,gf‘station with no other organs palpable. No fetal heart tones were audible. Costovertebral angh tcmd(>rness was present bilaterally. There \verc no nvurological abnormalities, yet the, patient appearccl confused at tin1t.s. Urinalysis sho\vcd -I-plus protc+nuria, granular casts, and 4 white cells per high-power field. The hcmatologic findings wart* ;is follows: hematocrit 17, hemoglobin lrvel 5.2 (;m., Coombs test ncgative, platelets 12,000, ictrric index 75 to 100 units, and a whitt’ cell count of 6,800 with a normal differential. The bleeding time was prolonged, but thr clotting time ~‘3s normal A tentative diagnosis of thrombotic thrombocytopcnia was made. After admission, the patient offcrc,d no complaints but was somcswhat incoherent. Tlz-o units
Table III* Physical
findings
Pallor Fever Purpura Mental changes Neurological changes Icterus Splenomegaly Hepatomegaly Hypertension Lymphadenopathy Arthropathy ‘F,om
Ante,.~
I
Presence Usually present Usually present 80% 50% 50% 50% 25% 25% 15% Rare Very rare -___---.-
Volume Kumber
of
83 2
packrd
Thrombotic
cells
were
given,
increasing
the
hematocrit to 24. Prednisolone, 25 mg., was given by an intravenous drip and repeated every 6 hours. Antibiotics were withheld. Fifteen hours after admission, the membranes ruptured spontaneously and irregular contractions began. Sterile vaginal examination showed a single footling breech presenting at a minus 2 station with a nonpulsating cord in the vagina. The cervix was dilated to 5 cm. and the amniotic fluid was blood tinged containing a few small clots. There was no active bleeding at this time. Twenty-one hours after admission with labor progressing slowly, oxytocin stimulation was initiated. At 9 A.M., one hour later, a complete breech extraction of a 4 pound, 2 ounce stillborn infant was performed over an intact perineum, and the placenta was manually extracted. The patient received no anesthesia. The mother remained critically ill in the immediate postpartum period and bled moderately, saturating 6 perineal pads. During this time, she showed signs of increasing lethargy and decreasing responsiveness. Facial and periorbital edema developed, An additional 500 C.C. of fresh whole blood was given, steroids continued, and oxygen administered. Six hours post partum, the patient was found in opisthotonos without voluntary respirations, and heart sounds were not audible. The pupils were dilated and fixed. The myocardium failed to respond to stimulation. The patient was pronounced dead at 4: 15 P.M., 6 hours, 5 minutes post partum and 28 hours after admission. The final clinical impression was thrombotic thrombocytopenic purpura with cerebral involvement accounting for the terminal event, although cardiac involvement with subsequent arrhythmias could not be ruled out. The pathologic report was as follows: gross petechiae were found on the subendocardium and epicardium, in the lungs, kidneys, and liver. Pulmonary congestion and edema were noted and the kidneys were nephrotic. Microscopic examination disclosed capillary platelet thrombosis of the heart, lungs, lymph nodes, liver, spleen, kidney, thyroid, pancreas, bone marrow, and brain. There were areas of focal necrosis and hemorrhage in the pituitary, brain, pancreas, and heart. The kidney showed hyaline degeneration of the tubules, acute congestion, and membranous glomerulonephritis. There was extramedullary hematopoiesis in the kidney, spleen, and liver. The cause of death was focal inter-
thrombocytopenic
stitial hemorrhage pulmonary edema.
of the The
purpura
myocardium microscopic
217
and acute diagnosis
was thrombotic thrombocytopenic purpura involvement of the heart, lungs, lymph liver, spleen, kidney, thyroid, pancreas, marrow, brain, and meninges.
