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Haemostasis in kala-azar
581 TRANSACTIONSOF THE ROYAL SOCIETYOF TROPICAL MEDICINE AND HYGIENE. Vol. 64. No. 4. 1970.
HAEMOSTASIS IN KALA-AZAR* A. K. BASU, J. B. CHATTERJEA, P. C. SEN G U P T A AND A. M. MUKHERJEE
Departments of Haematology and Pathology, School of Tropical Medicine, Calcutta, India Haemorrhagic manifestations are not infrequent in kala-azar (ROGERS, 1908). Varying grades of thrombocytopenia and deficiency of coagulation factors, V and X, were noted in 5 out of 7 patients with kala-azar (BAso et al, 1967). Bleeding manifestations were, however, present in only 2 of these patients. In the present communication, the results of detailed haemostatic investigations carried out in a larger series of patients are recorded.
Materials and methods The subjects of the study consisted of 20 in-patients in the Carmichael Hospital for Tropical Diseases, Calcutta. Diagnosis of kala-azar was confirmed in each case by the demonstration of Leishman-Donovan bodies either in the bone marrow and/or the splenic smear. Tests performed for evaluating the haemostatic status included the following: 1. Platelet count by indirect method (modified from DAMESHEK,1932). 2. Bleeding time (IvY et al., 1940) 3. Whole blood clotting time (LEE and WHITE, 1913). 4. One-stage plasma prothrombin time (QuicK, 1938). 5. Prothrombin consumption test as described by QUICK(1966). 6. Thromboplastin generation test (TGT) according to the method of BIGGS and DOUGLAS (1953). 7. Factor V and factor V I I I assay as described by DENSON (1966a). 8. Assessment of factor X l I I as described by DENSON (1966b).
Results A summary of relevant findings in individual patients is shown in Table I. All the tests were completely normal in 4 of the 20 subjects. Thrombocytopenla was present in 8. In 3 thrombocytopenla was the only abnormality with bleeding time ranging from 8 to 11 minutes; the platelet count in these varied from 60,000 to 99,000 per c.mm. (Table II). Thrombocytopenia was associated with other defects in 5 patients; bleeding time in these ranged from 8 to 10 minutes (Table III). Quick's one-stage prothrombin time was prolonged in 5 patients with plasma prothrombin activity ranging from 47 to 62% (Table IV). The prolonged one-stage prothrombin time could be corrected by normal serum in 3 (Nos. 2, 10 and 19). In the other 2, only fresh aluminium hydroxide-treated plasma had a corrective effect (Nos. 9 and 18). The T G T was abnormal in 3 of these 5 patients with low plasma prothrombin activity. Abnormality in T G T was due to plasma factors in 2 (Nos. 9 and 18) and to serum factors in one (No. 10). *Adapted from a paper presented at the X I I International Congress of the International Society of Haematology held in New York in September, 1968.
582
HAEMOSTASIS I N KALA-AZAR
In addition to the above 3, the T G T was also abnormal in 7 others (Table V). 2 had a serum defect (Nos. 8 and 17), 2 both plasma and serum defect (Nos. 3 and 4) and one (No. 1) plasma defect. Platelet suspensions from 2 others (Nos. 12 and 15) could not generate normal amounts of thromboplastin, when used with normal aluminium hydroxide adsorbed plasma and normal serum in the T G T . One of them (No. 12) also showed a serum defect, while the other (No. 15) showed a plasma defect. The Ivy bleeding time was borderline in the latter patient. Assay of individual coagulation factors was not done in all cases. The level of factor VIII and V was estimated in 3 patients only. Factor VIII activity was 30% of normal in No. 15 and the level of factor V was 38 and 25% respectively in Nos. 9 and 18. Assessment of factor XIII activity was made in 5; deficiency was noted in 2 cases (Table VI). One of these (No. 10) had also a prolonged one-stage prothrombin time and a serum defect in the T G T . In the other (No. 16), there was no other abnormality except deficiency of factor XIII. The tests were repeated in 8 patients after recovery from kala-azar. In 7, the repeat studies were