Journal of Postgraduate Medicine
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Year : 1981  |  Volume : 27  |  Issue : 2  |  Page : 109-15  

Platelet function and blood coagulation in tetanus.

SR Manikeri, NA Kshirsagar, SM Karandikar, FD Dastur, VV Awatramani, JJ Shah, JM Shah 

Correspondence Address:
S R Manikeri

How to cite this article:
Manikeri S R, Kshirsagar N A, Karandikar S M, Dastur F D, Awatramani V V, Shah J J, Shah J M. Platelet function and blood coagulation in tetanus. J Postgrad Med 1981;27:109-15

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Manikeri S R, Kshirsagar N A, Karandikar S M, Dastur F D, Awatramani V V, Shah J J, Shah J M. Platelet function and blood coagulation in tetanus. J Postgrad Med [serial online] 1981 [cited 2022 Jun 28 ];27:109-15
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Tetanus toxin blocks the synaptic transmission of inhibitory impulses within the central nervous system. The resulting disinhibition of neurones affects both the somatic and autonomic nervous systems. In the latter case, it serves to generate excessive sympathetic discharge.[8], [12], [13] In the former at critical sites such as the hypothalamus it alters impulse traffic to the pituitary.[14] Autonomic and endocrine functions are disturbed and multiple body systems are affected.

High concentrations of tetanus toxin produce microthrombi and perivascular haemorrhages in tissues of experimental animals early in the course of tetanus. Similar changes have been seen in the spinal cords of dogs dying of severe tetanus[19] and in a few human autopsies.[8] Patients of severe tetanus treated by total paralysis and assisted ventilation have been routinely anticoagulated because of the high risk of venous thrombosis and fatal pulmonary embolism.[16] These data have led us to study platelet function and blood coagulation in tetanus to define their role in the natural history of the disease.


Thirteen cases of tetanus aged between 18 and 50 years were studied; 9 were males and 4 females. The severity of the disease was documented by a score system,[17] first on admission and subsequently at 24 hour intervals [Table 1]. Six patients had severe tetanus, six moderate, and one mild. Therapy consisted of wound toilet, benzathine penicillin 1,200,000 units, antitetanus serum (horse A.T.S.) 10,000 I.U. and diazepam upto a maximum dose of 15 mg/kg/24 hours. Five patients had received 1 dose of tetanus toxoid prior to hospitalization buy none had a history of adequate active immunization against tetanus. Tracheostomy was performed, when required, to maintain a patent airway, and appropriate antibiotics used for any complicating infection. Nasogastric feeds given to severe cases provided 2000 calories and 70 grammes of protein. Two cases proved fatal. Blood samples were collected on admission, and each day thereafter if the disease was severe, but less frequently once the patient improved. Hess' test was performed at the peak of the disease.

Platelet count[4] (whole plasma), platelet aggregation,[3] and platelet adhesiveness [15] were determined using platelet rich plasma (PRP), while platelet poor plasma (PPP) was used for the following blood coagulation tests: prothrombin timers partial thromboplastin time, thrombin time,[2] euglobulin clot lysis time[6] and plasma fibrinogen[9] level.

Platelet aggregation was studied using Payton Aggregation Module. Adenosine diphosphate (ADP), epinephrine (E) and collagen (C) were used as aggregating agents.

The effect of drugs generally used in the therapy of tetanus (diazepam, tubocurarine, gentamicin, penicillin, chloramphenicol, streptomycin and tetanus antitoxin) on platelets was studied in vitro on PEP obtained from healthy volunteers. The effect of tetanus toxin-antitoxin combination was also studied.

Different concentrations of all these drugs in a volume of 0.1 ml were added to 0.8 ml PRP and incubated at 370C for one minute with continuous stirring. At the end of 1 minute the effect was studied on ADP induced platelet aggregation.

For the patient studies, platelet aggregation is expressed as per cent aggregation, normal range being 30-60%; for in vitro studies, the changes are expressed as per cent inhibition of aggregation, with aggregation in the control plasma expressed as 100% aggregation.


Platelet function tests were abnormal to a greater degree and more often than the coagulation tests. [Table 2] gives the results of platelet tests on the day of maximum severity of the disease in each patient.