with nodes, bone
Therapy There is no generally accepted treatment. The prognosis is most grave as only about 4 to 5 per cent of the 13 1 reported cases have ended in recovery and none of the patients with the complication of pregnancy have survived.“l Initially, the treatment is supportive including the use of steroids to suppress the process and to counteract adrenal insufficiency secondary to thrombi. Then we are presented with the age-old problem of surgical versus medical therapy. In 1959, Rubinstein and associate?O reported a case of thrombotic thrombocytopenic purpura treated with fresh whole blood exchange transfusions. The patient received 2 such exchange transfusions, one of 2,000 C.C. and another of 3,000 c.c., less than 12 hours after collection in siliconized containers. There was a dramatic improvement and the patient was discharged 4 weeks later becoming asymptomatic 15 months after discharge. This is the second such case these authors have treated with exchange transfusions. It appears to be a promising modality and one worthy of a trial. Recently, two additional cures of thrombotic thrombocytopenic pm-pm-a have appeared in the literature, both of these following massive doses of ACTH and cortisone.3A Surgically, splenectomy is the procedure of choice.13 Two remissions of thrombotic thrombocytopenic purpura following splenectomy have been reported recently by Siegel and associateP and Shapiro and associates52 and in each instance the surgical response was impressive. Hell and Loeb,34 in 1960, added another surgical cure but this patient had also received cortisone. Conservatism
in the pregnant
would
patient
seem
to
despite
be indicated
the reports
218
O’Leary
and
Marchetti
advocating immediate operation. Splenic engorgement secondary to pregnancy plus possible technical difficulties resulting from the uterine enlargement would further increase the hazards of the surgical procedure, not to mention the poor condition of the patient. Premature labor or abortion with the considerable danger of hemorrhage OI infection might also result from the intraperitoneal manipulation.“’ Certainly, a trial with exchange transfusion and large closes of steroids is indicated before operation. Once the patient improves. splenectomy may be performed if necessary in the first and second trimester. In the third trimester. cesarean section and splenectomy may bc performed if the fetus is \siable. If viabilit), has not been reached, treatment should consist of the use of steroids and exchanq transfusion with fresh whole blood. If eschange transfusion fails in any trimester. splenectomy is the only hope and may hr. attempted as a lifesaving feat.” Comment
This grand multipara died after 28 hours in the hospital; the rapidly fatal course was characteristic of Moschowitz’s disease. The history and prodromal signs were typical. The anemia was clinically obvious, but the purpuric manifestations were minimal, with only 2 pharyngeal petechiae. The neurological signs were headache, restlessness, and finally lethargy and confusion. The hematologic findings were classical: severe anemia and thrombocytopenia together with a ne
REFERENCES
Adams, R., Cammermeyer, J., and Fitzgerald, P.: J. Neurol. Neurosurg. & Psychiat. 11: 27, 1948. Antes, E. H.: Ann. Int. Med. 48: 512, 1958. Altschule, M.: New England J. Med. 227: 477, 1942. Ad&on, E., Heitzman, E., and Fennessey, J.: A. M. A. Arch. Int. Med. 94: 42, 1954.
indicated impaired renal function, which was confirmed hy an ele\Tated blood llrca nitrogen. should the outcome in this case have been altered? Had the patient attended the prenatal clinic: tile earlier institution of supportive therapy might have impaired the chances for a rernission. The severity of the status plus the presence of a 32 weeks’ gestation made the patient a very poor surgical risk. In view of the previously mentioned good results obtained in a few cases with the use of exchange transfusions, one can only conjecture as to what the outcome might have been had they been uscsd in this case. It is at least conceivable that the patient’s condition might have been sufficiently improved to permit the use of cesarean WCtion followed by splenectomy. The key to successful handling of thrornbotic thrombocytopenic purpura is early diagnosis, which is obtained by having a high index of suspicion that such a disorder esists. This lvill facilitate early diagnosis and treatment of this disease which is characterized by two seemingly opposite processrs. multiple thromboses and a defective rlottinp mechanism. Summary
‘I’hc fourth case of thrombotic thrombocytopenic purpura complicating pregnancy has been reported, the subject briefly reviewed. and therapy discussed as to the advantages and disadvantages of medical versus surgical treatment. WC art’ indebted to Jatnc.s I,. O’Leary, M.D., Charles Mueller, M.D.. and Charlrs Rath, M.D., for their
3.
6. 7. 8. 9.
ad\,irc
and support.
Barnes, A., and Doan, C.: .4&f. J. OUST. & GYNEC. 55: 864, 1948. Baehr, G., Klemperrr, P., and Schifrin, 4.: Tr. .4. i\m. Physicians 51: 43, 1936. Baez-Villasenor, J., and Ambrosius, K.: Ann. Int. Med. 46: 378, 1957. Barondess, J. A.: Am. .J. Med. 13: 29-1, 1952. Berlin, I., Sinclair, C., Richman, L.. and Read, W.: Virginia M. Month. 84: 293. 1957.
Volume Number
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
25. 26. 27. 28. 29. 30. 31. 32. 33.
34. 35. 36. 37. 38.
83 2
~;cz&,reim,
Thrombotic
A.:
J.
Mt.
Sinai
Hosp.