completely normal. In the eighth, improvement was noted in plasma prothrombin activity but the T G T was still abnormal. The haemostatic pattern in 6 patients with bleeding manifestations is shown in Table VII. Abnormality of individual haemostatic parameters as noted singly or in combination is shown in Table VIII. Discussion Apart from reports of thrombocytopenia and prolonged one-stage prothrombin time, no significant abnormality in haemostatic mechanisms appears to have been recorded by previous workers (CHAr~V~TY, 1947; CHAK~VARTY et al., 1949; SFN GUPTA; 1948, 1960). In an earlier communication, deficiency of factors V and X was recorded by us (B~u et al, loc. cir..). In the present series 16 of 20 patients had a haemostatic abnormality, the majority of the cases showing multiple defects. Thrombocytopenia was present in half of these 16 patients, either singly or in association with other defects. The bleeding time in these patients was prolonged disproportionately to the degree of thrombocytopenia. The capillary resistance test was, however, normal in all. Assay of individual coagulation factors was not done except in 3 patients in whom the levels of factors V and VIII were determined. Factor V was deficient in 2 and factor VIII in one. In all other patients, except the 2 with factor XIII deficiency, deficiency in coagulation factors, as reported here, was presumptive, being based on the correction of the one-stage prothrombin time and T G T . Most of the coagulation factors are known to be synthesized in the liver and kalaazar is known to be associated with marked hepatic dysfunction (CH~mgnv~m~: et al., 1949). The site of production of factor VIII is still a controversial issue. Recent experiments suggest that factor VIII is probably synthesized in the reticulo-endothelial cells (NORMAN et al, 1968). The low level of factor VIII in one patient of the present series and probable deficiency of this factor in 3 other patients may be due to the extensive involvement of the reticulo-endothelial system in kala-azar. It should, however, be mentioned that only 4 out of 20 cases of kala-azar showed deficiency of factor VIII though hyperplasia and parasitization of reticulo-endothelial cells occur in all cases of the disease. Although acquired deficiency of factor VIII has been reported in a number of systemic diseases, viz., leukaemia, cirrhosis of liver, systemic lupus erythematosus, no record of factor VIII deficiency in kala-azar is recorded in the literature.
A. K. BASU, J. B. C H A T T E R J E A , P . C. SEN G U P T A A N D A. M . M U K H E R J E E
TABLE I.
.~]
.-~
Z¢~
"~ z ~
~.~ e~
~
~' ~.~
Haemostatic data on 20 cases of kala-azar
~
~ =
TGTindefect
~'~
ii
~
×
~ ~
35
10
12
~ ~
thrombin time
TGT
o ~
~ ~ 1
m
72
55
583
--
+
--
Corrected by Serum
AI (OH)a plasma
Albumin Globulin (in g. %)
Deficient factor
3 '2
V I I I ;. t h r o m b o c y topema
5'9 2
35
10
ii
47
35
4"45
Serum
V I I ; thrombocytopenia
6"65 3
4
90
300
8
3
10
I0
90
60
100
+
+
--
--
Serum AI ( O H ) s plasma
82
2"45
V I I I and I X or X I thrombocytopenia
8'50 3" 2
N o abnormality
7'6 5
225
2
7
100
82
2" 05
N o abnormality
6"50
6
270
4
7
75
8
8
325
5
14
74
62
8
78
97
14
100
75
+
+
--
+
--
Serum AI (OH)3 plasma
--
Serum
--
VIII,
--
Thrombocytopenia
1 "8
IX, XI
IX
7.7 9
400
2
14
60
67
10
257
4
15
62
62
11
30
10
11
82
7O
--
+
--
+
AI (OH)s plasma Serum
A1 ( O H ) a plasma
2"4
Serum
6'3 -4.0
V (38%) X , clot lysis in 5 M urea Thrombocytopenia
7.5 12
240
6
9
68
72
+
- -
+
--
Serum platelet
3.2
I X , PFa
5'0 13
360
4
10
82
2.0
85
N o abnormality
6'7 14
210
6
11
84
95
15
240
7
8
95
78
16
300
4
9
98
Ii '
- -
--
+
+
--
AI (OH)8
3"2
plasma platelet
7'5 3.4
95
N o abnormality V I I I , PF3
X I I I (Clot lysis in 5 M urea)
7.5 17
20
I0
8
I00
5O
--
+
Serum
2.45
IX;. thrombocytopema
7.45 18
19
50
270
I0
4
10
12
52
i
62
40
--
+
--
AI (OH)8 plasma
AI ( O H ) a plasma
2.4
V (20%); t h r o m bocytopenla
7.4 78
Serum
1.5
VII
i
5-1 20
99
8
10
100
80
i,
2" 3 7'3
Thrombocytopenia
584
HAEMOSTASIS IN KALA-AZAR
TABLE I I .
