Acute Promyelocytic Leukemia with Disseminated Intravascular Coagulation AARON POLLIACK, Department

M.D.

of Pathology, Hadassah University Hospital and Hebrew Medical School, Jerusalem, Israel

University

ABSTRACT

of acute promyelocytic leukemia 3 - 5 and its recognition as a distinct clinical and anatomic entity, 7 only a few reports have dealt with the postmortem findings in this disease.2-11 Acute promyelocytic leukemia (APL) is characterized by a rapidly fatal course, hypofibrinogememia associated with a marked bleeding tendency, and a preponderance of abnormal promyelocytes in the bone marrow.7 The bleeding phenomena have been attributed to either fibrinolysis or consumption coagulopathy and defibrination. 6 - 12 - 16 Recently there appears to be more support for the latter hypothesis.6- "• 12 - 15 However, despite this, evidence of disseminated intravascular coagulation at autopsy has been obtained only in isolated cases.2-J1

The purpose of this report is to record three typical patients with acute promyelocytic leukemia, all of whom showed evidence of disseminated intravascular coagulation at autopsy.

SINCE THE FIRST REPORTS

Received October 2, 1970; accepted for publication October 21, 1970.

Report of Cases Case 1. A 17-year-old youth was admitted to another hospital because of a macular rash on the face and chest, and pyrexia of 3 weeks' duration. Routine examination of the peripheral blood disclosed numerous blast cells, and he was transferred to Hadassah Hospital for further investigation. Physical examination revealed petechiae on the soft palate and extremities. The liver and spleen were palpable 2 and 3 cm. beneath the costal margin, respectively, but there was no lymphadenopathy. T h e erythrocyte sedimentation rate (ESR) was 3:5

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Polliack, Aaron: Acute promyelocytic leukemia with disseminated intravascular coagulation. Amer. J. Clin. Path. 56: 155-161, 1971. Three patients with acute promyelocytic leukemia, all of whom had rapidly fatal downhill courses associated with marked bleeding tendencies, are described. Two of the three patients had hypofibrinogenemia. At autopsy, all patients had extensive hemorrhage involving internal organs, including the heart, liver, spleen, kidneys and brain. Massive hemorrhagic pulmonary edema was found in two patients. Striking leukemic involvement of the bone marrow was found, but only minimal to mild involvement of the spleen, liver, and lymph glands was evident. In addition, in all three cases autopsy disclosed evidence of disseminated intravascular clotting in small blood vessels. The significance of this finding in relation to the hypofibrinogenemia and bleeding phenomena encountered is discussed. This finding provides further support in favor of consumption (defibrination) as the cause of the bleeding diathesis in this disease.

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and sinusoids in the kidneys, lungs, liver, and spleen. Case 2. A 37-year-old woman was admitted to hospital in March 1970 for investigation of leukopenia, discovered accidentally a month previously. In December 1968 she had undergone a radical mastectomy and bilateral oophorectomy for adenocarcinoma of the right breast, followed by radiotherapy of 4,000 rads. Physical examination revealed an obese woman without palpable lymphadenopathy or splenomegaly. The liver was palpable 2 cm. below the costal margin. The ESR was 9/20 mm. per hr. (Westergren), hemoglobin 13.3 Gm. per 100 ml., platelets 134,000 per cu. mm., and leukocyte count 2,200 per cu. mm., with 76% lymphocytes. Trephine biopsy showed a normal cellular marrow; however, in the smear there was a preponderance of myelocytes and metamyelocytes. The serum vitamin B 1 2 level was 2,200 pg. per ml. in the absence of abnormal liver function tests. Within the next 3 weeks the hemoglobin level dropped to 8.2 Gm. per 100 ml., the platelet count decreased to 44,000 per cu. mm., and the leukocyte count to 1,240 per cu. mm. with 6% promyelocytes. A low leukocyte alkaline phosphatase score of 52 was found. Repeated marrow smear showed replacement of the hematopoietic tissue by promyelocytes (Fig. 2). Despite transfusions and antibiotic therapy, the patient's condition deteriorated rapidly. The plasma prothrombin dropped to 44% of normal and gingival bleedingwas noticed. Dyspnea and cough preceded death due to pulmonary edema and massive hemoptysis. Significant postmortem findings included extensive hemorrhages in the skin, mucosal and serosal surfaces, and kidneys. There was marked hemorrhagic pulmonary edema (Fig. 3). In addition, there were signs of a right radical mastectomy with lymphedema of the right arm. The spleen weighed 380 Gm. and showed congestion hemosiderosis