10:
287,
Buie, R.: North Carolina M. J. 18: 509, 1957. Blackman, N., Cohen, B., and Watson, ,J.: J. A. M. A. 148: 546, 1952. Burris, M.: Ochsner Clin. Rep. 1: 46. 1955. Brown, E., and Norman, J,:- New York J. Med. 46: 216. 1946. Beigehnan, P:: A. M. A. Arch. Path. 51: 213, 1951. Carter, J.: Am. J. M. SC. 213: 585, 1947. Clement, R.: Blood 14: 100, 1959. Cooper, T., Stickney, J., Pease, G., and Bennett. W.: Am. T. Med. 13: 374. 1952. Craig, J., and Gitiin, D.: Am. J. ‘Path. 33: 251, 1957. 8: 382, 1953. Dameshek, W.: Blood Ehrich, W., and Seifter, W.: Arch. Path. 47: 446, 1949. Engel, G., Scheinker, I., and Humphrey, I).: Ann. Int. Med. 26: 919, 1947. Epstein, F., Deschamps, S., and Chiffelle, T.: Yale T. Biol. & Med. 20: 571. 1948. Evans, R., Takahashi, K., Duane, R., Payne, R., and Liu, G.: A. M. A. Arch. Int. Med. 87: 48, 1951. Fisher, E., and Creed, D.: Am. J. Clin. Path. 25: 620, 1955. Fitzgerald, P., Auerbach, O., and Frame, E.: Blood 2: 519, 1947. Fuller, E., and Ward, W.: J. Kentucky M. A. 55: 427, 1957. Gendel, B., Young, J., and Kraus, A.: Am. J. Med. 13: 3, 1952. Gitlow, S., and Goldmark, C.: Ann. Int. Med. 13: 1046, 1939. Golenberg, P., Thayer, J., and Hastings, I,.: New England J. Med. 243: 252, 1950. Gore, I.: Am. J. Path. 26: 155, 1950. Green, W., and Green, T.: Ann. Int. Med. 39: 371, 1953. Hauser, A., Beyer, A., and Burger, R.: A. M. A. Arch. Neurol. & Psychiat. 65: 672, 1951. Hell, J., and Loeb, H.: J. A. M. A. 173: 778, 1960. Katz, K., and Jackler, J.: Boston Med. Quart. 6: 118, 1955. Kingsley, J., and Aquino, R.: Ann. Int. Med. 49: 934, 1958. La&o, M., Alvarez, A., and Feldman, F.: Ann. Int. Med. 42: 1308, 1955. McElin, T., Mussey, R., and Watkins, C.:
41. 42. 43. 44. 45. 46. 47. 48. 49. 50.
51. 52. 53. 54. 55.
56. 57. 58. 59. 60. 61. 62. 63. 64. 65.
purpura
219
J. OBST. & GYNEC. 59: 1036, 1950. March, H.: Circulation 10: 43, 1954. Meacham, G., Orbison, J., Heinle, R., Steele, H., and Schaefer, J.: Blood 6: 706, 1951. Miner, P., Nutt, R., and Thomas, M.: A~II. J. OBST. & GYKEC. 70: 611. 1955. Moschowitz, E.: Arch. ‘Int. Med. 36: 89, 1925. Moore, R., and Schoenberg, M.: Blood 25: 511, 1960. Muirhead, E., Grass, G., and Hill, J.: Am. J. Clin. Path. 18: 523, 1948. Orbison, J.: Am. J. Path. 28: 129, 1952. Pagel, W.: Am. J. M. SC. 218: 425, 1949. Quick, A.: Hemorrhagic Disorders, Philadelphia, 1957. Lea & Febieer. keisfield, D.: Obst. & Gynec. Surv. 14: 303, 1959. Revill, R., and Wilson, M.: Brit. M. J. 2: 81, 1954. Rubinstein, M., Kagan, B., Merliss, R., MacGillviray, M., and Sacks, H.: Ann. Int. Med. 51: 1409, 1959. Siegel, B., Friedman, F., Kessler, S., and Schwartz, S.: Ann. Int. Med. 4’7: 1022, 1957. Shapiro, H., Daktor, D., and Churg, J.: Ann. Int. Med. 47: 582, 1957. Singer, K., Motulsky, A., and Shanberge, J.: Blood 5: 434, 1950. Singer, K., Bornstein, F., and Wile, S.: Blood 2: 542. 1947. Stefanini, M., and Dameshek, W.: The Hemorrhagic Disorders, New York, 1955, Grunt & Stratton, Inc. Stuart, A., and MacGregor-Robertson, G.: Lancet 1: 475, 1956. Stone, J., and Alcott, D.: California Med. 83: 35, 1954. Symmers, W., and Barrowcliff, D.: J. Path. & Bact. 63: 522, 1951. Tackett, H., and Jones, R.: Circulation 5: 920, 1952. Trobough, F., Markowitz, M., Davidson, C., and Crowley, W.: Arch. Path. 41: 327, 1946. Tennant, R., and McAdama, G.: Connecticut Med. 22: 9, 1958. Vassar, P., and Spain, D.: Circulation 8: 664, 1953. Wasserman, E.: Am. J. Med. 24: 648, 1958. Wintrobe. M.: Clinical Hematoloev. Philadelphia, 1956, Lea & Febiger. “” Wyatt, J., and Lee, R.: Arch. Path. 49: 582, 1950. AM.