Relevant data on 3 patients with thrombocytopenla only Platelets 103/c.mm.
Bleeding time
Prothrombin consumption
7
75
8
77
11
30
10
70
99
8
80
Case No.
Bleeding manifestations
20
Epistaxis
TABLE I I I .
Relevant data on 5 patients with thrombocytopenia and other defects Other defects
Case
No.
Bleeding manifestations
1
2
Epistaxis
3
Platelets lOS/c.mm.
Bleeding time (rain.)
Prothrombin consumption
35
10
55
35
10
35
90
8
60
+ +
%
17
Epistaxis Purpura
20
10
60
18
Epistaxis
50
10
40
TABLE IV.
Casq
No, 2
Bleeding manifestations Epistaxis
Plasma prothrombin activity
%
47
One stage prothrombin time corrected by
+ +
+
(OH)
_•.A• --
10
62
+
52
-
62
+
Epistaxis
T G T defect in
plasma 3 Serum
60
19
TGT with cephalin
Relevant data on 5 patients with low plasma prothrombin activity
9
18
One stage prothrombin time
4-
+
Plas~ rla
Deficient factor VII
-
+
V (38%)
+
--
X
v (20%) VII
A. K. BASU, J. B. CHATTERJEA,P. C. SEN GUPTAAND A. M. MUKHERJEE TABLE V.
Relevant data on 10 patients showing defective thromboplastin generation and plasma prothrombin activity Plasma prothrombin activity
T G T defect in Cas, No,
585
Bleeding manifestations
%
Serum Plasma Platelets
1
3
One stage prothrombin Deficitime ency corrected by, of
72
VIII
--
92
V I I I , IX or XI
--
70
Do
--
AC
--
+
+
+
+
100 60 10
+
12
+
-
15
-
+
A1 (OH)3
62
I
L
plasma
V (38%)
Serum
X
+
72
IX, PFz
+
95
VIII (30%) PP3
17
Epistaxis Purpura
100
18
Epistaxis
52
TABLE VI.
IX
X A1 (OH)s plasma
v (20%)
Relevant data on 2 patients with de 3ressed factor X l I I
Clot lysis in 5M urea
Platelets 10S/c.mm.
Plasma prothrombin activity
TGT
10
Complete
450
62
Serum defect
16
Complete
300
98
Normal
Case No.
Bleeding manifestations
Marked deficiency of factor X I I I has been noted in persons suffering from various diseases including liver disease and leukaemia (NusBAUM and MORSE, 1964), but deficiency of factor X l I I in kala-azar has not been reported previously. It is interesting to note that in spite of multiple haemostatic defects, bleeding manifestations were found only in 6. Relevant data in these 6 patients are shown in Table VII. I n one (No. 13), there w a s n ° significant abnormality in platelets or coagulation factors. In the present series, there was no correlation between the observed coagulation defects, either with the bleeding manifestations or the serum protein pattern. Albumin levels in these patients ranged between 1.5 and 4-95 g. and globulin between 5-0 and 8.5 g. (Table I).
586
HAEMOSTASIS I N KALA-AZAR
TABLEVII.
Haemostatic profile in 6 patients with bleeding manifestations Plasma prothrombin activity
Case No.
Platelets 108/c.mm.