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mm. per hr. (Westergren), hemoglobin 11.4 Gm. per 100 ml., platelets 38,000 per cu. mm., leukocyte count 600 per cu. mm. with 70% lymphocytes, 4% polymorphonuclear neutrophils, and 26% promyelocytes. Clotting and bleeding times were both prolonged: 11 min. and more than 12 min., respectively. The plasma prothrombin was 30% of normal and fibrinogen 135 mg. per 100 ml. The euglobulin clot lysed within 4 min. Liver function tests were normal. Serum vitamin B ] 2 was 9,600 pg. per ml. The bone marrow consisted almost exclusively of promyelocytes containing abundant Auer bodies. Therapy with blood transfusions, 6 mercaptopurine (6-MP), and epsilon aminocaproic acid (EACA) was begun. However, the patient's condition deteriorated rapidly, and the leukocyte count rose to 12,000 per cu. mm. Extensive subcutaneous hemorrhages and oral ulcerations developed in rapid succession. Replacement of 6-MP by vincristine did not alter the course of the disease, and the patient died a month after the initial diagnosis of leukemia was made. Postmortem examination revealed multiple petechiae and ecchymoses in mucosal and serosal surfaces and in many organs, including the pericardium, pleura, epiglottis, bowel mucosa, skin, and kidneys. Striking parenchymal hemorrhages were found in the liver, spleen, and myocardium. There was marked hemorrhagic pulmonary edema, with 350 ml. of blood-stained fluid in each pleural cavity. The spleen was mildly enlarged, firm, and weighed 250 Gm. The liver was firm and weighed 1,810 Gm. There was no striking lymphadenopathy. Histologically, there was marked infiltration of the bone marrow by sheets of primitive cells of the myeloid series, primarily promyelocytes. Leukemic involvement was moderate in the spleen and minimal in the liver and lymph nodes. Multiple fibrin thrombi were found in the glomerular capillaries (Fig. 1) and in small arteries

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Fie. 1 (upper). Fibrin thrombi in glomerular capillaries. Phosphotungstic acid hematoxylin. X 330.

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Fie. 2 (lower). Bone marrow smear showing many promyelocytes with p r o m i n e n t cytoplasmic granulation. May-Grunwald Ciemsa. X 1,500.

and moderate leukemic infiltration with large mononuclear cells on histologic examination. The liver weighed 2,650 Gm. and showed moderate fatty change with almost no leukemic infiltration other than the presence of primitive myeloid cells in the sinusoids. The bone marrow was extensively infiltrated by leukemic cells of

the myeloid series, predominantly promyelocytes (Fig. 4). Multiple fibrin thrombi were encountered in the glomerular capillaries and in arterioles and sinusoids of the liver, lungs, spleen, and adrenal glands. Case 3. A 45-year-old man was admitted in May 1970 for investigation of leukopenia and thrombocytopenia of recent on-

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FIG. 3 (upper). Histologic section s h o w i n g marked hemorrhagic pulmonary edema. Hematoxylin and eosin. x 105.

set. In 1953 and 1965 he had received radiotherapy for a mediastinal mass that disappeared entirely after therapy. Examination revealed a pale and slightly icteric man with a temperature of 38 C. There was no enlargement of the liver, spleen, or lymph nodes. The hemoglobin was 11.8 Gm. per 100 ml., platelets 44,000 per cu. mm., and the leukocyte count 2,400 per cu. mm. with a normal differential. The ESR

was 12/25 mm. per hr. (Westergren), plasma prothrombin 40% of normal, and serum bilirubin 3.1% rag., of which 0.4% was conjugated. Since repeated attempts at marrow aspiration failed, a trephine biopsy was performed; it disclosed many myeloid precursor cells with only a few mature granulocytes. Within 2 weeks the hemoglobin level dropped to 8 Gm. per 100 ml. and subcutaneous hemorrhages were no-

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FIG. 4 (lower). Histologic section of bone marrow of autopsy showing extensive leukemic infiltration. Hematoxylin and eosin. X 105.