39. 40.
thrombocytopenic
thrombocytopenic
purpura in pregnancy JAMES ANDREW Wathington,
A.
O’LEARY, A.
M.D.
MARCHETTI.
M.D.
D. c,:
THROMBOTIC thrombocytopenic purpura is a hemorrhagic disorder which frequently is diagnosed late in the course of the disease and almost always ends in the death of the patient. Although thrombotic thrombocytopenic purpura is becoming less rare on the medical pavilioq” it is still unusually rare in pregnancy even though the highest incidence is found among young women. The cause for the high mortality is inherent in the disease itself.!’ plus the late recognition of the entity because of its rarity.“’ The primary purpose of this paper is to report the fourth case of this disorder in pregnancy and to add another entity in the differential diagnosis of bleeding in pre‘:‘nancy. In addition, the position of thromhotic thrombocytopenic purpura among thrx hemorrhagic disorders will he discussed and the clinical signs, symptoms, and treatment briefly reviewed.
ages’? but occurs more frequently among women in the childbearing age.? There is no apparent racial predilection. Two forms have been described, the acute form which is highly fatal and with which we arc concerned, and a more chronic forl;n which lasts for months’ (Fig. 1 ‘. Classification
Wintrohe”” has divided the purpuras into thrombocytopenic and nonthrombocytopenic. The thrombocytopenic group has two large subdivisions; the first is the familiar idiopathic thrombocytopenic purpura, which is characterized by petechiae and ecchymoses, the absence of hemolytic anemia and fever, and a good response to cortisone 01 ACTH. The second subdivision is the symptomatic thrombocytopenic purpura, meaning secondary to, or complicating, another disease in which thrombotic thrombocytopenic purpura and other purpuras secondary to infections a.nd chemical and physical qents are to be found. Although classified as a symptomatic purpura? it arises dt ll02’0 and is not truly 3 symptomatic purpura (Table I\.
Definition
Thrombotic thrombocytopenic purpura was first described in 1925 by Moschowitz LiS ‘%an acute febrile pleiochromic anemia with hyalinr thrombosis of the terminal arterioles and capillaries.““l. ,I’ It is a syndrome consisting of three basic elements’“‘: thrombocytopenia with purpura, severe hemolytic anemia. and grave cerebral manifestations.‘. 3o It involves both sexes and all From the Depmtment Gynecology, Hospital.
Georgetown
of Obstetrics Uniuer.tit)
Pathology
An understanding of the basic pathology, histopathology, and pathogenesis will lead to a better appreciation of the clinical manifestations of Moschowitz’s”” disease. The pathognomonic lesion and striking feature are the platelet thrombi in the terminal artrrioles and capillaries involving
and
214
Thrombotic
many organs. I42 I67 25 The most frequently involved are the brain, heart, adrenal cortex, kidney, liver, spleen, and lymph nodeslo, 29 There are many theories advanced to explain the etiology of the thrombi >19, ‘I, 45, 58 but at present the exact cause is still obscure.22, 26, 43 It is generally held that the platelets are secondarily deposited on a damaged endothelium3g, 48 with partial occlusion of the vessel; hence, only minimal parenchymal necrosis.” 23 The fact tha.t the primary lesion is in the vessel wall has led many to classify thrombotic thrombocytopenic purpura as a collagen disease 15, 37. 40 Four basic elements are involved in the pathogenesis of thrombotic throbocytopenic purpura: the vessel wall, platelets, megakaryocytes, and red cells. Adelson and associateP have best described the current concept of the pathogenesis as “an immunohematologic disorder” involving the above elements. The antibody or antibodies which are responsible have not as yet been isolated.5G The increased destruction and decreased production of platelets have been clearly proved. Clinical
picture
The onset is acute and usually without a proved cause. I2 The prodromas are many, involve various organ systems, and are not usually appreciated until the full-blown picture is established*O (Table II). The clinical course is acute with sudden onset of fever, weakness, pallor, mild jaundice, and hemorrhagic manifestations3s ’ The basic triad of the symptomatology soon becomes apparent, namely, purpura, hemolytic anemia, and acute illness with cerebral manifestations. The thrombocytopenia may be mild but is usually severe with petechial hemorrhages primarily seen on the arms and legs, although mucous membrane hemorrhages may also be 0bserved.l’ Some patients have had platelet counts of zero. The hemolytic anemia is accompanied by hepatosplenomegaly, icterus, and marked pallor.“3
thrombocytopenic
purpura
215
The central nervous system thrombi result in both mental and neurological changes which may be so mild as to go unnoticed. The signs which are generally present are restlessness, irritability, confusion, and stupor or coma. 33 Neurologically, one finds abnormal reflexes, ataxia, aphasia, and partial motor paralysis, but these are usually only temporary. ‘2 65 Reisfield48 was impressed by the intermittent and transient nature of these signs and attributed them to partial vessel thrombosis (Table III). laboratory
findings
White blood cell counts are not helpful but frequently may show a leukemoid reaction.