2
35
47
Normal
Epistaxis +
11
30
82
Normal
Epistaxis +
13
350
82
Normal
Purpura (scanty)
17
20
100
Serum defect
Epistaxis + Purpura +
18
50
52
Plasma defect
Epistaxis + +
20
99
70
Normal
Slight epistaxis
%
TGT
Degree and type of bleeding
d
Deficiency of
Number of patients
Platelets (Number)
8
PF3
2
V
2*
VII
2
VIII
4 (1)*
IX
4
X
1
XI
2
TABLEVIII. A summary of abnormalities in different haemostatic parameters, singly or in combination
XIII *Confirmed by assay **Complete clot lysis in 5M urea The exact cause of the deficiency of coagulation factors in kala-azar is not known, but it is unlikely to be secondary to hepatic dysfunction alone. I n kala-azar, there is obviously a gross derangement of protein synthesis, manifested by hypoalbuminaemia and marked hypergamma-globulinaemia which sometimes assume serious proportions (SEN GUPTA et al, 1953). Macroglobulins have also been demonstrated (SEN Gm'TA, 1965). Depression of essential coagulation factors is possibly related to an aberrant system of protein synthesis by which abnormal proteins are elaborated at the cost of normal proteins. This is probably mediated by the impact of LeishmanDonovan bodies on the reticulo-endothelial system. These abnormal proteins may possibly interfere with the functional efficiency of the platelets and available coagulation factors. But there are cases of kala-azar showing abnormal proteins but no haemorrhage or coagulation defect (cases No. 4, 5, 13, 14).
A. K. BASU, J. B. CHATTERJEA, P. C. SEN GUPTA AND A. M. MUKHERJEE
587
Summary 20 patients with kala-azar were studied to evaluate their haemostatic status. 16 showed significant abnormality. In 11 multiple haemostatic defects were present. Thrombocytopenia alone or in combination with other defects, was noted in 8. Onestage prothrombin time, and/or thromboplastin generation test showed patterns resembling deficiency of factors V, VII, V I I I , IX, X, XI and platelet factor 3. Deficiency of factor V was confirmed in 2 and that of factor V I I I in one. Deficiency of factor X I I I was noted in 2. Repeat studies, after recovery from kala-azar, were done in 8. In 7 of these the tests had become normal and in the eighth, marked improvement was noticed. REFERENCES BASU, A. K., SEN GUPTA,P. C. & CHATTERJEA,J. B. (1967). Bull. Calcutta Sch. trop. Med., 15, 45. BIGGS, R. & DOUGLAS,A. S. (1953). ft. clin. Path., 6, 23. CI-IAKRAVARTY,N. K. (1947). The Adrenocortical mid Hepatic Dysfunction in Kala-azar and their Role in the Morbid Process of the Disease. Thesis for M.D. Calcutta University. , SEN GUPTA, P. C., BOSE, J. P. & DE, U. N. (1949). Indian ft. reed. Res., 37, 113. DAMESHEK, W. (1932). Arch. intern. Med., 50, 579. DENSON, K. W. E. (1966a). In Treatment of Haemophilia and other Coagulation Disorders, p. 350-368. Oxford: Blackwell Scientific Publications. (1966b). Ibid., p. 373. IvY, A. C., NELSON, D. & BUCHER, G. (1940). J. Lab. clin. Med., 26, 1812. LEE, R. I. & WHITE, P. D. (1913). Am. ft. reed. Sci., 14.5, 495. NORMAN, J. C., COVELLI,V. H. & SISE, H. S. (1968). Ann. intern. Med., 78, 700. NOSBAIIM, M. & MORSE, B. S. (1964). Blood, 23, 669. QUICK, A. J. (1938). ft. Am. reed. Ass., 110, 1658. - (1966). Am. J. clin. Path., 45, 105. ROGERS, L. (1908). Fevers in the Tropics. London: Henry Frowde, Hodder & Stoughton. SEN GUPTA, P. C. (1948). Researches on Kala-azar in India, 1938-48. Proc. 4th lnt. Congr. trop. Med. Malar., Washington, D.C. (1960). In A Handbook of Tropical Diseases, by J. C. Banerjea and P. B. Bhattacharya, p. 110-111. Calcutta: Academic Publishers. - (1965). Parassitologia, 7, 1. , RAo, S. S., LAHIRI, D. C. & BHATTACHARYYA,B. (1953). ft. Indian reed. Ass., 22, 433.