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Discussion Croizat and Favre-Gilly reported a case of APL in 1949B; however, Hillestadt 7 first recognized this disease as a distinct clinical and anatomic entity in 1957. Since then

FIG. 5. Macroscopic appearance of the brain in Case 3 showing extensive subarachnoid hemorrhage.

more than 65 cases have been reported, 6 ' 12 and its incidence has been estimated at about 6.8% of all cases of acute leukemia.2 Both Rosenthal 14 and Didisheim and coworkers 6 reviewed their experience with the disease and emphasized the unusual coagulation defects associated with it. Apart from descriptions by Bernard and associates 2 ' 3 and three autopsied cases reported by Pittman and colleagues,11 there have been relatively few reports stressing the autopsy findings in APL.°>12 In general the findings in APL are similar to those encountered in acute myelogenous leukemia (AML), but bleeding is more frequent and extensive. In addition extensive infiltration of the bone marrow by abnormal promyelocytes is a constant feature of APL, and there is only mild to moderate involvement of the spleen, often confined to the red pulp. 3 Liver involvement is usually sparse or absent and lymph node involvement is variable. 2 Occasionally cerebral, renal, and pulmonary infiltration occurs. 2 -"

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ticed. The serum vitamin B 12 , which had been 500 pg. per ml. a week before admission, increased gradually to 2,000 pg. per ml. Liver function tests were all within normal limits. Repeated bone marrow aspiration showed replacement of the hematopoietic tissue by atypical pleomorphic promyelocytes with pale cytoplasm and coarse cytoplasmic granulation. The leukocyte count rose to 7,000 per cu. mm. and many myelocytes and promyelocytes were present in the peripheral smear. The alkaline phosphatase score of the peripheral granulocytes was 77, and that of the marrow smear was entirely negative. T h e bleeding tendency worsened and massive hematuria developed. The bleeding time was 4 min., clotting time 7 min., and spontaneous dissolution of the clot was noted within minutes. The euglobulin clot lysis time was 30 min. Factor V activity was 52% and the fibrinogen level was 135 mg. per 100 ml. Blood transfusions, 6-MP, and heparin were administered, but the patient's condition deteriorated rapidly with a further decrease in fibrinogen to 107 mg. per 100 ml., and he died in coma. Postmortem examination revealed evidence of a marked hemorrhagic diathesis, and hemorrhages were present in the mucosal and serosal surfaces, spleen, endocardium, skin, lungs, kidneys, and peripelvic tissues. The cause of death was an extensive subarachnoid and intracerebral hemorrhage (Fig. 5). The spleen weighed 340 Gm. and the liver 2,340 Gm. There was no gross lymphadenopathy. Histologically, leukemic infiltration was striking in the bone marrow but only moderate in the spleen, liver, and lymph nodes. Fibrin thrombi were present in the glomerular capillaries.

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in AML. 1 Much controversy exists as to the pathogenesis of the hypofibrinogenemia and the consequent bleeding diathesis in APL. The absence of gross hepatic involvement and altered liver function tests in these cases excludes the possibility of decreased fibrinogen production as its cause. Fibrinogenemia has been attributed to increased fibrinogen utilization, as a result of either defibrination (consumption) or fibrinolysis.1'0-1216 Bernard and co-workers3 and others 4 ' 1 0 favored a circulating fibrinolysin as the cause, but they failed to prove the presence of increased fibrinolysis by laboratory tests. Didisheim and associates ° felt that the most likely explanation was intravascular coagulation despite the frequent absence of fibrin thrombi at autopsy. This assumption was based on the findings of thrombocytopenia, factor V deficiency, and hypofibrinogenemia, the absence of increased fibrinolytic activity, and the finding of occasional rapid clotting of blood in vitro despite the presence of citrate. Pittman and colleagues 11 were unable to obtain evidence to support one hypothesis more than another, and concluded that although consumption was the most likely mechanism there was evidence that both mechanisms played roles. In 1969, Rand and associates12 also presented evidence to suggest that both mechanisms appear to be involved in the production of fibrinogenopenia. However, it appears that activation of consumption antedates activation of fibrinolysis.13 Generally, disseminated intravascular coagulation has been infrequently encountered at autopsy; nevertheless, this does not negate the diagnosis of consumption coagulopathy, 8 ' " as it is possible that the intravascular conversion of fibrinogen to fibrin is not always reflected by the anatomic presence of thrombi. However, if thrombi are found, it is direct evidence of an intravascular clotting process. Thus, the pres-