Table I. Classification condensed
of purpuras Wintrobe’s fourth
from
as editions’
I. Thrombocytopenic purpura A. Idiopathic thrombocytopenic purpura B. Symptomatic thrombocytopenic purpura 1. Secondary to chemical and physical agents 2. Hemopoietic disorders a. Thrombotic thrombocytopenic purpura b. Leukemia c. Anemia d. Hypersplenism 3. Infections 4. Hemangioendothelioma and miscellaneous II. Nonthrombocytopenic purpura A. Allergic-Henoch-Schonlein purpura B. Symptomatic-infections, chemicals, avitaminosis ,and chronic diseases C. Miscellaneous
Table II” Symptom Weakness Headache Anorexia Vomiting Abdominal Fever Hematuria Cough Arthralgia Numbness Intestinal “From
Antes.2
I
and and
fatigue nausea
distress and
bleeding
dysuria
70 65 45 30 20 20 15 10 12 8 7 5
216
O’Leary
and
Marchetti
and frontal headaches of one wec~k’s durati( ,I,. 90 pertinent family history was obtained and \h(* denied any recent ingestion of drugs or c.cu1lac.t
GlXV.9 Cerebral
!4anirestation3
with toxic substances except that to admission, while her husband the kitchen, she inhaled turpcntinc
Furpum
Fig. 1. Triad
of symptomatology
in an acutely
ill
patient.
Platelets are depressed and may be completely absent.3” Blood smears show a normochromic, normocytic anemia with an increase in reticulocytes and spherocytes.2s The red cell surviva1 time is decreased as is the red cell count.;“’
A negative Coombs test is a helpful diagnostic aid since one would expect a positive reaction in view of the acquired hemolytic anemia. 47 This is a good differential point in the diagnosis of thrombotic thrombocytopenic purpura from idiopathic thrombocytopenic purpura with superimposed hemolytic anemia.“4 Prolonged bleeding time and poor clot retraction are common while the clotting time
is normal.“.
Urinalysis cast
formation,
renal
damage
Case
.“’ frequently
shows
hematuria,
and
albuminuria, reflecting secondary to the thrombi.
report
A 36year-old
Negro
woman,
gravida
ix,
para
viii, who had had 1 abortion and whose expected date of confinement was May 8, 1960, was admitted to the Georgetown University Hospital on March 4, 1960, because of severe anemia (hematocrit 20). This was discovered when she was admitted to the emergency room complaining of a sore throat. History on admission disclosed that she had complained of a sore throat, swelling in the neck, fever, chills, black watery diarrhea, and mild cramping abdominal pain for about 3 weeks; however, she had not attended the prenatal clinic at any time. She had also noticed occasional bleeding of the gums with brushing and had one episode of cpistaxis one week previously which was moderately severe. There were generalized
2 weeks prior \vas painting fumes.