HAEMOSTASIS IN KALA-AZAR* A. K. BASU, J. B. CHATTERJEA, P. C. SEN G U P T A AND A. M. MUKHERJEE
Departments of Haematology and Pathology, School of Tropical Medicine, Calcutta, India Haemorrhagic manifestations are not infrequent in kala-azar (ROGERS, 1908). Varying grades of thrombocytopenia and deficiency of coagulation factors, V and X, were noted in 5 out of 7 patients with kala-azar (BAso et al, 1967). Bleeding manifestations were, however, present in only 2 of these patients. In the present communication, the results of detailed haemostatic investigations carried out in a larger series of patients are recorded.
Materials and methods The subjects of the study consisted of 20 in-patients in the Carmichael Hospital for Tropical Diseases, Calcutta. Diagnosis of kala-azar was confirmed in each case by the demonstration of Leishman-Donovan bodies either in the bone marrow and/or the splenic smear. Tests performed for evaluating the haemostatic status included the following: 1. Platelet count by indirect method (modified from DAMESHEK,1932). 2. Bleeding time (IvY et al., 1940) 3. Whole blood clotting time (LEE and WHITE, 1913). 4. One-stage plasma prothrombin time (QuicK, 1938). 5. Prothrombin consumption test as described by QUICK(1966). 6. Thromboplastin generation test (TGT) according to the method of BIGGS and DOUGLAS (1953). 7. Factor V and factor V I I I assay as described by DENSON (1966a). 8. Assessment of factor X l I I as described by DENSON (1966b).
Results A summary of relevant findings in individual patients is shown in Table I. All the tests were completely normal in 4 of the 20 subjects. Thrombocytopenla was present in 8. In 3 thrombocytopenla was the only abnormality with bleeding time ranging from 8 to 11 minutes; the platelet count in these varied from 60,000 to 99,000 per c.mm. (Table II). Thrombocytopenia was associated with other defects in 5 patients; bleeding time in these ranged from 8 to 10 minutes (Table III). Quick's one-stage prothrombin time was prolonged in 5 patients with plasma prothrombin activity ranging from 47 to 62% (Table IV). The prolonged one-stage prothrombin time could be corrected by normal serum in 3 (Nos. 2, 10 and 19). In the other 2, only fresh aluminium hydroxide-treated plasma had a corrective effect (Nos. 9 and 18). The T G T was abnormal in 3 of these 5 patients with low plasma prothrombin activity. Abnormality in T G T was due to plasma factors in 2 (Nos. 9 and 18) and to serum factors in one (No. 10). *Adapted from a paper presented at the X I I International Congress of the International Society of Haematology held in New York in September, 1968.
582
HAEMOSTASIS I N KALA-AZAR
In addition to the above 3, the T G T was also abnormal in 7 others (Table V). 2 had a serum defect (Nos. 8 and 17), 2 both plasma and serum defect (Nos. 3 and 4) and one (No. 1) plasma defect. Platelet suspensions from 2 others (Nos. 12 and 15) could not generate normal amounts of thromboplastin, when used with normal aluminium hydroxide adsorbed plasma and normal serum in the T G T . One of them (No. 12) also showed a serum defect, while the other (No. 15) showed a plasma defect. The Ivy bleeding time was borderline in the latter patient. Assay of individual coagulation factors was not done in all cases. The level of factor VIII and V was estimated in 3 patients only. Factor VIII activity was 30% of normal in No. 15 and the level of factor V was 38 and 25% respectively in Nos. 9 and 18. Assessment of factor XIII activity was made in 5; deficiency was noted in 2 cases (Table VI). One of these (No. 10) had also a prolonged one-stage prothrombin time and a serum defect in the T G T . In the other (No. 16), there was no other abnormality except deficiency of factor XIII. The tests were repeated in 8 patients after recovery from kala-azar. In 7, the repeat studies were completely normal. In the eighth, improvement was noted in plasma prothrombin activity