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In each of the three patients reported in this study, the distribution of the disease was in keeping with that described above, and in general, liver and lymph nodes were involved minimally, splenic infiltration was minimal to moderate, and the bone marrow was packed with leukemic cells predominantly promyelocytic in character. These large leukemic cells were characterized by a slightly basophilic cytoplasm containing coarse granules and an immature nucleus, often showing one or two nucleoli occasionally obscured by cytoplasmic granules. APL is characterized by a rapidly fatal downhill course associated with bleeding phenomena and hypofibrinogenemia. In Bernard's series,2 the most frequent sites of hemorrhage appeared to be cerebromeningeal and gastrointestinal. Hemorrhage was also found in other organs, including the spleen and lungs. Similar sites of fatal bleeding have been noted in other reports.0- "• 1 2 Occasionally, hemorrhagic infarction of visceral organs has been encountered.2' J1 In the three patients reported here it is of interest that, in addition to the massive intracranial hemorrhage found in the third, hemorrhagic pulmonary edema was present in both of the others. In addition, extensive hemorrhage was encountered in the liver, myocardium, spleen, and kidneys, as well as in mucosal and serosal surfaces. In contrast to the bleeding in other acute leukemias, which is usually due to thrombocytopenia, qualitative platelet deficiency, vascular endothelial damage, including leukemic infiltration of the vessel walls, or circulating anticoagulants, 1 - 9 the hemorrhagic diathesis in APL is associated with hypofibrinogenemia. In certain instances AML is also characterized by hemorrhagic phenomena on the basis of hypofibrinogenemia due to increased fibrinolysis, but only rarely has widespread intravascular coagulation been encountered at autopsy

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ence of intravascular thrombi in all of our patients, associated with hypofibrinogenemia in two of them, is important and presents further evidence to favor increased consumption as the underlying mechanism of the fibrinogenopenia and consequent hemorrhagic phenomena encountered in this disease. References

6. Didisheim P, Teombold JS, Vanderroort RLE, et al.: Acute promyelocytic leukemia with fibrinogen and factor V deficiencies. Blood 23: 717-728, 1964 7. Hillestad LK: Acute promyelocytic leukemia. Acta Med Scand 159:189-194, 1957 8. Page EW, Fulton LD, Glendening MB: T h e cause of the blood coagulation defect following abruptio placentae. Amer J Obstet Gynec 61:1116-1122, 1951 9. Perry S, Baker M: Coagulation defects in leukemia. J Lab Clin Med 50:229-241, 1957 10. Pisciotta AV, Schalz EJ: Fibrinolytic purpura in acute leukemia. Amer J Med 19:824-828, 1955 11. Pittman GR, Senhauser DA, Lowney JF: Acute promyelocytic leukemia. A report of 3 autopsied cases. Amer J Clin Path 46:214-220, 1966 12. Rand JJ, Moloney WC, Sise HS: Coagulation defects in acute promyelocytic leukemia. Arch Intern Med 123:39-47, 1969 13. Rodriguez-Erdman F: Bleeding due to increased intravascular blood coagulation. Hemorrhagic syndromes caused by consumption of bloodclotting factors. New Eng J Med 273:13701378, 1965 14. Rosenthal RL: Acute promyelocytic leukemia associated with hypofibrinogenemia. Blood 21: 495-508, 1963 15. Verstrate M, Vermylen C, Vermylen J, et al.: Excessive consumption of blood coagulation components as a cause of hemorrhagic diathesis. Amer J Med 38:899-908, 1965

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1. Baker WG, Bang NU, Nachman RL, et al.: Hypolibrinogencmic haemorrhage in acute myelogenous leukemia treated with heparin. With autopsy findings of widespread intravascular clotting. Ann Intern Med 61:116-124, 1964 2. Bernard J, Lasnerct J, Chome J, et al.: A cytological and histological study of acute promyelocytic leukemia. J Clin Path 16:319324, 1963 3. Bernard J, Mallie G, Boulay J, et al.: La leucose aigue a promyelocytes. Schweiz Med Wschr 89:604-608, 1959 4. Cooperberg AA, Hieman GMA: Fibrinogenopenia and fibrinolysis in acute myelogenous leukemia. Ann Intern Med 42:706-711, 1955 5. Croizat P, Favrc-Gilly J: Les aspects du syndrome hemorrogique des leucemics. Sangre (Hare) 20:417-421, 1949

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