Two years previously, at the time of the last pregnancy, she was treated for an iron dcficicmcy anemia secondary to malnutrition, and post partum required a blood transfusion. C)thcrwisr, the past history was ncgativc.. Physical examination showed scv~rc pallor; rectal temperature was lOO.@ F., pulse 120, and blood pressure 110 systolic, 70 diastolic. The sclcrae were mildly icteric and th(a conjunctivae pale. The tonsils were enlarged \jith qucstionable hemorrhage or exudate and t\\ o stnall petechiac \vcre noted in the pharynx. Cervical lymph nodes wvrc palpable and tender. The lungs were clear and there were nu cardiac allnormalities c’xcc‘pt for the tachycnrdia. Al)dominal examination showed the uterus to bc cmlargcd to the size of a 32 weeks’ ,gf‘station with no other organs palpable. No fetal heart tones were audible. Costovertebral angh tcmd(>rness was present bilaterally. There \verc no nvurological abnormalities, yet the, patient appearccl confused at tin1t.s. Urinalysis sho\vcd -I-plus protc+nuria, granular casts, and 4 white cells per high-power field. The hcmatologic findings wart* ;is follows: hematocrit 17, hemoglobin lrvel 5.2 (;m., Coombs test ncgative, platelets 12,000, ictrric index 75 to 100 units, and a whitt’ cell count of 6,800 with a normal differential. The bleeding time was prolonged, but thr clotting time ~‘3s normal A tentative diagnosis of thrombotic thrombocytopcnia was made. After admission, the patient offcrc,d no complaints but was somcswhat incoherent. Tlz-o units
Table III* Physical
findings
Pallor Fever Purpura Mental changes Neurological changes Icterus Splenomegaly Hepatomegaly Hypertension Lymphadenopathy Arthropathy ‘F,om
Ante,.~
I
Presence Usually present Usually present 80% 50% 50% 50% 25% 25% 15% Rare Very rare -___---.-
Volume Kumber
of
83 2
packrd
Thrombotic
cells
were
given,
increasing
the
hematocrit to 24. Prednisolone, 25 mg., was given by an intravenous drip and repeated every 6 hours. Antibiotics were withheld. Fifteen hours after admission, the membranes ruptured spontaneously and irregular contractions began. Sterile vaginal examination showed a single footling breech presenting at a minus 2 station with a nonpulsating cord in the vagina. The cervix was dilated to 5 cm. and the amniotic fluid was blood tinged containing a few small clots. There was no active bleeding at this time. Twenty-one hours after admission with labor progressing slowly, oxytocin stimulation was initiated. At 9 A.M., one hour later, a complete breech extraction of a 4 pound, 2 ounce stillborn infant was performed over an intact perineum, and the placenta was manually extracted. The patient received no anesthesia. The mother remained critically ill in the immediate postpartum period and bled moderately, saturating 6 perineal pads. During this time, she showed signs of increasing lethargy and decreasing responsiveness. Facial and periorbital edema developed, An additional 500 C.C. of fresh whole blood was given, steroids continued, and oxygen administered. Six hours post partum, the patient was found in opisthotonos without voluntary respirations, and heart sounds were not audible. The pupils were dilated and fixed. The myocardium failed to respond to stimulation. The patient was pronounced dead at 4: 15 P.M., 6 hours, 5 minutes post partum and 28 hours after admission. The final clinical impression was thrombotic thrombocytopenic purpura with cerebral involvement accounting for the terminal event, although cardiac involvement with subsequent arrhythmias could not be ruled out. The pathologic report was as follows: gross petechiae were found on the subendocardium and epicardium, in the lungs, kidneys, and liver. Pulmonary congestion and edema were noted and the kidneys were nephrotic. Microscopic examination disclosed capillary platelet thrombosis of the heart, lungs, lymph nodes, liver, spleen, kidney, thyroid, pancreas, bone marrow, and brain. There were areas of focal necrosis and hemorrhage in the pituitary, brain, pancreas, and heart. The kidney showed hyaline degeneration of the tubules, acute congestion, and membranous glomerulonephritis. There was extramedullary hematopoiesis in the kidney, spleen, and liver. The cause of death was focal inter-
thrombocytopenic
stitial hemorrhage pulmonary edema.
of the The
purpura
myocardium microscopic
217
and acute diagnosis
was thrombotic thrombocytopenic purpura involvement of the heart, lungs, lymph liver, spleen, kidney, thyroid, pancreas, marrow, brain, and meninges.