but the T G T was still abnormal. The haemostatic pattern in 6 patients with bleeding manifestations is shown in Table VII. Abnormality of individual haemostatic parameters as noted singly or in combination is shown in Table VIII. Discussion Apart from reports of thrombocytopenia and prolonged one-stage prothrombin time, no significant abnormality in haemostatic mechanisms appears to have been recorded by previous workers (CHAr~V~TY, 1947; CHAK~VARTY et al., 1949; SFN GUPTA; 1948, 1960). In an earlier communication, deficiency of factors V and X was recorded by us (B~u et al, loc. cir..). In the present series 16 of 20 patients had a haemostatic abnormality, the majority of the cases showing multiple defects. Thrombocytopenia was present in half of these 16 patients, either singly or in association with other defects. The bleeding time in these patients was prolonged disproportionately to the degree of thrombocytopenia. The capillary resistance test was, however, normal in all. Assay of individual coagulation factors was not done except in 3 patients in whom the levels of factors V and VIII were determined. Factor V was deficient in 2 and factor VIII in one. In all other patients, except the 2 with factor XIII deficiency, deficiency in coagulation factors, as reported here, was presumptive, being based on the correction of the one-stage prothrombin time and T G T . Most of the coagulation factors are known to be synthesized in the liver and kalaazar is known to be associated with marked hepatic dysfunction (CH~mgnv~m~: et al., 1949). The site of production of factor VIII is still a controversial issue. Recent experiments suggest that factor VIII is probably synthesized in the reticulo-endothelial cells (NORMAN et al, 1968). The low level of factor VIII in one patient of the present series and probable deficiency of this factor in 3 other patients may be due to the extensive involvement of the reticulo-endothelial system in kala-azar. It should, however, be mentioned that only 4 out of 20 cases of kala-azar showed deficiency of factor VIII though hyperplasia and parasitization of reticulo-endothelial cells occur in all cases of the disease. Although acquired deficiency of factor VIII has been reported in a number of systemic diseases, viz., leukaemia, cirrhosis of liver, systemic lupus erythematosus, no record of factor VIII deficiency in kala-azar is recorded in the literature.
A. K. BASU, J. B. C H A T T E R J E A , P . C. SEN G U P T A A N D A. M . M U K H E R J E E
TABLE I.
.~]
.-~
Z¢~
"~ z ~
~.~ e~
~
~' ~.~
Haemostatic data on 20 cases of kala-azar
~
~ =
TGTindefect
~'~
ii
~
×
~ ~
35
10
12
~ ~
thrombin time
TGT
o ~
~ ~ 1
m
72
55
583
--
+
--
Corrected by Serum
AI (OH)a plasma
Albumin Globulin (in g. %)
Deficient factor
3 '2
V I I I ;. t h r o m b o c y topema
5'9 2
35
10
ii
47
35
4"45
Serum
V I I ; thrombocytopenia
6"65 3
4
90
300
8
3
10
I0
90
60
100
+
+
--
--
Serum AI ( O H ) s plasma
82
2"45
V I I I and I X or X I thrombocytopenia
8'50 3" 2
N o abnormality
7'6 5
225
2
7
100
82
2" 05
N o abnormality
6"50
6
270
4
7
75
8
8
325
5
14
74
62
8
78
97
14
100
75
+
+
--
+
--
Serum AI (OH)3 plasma
--
Serum
--
VIII,
--
Thrombocytopenia
1 "8
IX, XI
IX
7.7 9
400
2
14
60
67
10
257
4
15
62
62
11
30
10
11
82
7O
--
+
--
+
AI (OH)s plasma Serum
A1 ( O H ) a plasma
2"4
Serum
6'3 -4.0
V (38%) X , clot lysis in 5 M urea Thrombocytopenia
7.5 12
240
6
9
68
72
+
- -
+
--
Serum platelet
3.2
I X , PFa
5'0 13
360
4
10
82
2.0
85
N o abnormality
6'7 14
210
6
11
84
95
15
240
7
8
95
78
16
300
4
9
98
Ii '
- -
--
+
+
--
AI (OH)8
3"2
plasma platelet
7'5 3.4
95
N o abnormality V I I I , PF3
X I I I (Clot lysis in 5 M urea)
7.5 17
20
I0
8
I00
5O
--
+
Serum
2.45
IX;. thrombocytopema
7.45 18
19
50
270
I0
4
10
12
52
i
62
40
--
+
--
AI (OH)8 plasma
AI ( O H ) a plasma
2.4
V (20%); t h r o m bocytopenla
7.4 78
Serum
1.5
VII
i
5-1 20
99
8
10
100
80
i,
2" 3 7'3
Thrombocytopenia
584
HAEMOSTASIS IN KALA-AZAR
TABLE I I .