There was a statistically significant correlation between disease severity (score) and inhibition of platelet aggregation and adhesiveness (ADP: p < 0.05; E: p < 0.001; C: p < 0.001; Adhesiveness: p < 0.01; r values: -0.371, -0.535, -0.526 and -0.430 respectively). Collagen induced aggregation was completely inhibited in patients with score 8-20 and that by E and ADP was inhibited in some patients. Relation of severity of disease (score) to inhibition of platelet aggregation was even more evident when platelet function throughout the course of disease was studied. [Figs. 1] and [Fig. 2] give details of platelet aggregation tests in 2 patients as an example. Inhibition of aggregation and adhesiveness occurred when the score was maximum and such inhibition was irrespective of the duration of drug treatment. Platelet aggregation and adhesiveness were above normal at the onset of the disease and during the recovery phase. Patient number severe-6 expired on the 2nd day. Platelet aggregation and adhesiveness were normal on day 1 despite the score of 20. Coagulation tests were normal except for prolonged PT (25-27 sets) in some patients [Table 2]. Some additional features regarding complications and additional treatment are given in [Table 2]. Results of the in vitro studies with drugs, toxin and antitoxin are given in [Table 3]. Toxin and antitoxin were found to impair platelet aggregation in a concentration dependent manner. Addition of toxin and antitoxin together in that order did not alter the inhibited response, whilst when introduced in the reverse order, there was an enhancement of the inhibitory response. Diazepam was found to impair platelet aggregation in therapeutic concentration.


Tests for coagulation factors and the integrity of the blood vessel wall were normal in almost all patients. Platelet aggregation to collagen and aggregation to E and ADP in some patients were often completely inhibited at the peak of disease, whilst at the onset and during recovery they were above normal. A number of factors could have contributed to these changes in platelets.

The receptors for tetanus toxin are membrane glycolipids which chemically belong to the family of gangliosides. They have a precise chemistry (GGn/S/ SLC) and (S/GGn S/SLC)*. These gangliosides bind toxin maximally, and possess the common structural feature in the sugar moiety of two sialic acid residues linked together but distinct from any terminally situated sialic acid. Toxin receptors are largely confined to the neural tissues.[20] Platelets also contain small amounts of gangliosides in their membranes but these are chemically different.[7] It is unlikely, therefore, that the toxin acts significantly on platelet membranes. Furthermore, platelet function is maximally disturbed at the height of disease at a time when toxin is absent in the circulation and is bound irreversibly to the neural tissue. This supports the contention that no direct interaction between toxin and platelet membranes occurs.

Depressed platelet function is more likely the consequence of toxin acting through the nervous system. Excessive sympathetic discharge could well explain the increase in platelet activity at the onset and in the recovery phase of the disease. 5-Hydroxytryptamine and epinephrine levels have been measured in tetanus and are significantly elevated.[17] Despite this, platelet function at the peak of disease is depressed which does not fit neatly into any known drug or disease induced abnormalities e.g. inhibition of release reaction.[11]

Severe tetanus is complicated by other factors such as the stress of illness, muscles spasms, hyperventilation, hypoxia and secondary pulmonary infection. It is not known exactly how these factors either singly or in combination affect the platelet function. Mental stress has been claimed to inhibit platelet aggregation.[1] Hyperventilation and muscle spasm increase PGI2 levels which inhibit platelet aggregation.[10] However PGI: has a half life of only 2 to 3 minutes,[10] The enhanced effect of antitoxin-toxin combination in the in vitro tests could be through a mechanism similar to that occurring in macroglobulinemia. Any effect of toxin directly on platelets is more difficult to explain.

Depression of platelet function correlated far better with the clinical severity of disease than with the duration of any of the drugs used. Hence whilst drugs could have contributed to the findings they were not the important factors.

As mentioned before, coagulation tests were almost all normal. Prolonged P.T. in some patients seen at the peak of the disease was related to the inhibition of platelet aggregation since platelet factor III is required for conversion of factor X to Xa in the coagulation sequence.

In conclusion, factors leading to platelet changes in tetanus must remain largely speculative. The findings of these platelet abnormalities are, however, important and may relate to the microcirculatory changes, already referred to, in severe tetanus.


We are thankful to M/s. Burroughs Wellcome India Ltd., Bombay for the gift of tetanus toxin vials.

We thank the Dean, Seth G.S. Medical College and K.E.M. Hospital, Bombay, for permitting us to carry out this study.


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