with nodes, bone
Therapy There is no generally accepted treatment. The prognosis is most grave as only about 4 to 5 per cent of the 13 1 reported cases have ended in recovery and none of the patients with the complication of pregnancy have survived.“l Initially, the treatment is supportive including the use of steroids to suppress the process and to counteract adrenal insufficiency secondary to thrombi. Then we are presented with the age-old problem of surgical versus medical therapy. In 1959, Rubinstein and associate?O reported a case of thrombotic thrombocytopenic purpura treated with fresh whole blood exchange transfusions. The patient received 2 such exchange transfusions, one of 2,000 C.C. and another of 3,000 c.c., less than 12 hours after collection in siliconized containers. There was a dramatic improvement and the patient was discharged 4 weeks later becoming asymptomatic 15 months after discharge. This is the second such case these authors have treated with exchange transfusions. It appears to be a promising modality and one worthy of a trial. Recently, two additional cures of thrombotic thrombocytopenic pm-pm-a have appeared in the literature, both of these following massive doses of ACTH and cortisone.3A Surgically, splenectomy is the procedure of choice.13 Two remissions of thrombotic thrombocytopenic purpura following splenectomy have been reported recently by Siegel and associateP and Shapiro and associates52 and in each instance the surgical response was impressive. Hell and Loeb,34 in 1960, added another surgical cure but this patient had also received cortisone. Conservatism
in the pregnant
would
patient
seem
to
despite
be indicated
the reports
218
O’Leary
and
Marchetti
advocating immediate operation. Splenic engorgement secondary to pregnancy plus possible technical difficulties resulting from the uterine enlargement would further increase the hazards of the surgical procedure, not to mention the poor condition of the patient. Premature labor or abortion with the considerable danger of hemorrhage OI infection might also result from the intraperitoneal manipulation.“’ Certainly, a trial with exchange transfusion and large closes of steroids is indicated before operation. Once the patient improves. splenectomy may be performed if necessary in the first and second trimester. In the third trimester. cesarean section and splenectomy may bc performed if the fetus is \siable. If viabilit), has not been reached, treatment should consist of the use of steroids and exchanq transfusion with fresh whole blood. If eschange transfusion fails in any trimester. splenectomy is the only hope and may hr. attempted as a lifesaving feat.” Comment
This grand multipara died after 28 hours in the hospital; the rapidly fatal course was characteristic of Moschowitz’s disease. The history and prodromal signs were typical. The anemia was clinically obvious, but the purpuric manifestations were minimal, with only 2 pharyngeal petechiae. The neurological signs were headache, restlessness, and finally lethargy and confusion. The hematologic findings were classical: severe anemia and thrombocytopenia together with a ne
REFERENCES
Adams, R., Cammermeyer, J., and Fitzgerald, P.: J. Neurol. Neurosurg. & Psychiat. 11: 27, 1948. Antes, E. H.: Ann. Int. Med. 48: 512, 1958. Altschule, M.: New England J. Med. 227: 477, 1942. Ad&on, E., Heitzman, E., and Fennessey, J.: A. M. A. Arch. Int. Med. 94: 42, 1954.
indicated impaired renal function, which was confirmed hy an ele\Tated blood llrca nitrogen. should the outcome in this case have been altered? Had the patient attended the prenatal clinic: tile earlier institution of supportive therapy might have impaired the chances for a rernission. The severity of the status plus the presence of a 32 weeks’ gestation made the patient a very poor surgical risk. In view of the previously mentioned good results obtained in a few cases with the use of exchange transfusions, one can only conjecture as to what the outcome might have been had they been uscsd in this case. It is at least conceivable that the patient’s condition might have been sufficiently improved to permit the use of cesarean WCtion followed by splenectomy. The key to successful handling of thrornbotic thrombocytopenic purpura is early diagnosis, which is obtained by having a high index of suspicion that such a disorder esists. This lvill facilitate early diagnosis and treatment of this disease which is characterized by two seemingly opposite processrs. multiple thromboses and a defective rlottinp mechanism. Summary
‘I’hc fourth case of thrombotic thrombocytopenic purpura complicating pregnancy has been reported, the subject briefly reviewed. and therapy discussed as to the advantages and disadvantages of medical versus surgical treatment. WC art’ indebted to Jatnc.s I,. O’Leary, M.D., Charles Mueller, M.D.. and Charlrs Rath, M.D., for their
3.
6. 7. 8. 9.
ad\,irc
and support.
Barnes, A., and Doan, C.: .4&f. J. OUST. & GYNEC. 55: 864, 1948. Baehr, G., Klemperrr, P., and Schifrin, 4.: Tr. .4. i\m. Physicians 51: 43, 1936. Baez-Villasenor, J., and Ambrosius, K.: Ann. Int. Med. 46: 378, 1957. Barondess, J. A.: Am. .J. Med. 13: 29-1, 1952. Berlin, I., Sinclair, C., Richman, L.. and Read, W.: Virginia M. Month. 84: 293. 1957.
Volume Number
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
25. 26. 27. 28. 29. 30. 31. 32. 33.
34. 35. 36. 37. 38.
83 2
~;cz&,reim,
Thrombotic
A.:
J.
Mt.
Sinai
Hosp.