Relevant data on 3 patients with thrombocytopenla only Platelets 103/c.mm.
Bleeding time
Prothrombin consumption
7
75
8
77
11
30
10
70
99
8
80
Case No.
Bleeding manifestations
20
Epistaxis
TABLE I I I .
Relevant data on 5 patients with thrombocytopenia and other defects Other defects
Case
No.
Bleeding manifestations
1
2
Epistaxis
3
Platelets lOS/c.mm.
Bleeding time (rain.)
Prothrombin consumption
35
10
55
35
10
35
90
8
60
+ +
%
17
Epistaxis Purpura
20
10
60
18
Epistaxis
50
10
40
TABLE IV.
Casq
No, 2
Bleeding manifestations Epistaxis
Plasma prothrombin activity
%
47
One stage prothrombin time corrected by
+ +
+
(OH)
_•.A• --
10
62
+
52
-
62
+
Epistaxis
T G T defect in
plasma 3 Serum
60
19
TGT with cephalin
Relevant data on 5 patients with low plasma prothrombin activity
9
18
One stage prothrombin time
4-
+
Plas~ rla
Deficient factor VII
-
+
V (38%)
+
--
X
v (20%) VII
A. K. BASU, J. B. CHATTERJEA,P. C. SEN GUPTAAND A. M. MUKHERJEE TABLE V.
Relevant data on 10 patients showing defective thromboplastin generation and plasma prothrombin activity Plasma prothrombin activity
T G T defect in Cas, No,
585
Bleeding manifestations
%
Serum Plasma Platelets
1
3
One stage prothrombin Deficitime ency corrected by, of
72
VIII
--
92
V I I I , IX or XI
--
70
Do
--
AC
--
+
+
+
+
100 60 10
+
12
+
-
15
-
+
A1 (OH)3
62
I
L
plasma
V (38%)
Serum
X
+
72
IX, PFz
+
95
VIII (30%) PP3
17
Epistaxis Purpura
100
18
Epistaxis
52
TABLE VI.
IX
X A1 (OH)s plasma
v (20%)
Relevant data on 2 patients with de 3ressed factor X l I I
Clot lysis in 5M urea
Platelets 10S/c.mm.
Plasma prothrombin activity
TGT
10
Complete
450
62
Serum defect
16
Complete
300
98
Normal
Case No.
Bleeding manifestations
Marked deficiency of factor X I I I has been noted in persons suffering from various diseases including liver disease and leukaemia (NusBAUM and MORSE, 1964), but deficiency of factor X l I I in kala-azar has not been reported previously. It is interesting to note that in spite of multiple haemostatic defects, bleeding manifestations were found only in 6. Relevant data in these 6 patients are shown in Table VII. I n one (No. 13), there w a s n ° significant abnormality in platelets or coagulation factors. In the present series, there was no correlation between the observed coagulation defects, either with the bleeding manifestations or the serum protein pattern. Albumin levels in these patients ranged between 1.5 and 4-95 g. and globulin between 5-0 and 8.5 g. (Table I).
586
HAEMOSTASIS I N KALA-AZAR
TABLEVII.
Haemostatic profile in 6 patients with bleeding manifestations Plasma prothrombin activity
Case No.
Platelets 108/c.mm.
2
35
47
Normal
Epistaxis +
11
30
82
Normal
Epistaxis +
13
350
82
Normal
Purpura (scanty)
17
20
100
Serum defect
Epistaxis + Purpura +
18
50
52
Plasma defect
Epistaxis + +
20
99
70
Normal
Slight epistaxis
%
TGT
Degree and type of bleeding
d
Deficiency of
Number of patients
Platelets (Number)
8
PF3
2
V
2*
VII
2
VIII
4 (1)*
IX
4
X
1
XI
2
TABLEVIII. A summary of abnormalities in different haemostatic parameters, singly or in combination
XIII *Confirmed by assay **Complete clot lysis in 5M urea The exact cause of the deficiency of coagulation factors in kala-azar is not known, but it is unlikely to be secondary to hepatic dysfunction alone. I n kala-azar, there is obviously a gross derangement of protein synthesis, manifested by hypoalbuminaemia and marked hypergamma-globulinaemia which sometimes assume serious proportions (SEN GUPTA et al, 1953). Macroglobulins have also been demonstrated (SEN Gm'TA, 1965). Depression of essential coagulation factors is possibly related to an aberrant system of protein synthesis by which abnormal proteins are elaborated at the cost of normal proteins. This is probably mediated by the impact of LeishmanDonovan bodies on the reticulo-endothelial system. These abnormal proteins may possibly interfere with the functional efficiency of the platelets and available coagulation factors. But there are cases of kala-azar showing abnormal proteins but no haemorrhage or coagulation defect (cases No. 4, 5, 13, 14).
A. K. BASU, J. B. CHATTERJEA, P. C. SEN GUPTA AND A. M. MUKHERJEE
587
Summary 20 patients with kala-azar were studied to evaluate their haemostatic status. 16 showed significant abnormality. In 11 multiple haemostatic defects were present. Thrombocytopenia alone or in combination with other defects, was noted in 8. Onestage prothrombin time, and/or thromboplastin generation test showed patterns resembling deficiency of factors V, VII, V I I I , IX, X, XI and platelet factor 3. Deficiency of factor V was confirmed in 2 and that of factor V I I I in one. Deficiency of factor X I I I was noted in 2. Repeat studies, after recovery from kala-azar, were done in 8. In 7 of these the tests had become normal and in the eighth, marked improvement was noticed. REFERENCES BASU, A. K., SEN GUPTA,P. C. & CHATTERJEA,J. B. (1967). Bull. Calcutta Sch. trop. Med., 15, 45. BIGGS, R. & DOUGLAS,A. S. (1953). ft. clin. Path., 6, 23. CI-IAKRAVARTY,N. K. (1947). The Adrenocortical mid Hepatic Dysfunction in Kala-azar and their Role in the Morbid Process of the Disease. Thesis for M.D. Calcutta University. , SEN GUPTA, P. C., BOSE, J. P. & DE, U. N. (1949). Indian ft. reed. Res., 37, 113. DAMESHEK, W. (1932). Arch. intern. Med., 50, 579. DENSON, K. W. E. (1966a). In Treatment of Haemophilia and other Coagulation Disorders, p. 350-368. Oxford: Blackwell Scientific Publications. (1966b). Ibid., p. 373. IvY, A. C., NELSON, D. & BUCHER, G. (1940). J. Lab. clin. Med., 26, 1812. LEE, R. I. & WHITE, P. D. (1913). Am. ft. reed. Sci., 14.5, 495. NORMAN, J. C., COVELLI,V. H. & SISE, H. S. (1968). Ann. intern. Med., 78, 700. NOSBAIIM, M. & MORSE, B. S. (1964). Blood, 23, 669. QUICK, A. J. (1938). ft. Am. reed. Ass., 110, 1658. - (1966). Am. J. clin. Path., 45, 105. ROGERS, L. (1908). Fevers in the Tropics. London: Henry Frowde, Hodder & Stoughton. SEN GUPTA, P. C. (1948). Researches on Kala-azar in India, 1938-48. Proc. 4th lnt. Congr. trop. Med. Malar., Washington, D.C. (1960). In A Handbook of Tropical Diseases, by J. C. Banerjea and P. B. Bhattacharya, p. 110-111. Calcutta: Academic Publishers. - (1965). Parassitologia, 7, 1. , RAo, S. S., LAHIRI, D. C. & BHATTACHARYYA,B. (1953). ft. Indian reed. Ass., 22, 433.