10:
287,
Buie, R.: North Carolina M. J. 18: 509, 1957. Blackman, N., Cohen, B., and Watson, ,J.: J. A. M. A. 148: 546, 1952. Burris, M.: Ochsner Clin. Rep. 1: 46. 1955. Brown, E., and Norman, J,:- New York J. Med. 46: 216. 1946. Beigehnan, P:: A. M. A. Arch. Path. 51: 213, 1951. Carter, J.: Am. J. M. SC. 213: 585, 1947. Clement, R.: Blood 14: 100, 1959. Cooper, T., Stickney, J., Pease, G., and Bennett. W.: Am. T. Med. 13: 374. 1952. Craig, J., and Gitiin, D.: Am. J. ‘Path. 33: 251, 1957. 8: 382, 1953. Dameshek, W.: Blood Ehrich, W., and Seifter, W.: Arch. Path. 47: 446, 1949. Engel, G., Scheinker, I., and Humphrey, I).: Ann. Int. Med. 26: 919, 1947. Epstein, F., Deschamps, S., and Chiffelle, T.: Yale T. Biol. & Med. 20: 571. 1948. Evans, R., Takahashi, K., Duane, R., Payne, R., and Liu, G.: A. M. A. Arch. Int. Med. 87: 48, 1951. Fisher, E., and Creed, D.: Am. J. Clin. Path. 25: 620, 1955. Fitzgerald, P., Auerbach, O., and Frame, E.: Blood 2: 519, 1947. Fuller, E., and Ward, W.: J. Kentucky M. A. 55: 427, 1957. Gendel, B., Young, J., and Kraus, A.: Am. J. Med. 13: 3, 1952. Gitlow, S., and Goldmark, C.: Ann. Int. Med. 13: 1046, 1939. Golenberg, P., Thayer, J., and Hastings, I,.: New England J. Med. 243: 252, 1950. Gore, I.: Am. J. Path. 26: 155, 1950. Green, W., and Green, T.: Ann. Int. Med. 39: 371, 1953. Hauser, A., Beyer, A., and Burger, R.: A. M. A. Arch. Neurol. & Psychiat. 65: 672, 1951. Hell, J., and Loeb, H.: J. A. M. A. 173: 778, 1960. Katz, K., and Jackler, J.: Boston Med. Quart. 6: 118, 1955. Kingsley, J., and Aquino, R.: Ann. Int. Med. 49: 934, 1958. La&o, M., Alvarez, A., and Feldman, F.: Ann. Int. Med. 42: 1308, 1955. McElin, T., Mussey, R., and Watkins, C.:
41. 42. 43. 44. 45. 46. 47. 48. 49. 50.
51. 52. 53. 54. 55.
56. 57. 58. 59. 60. 61. 62. 63. 64. 65.
purpura
219
J. OBST. & GYNEC. 59: 1036, 1950. March, H.: Circulation 10: 43, 1954. Meacham, G., Orbison, J., Heinle, R., Steele, H., and Schaefer, J.: Blood 6: 706, 1951. Miner, P., Nutt, R., and Thomas, M.: A~II. J. OBST. & GYKEC. 70: 611. 1955. Moschowitz, E.: Arch. ‘Int. Med. 36: 89, 1925. Moore, R., and Schoenberg, M.: Blood 25: 511, 1960. Muirhead, E., Grass, G., and Hill, J.: Am. J. Clin. Path. 18: 523, 1948. Orbison, J.: Am. J. Path. 28: 129, 1952. Pagel, W.: Am. J. M. SC. 218: 425, 1949. Quick, A.: Hemorrhagic Disorders, Philadelphia, 1957. Lea & Febieer. keisfield, D.: Obst. & Gynec. Surv. 14: 303, 1959. Revill, R., and Wilson, M.: Brit. M. J. 2: 81, 1954. Rubinstein, M., Kagan, B., Merliss, R., MacGillviray, M., and Sacks, H.: Ann. Int. Med. 51: 1409, 1959. Siegel, B., Friedman, F., Kessler, S., and Schwartz, S.: Ann. Int. Med. 4’7: 1022, 1957. Shapiro, H., Daktor, D., and Churg, J.: Ann. Int. Med. 47: 582, 1957. Singer, K., Motulsky, A., and Shanberge, J.: Blood 5: 434, 1950. Singer, K., Bornstein, F., and Wile, S.: Blood 2: 542. 1947. Stefanini, M., and Dameshek, W.: The Hemorrhagic Disorders, New York, 1955, Grunt & Stratton, Inc. Stuart, A., and MacGregor-Robertson, G.: Lancet 1: 475, 1956. Stone, J., and Alcott, D.: California Med. 83: 35, 1954. Symmers, W., and Barrowcliff, D.: J. Path. & Bact. 63: 522, 1951. Tackett, H., and Jones, R.: Circulation 5: 920, 1952. Trobough, F., Markowitz, M., Davidson, C., and Crowley, W.: Arch. Path. 41: 327, 1946. Tennant, R., and McAdama, G.: Connecticut Med. 22: 9, 1958. Vassar, P., and Spain, D.: Circulation 8: 664, 1953. Wasserman, E.: Am. J. Med. 24: 648, 1958. Wintrobe. M.: Clinical Hematoloev. Philadelphia, 1956, Lea & Febiger. “” Wyatt, J., and Lee, R.: Arch. Path. 49: 582, 1950. AM.
39. 40.
thrombocytopenic