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Megakaryocytes and Platelets
202
T
Our immediate criticism is not so much of the main difficulty lies in diagnosis. It is curious that all to as the modern advances in the treatment of occlusion exercise some central control of attempt crudity in the present arrangements with their reliance and strangulation-suction drainage, antibiotics, and on the simple rule of uniformity. The hospital services intravenous therapy-are directed to overcoming are vast and complex, and the complexity will have to the late features of the obstruction. There is no need be matched in the arrangements made. If you have for them in the great majority of early occlusions an extensive railway system it is necessary to have and strangulations.. Early diagnosis permits safe and a Bradshaw, and the Bradshaw must take accountspeedy surgery on a patient whose physiology is of the gradients of every little branch line. It is no still nearly normal. It is failure on the part either of use to say " we shall assume that all trains run at the the patient to summon medical aid or of the doctor It is no use to say " we same speed everywhere." to achieve a diagnosis that provides the case in shall leave it to each little line to settle matters for which the correct use of modern aids makes the itself." Nor, where hospitals are concerned, is it difference between life and death. The patient is wise to say " we shall assume that everything that often responsible for delay, but doctors still some. is called a hospital is equal to everything else that is times miss strangulated inguinal hernias because they - called a hospital, and anyone working in one hospital have not looked for them, or, with more excuse, mustbe paid just the same as someone working in internal obstructions because they could feel no another "-just because they happen to be graded to fall lumps. To watch a patient with severe colicky pain into the same categories in discussions which set out in the abdomen and vomiting until he shows dis. to discover minima for the various groups. tension, dehydration, shock, and signs of infection is to wait dangerously long. Any patient in whom the symptoms give reasonable ground for suspecting Obstruction obstruction needs to be in hospital. There, doubts OBSTRUCTION of the small intestine is of three main can often be dispelled by a plain X-ray film of the types, which may to some extent overlap. It may be abdomen to reveal distended coils of bowel which an ileus, where the fault lies in the propulsive mechaare not clinically obvious. nism of the gut and no organic obstruction is present ; The patient reaching hospital with a late obstruction it may be an occlusion of the lumen of the bowel ; offers a pretty problem to the surgeon if the cause is or it may be a strangulation, when cessation of the not clear. If there is a tender irreducible hernia, all blood-supply to a segment of the bowel overshadows is reasonably plain sailing. But if the only abnormal in importance the probable concomitant occlusion is a distended abdomen it is difficult to of the lumen. The distinction between these three physical sign know whether to wait, so that suction and intramain classes of obstruction has become of cardinal venous medication can make-the with a bowel importance in the past few years because continuous occlusion safe for surgery, or patient whether to operate gastro- intestinal suction has been shown to be at once and not prejudice the chances of a patient astonishingly successful in the right type of case with an internal strangulation. Two points are but dangerous in the wrong type. In ileus gastroof some help in these circumstances. Localised intestinal suction is the correct and usually the only tenderness in the abdomen, with rebound tenderness, treatment needed-it goes almost without saying indicates infection and therefore strangulation ; and that the water and chlorides removed must be replaced abdominal pain continuing after an hour. or two of intravenously. In occlusion of the bowel lumen gastro-intestinal suction shows that the pain is not due suction is a valuable and often life-saving part of the to colicky contractions of the intestine but to somepreparation for operation ; it may be prolonged and thing else-probably a strangulation. COLLER and occasionally may by itself relieve the occlusion. But BUXTON,2 in reviewing 198 small-bowel obstructions, in strangulation suction is a highly dangerous form contend that even in occlusion operation is indicated of treatment if prolonged for more than the time as soon as possible. They record three cases in which needed to empty the upper reaches of the alimentary suction drainage relieved the symptoms but the tract and so prevent the patient drowning in his bowel perforated at the site of an occluding carcinoma. vomit during induction of the anaesthetic. In in attempts to get a MillerTheir success-rate of strangulation no amount of suction can prevent Abbott tube past the68% will be envied those pylorus organisms and plasma escaping through a dying who have often had to be content with gastricbysuction bowel wall, or stop arterial blood being pumped into because a long tube could not be induced to go a capillary bed from which there is no venous return. further. They found that peritonitis was the comThe sooner this migration of the right things to monest cause of death, and they emphasise again the wrong places is checked by operation the better that early diagnosis is the key to lowered mortality. the patient’s chances. AiRD, who has so lucidly interpreted for surgeons the original work of himself and Platelets and others, has said : " In some quarters the has of IN the early days introduction of suction drainage given a fall haematology almost every in the fatality-rate of occlusion but a rise in that blood-cell was proposed by someone as the mother of strangulation, operation in the latter condition cell of the platelets. In 1906 J. H. WRIGHT contended failure to that sometimes being dangerously delayed by blood-platelets are formed from the cytoplasm it from occlusion." of distinguish megakaryocytes, the giant granular cells of the The principles of treatment for small-bowel obstrucbone-marrow ; he suggested that these cells push tions are easy to understand. Apart from ileus, pseudopodia into the lumen of blood-vessels, and whose cause and presence are usually obvious, the when the pseudopodia break off the fragments form
Small-gut
Megakaryocytes
1
Aird, I.
A
Companion in Surgical Studies. Edinburgh, 1949.
2. Coller, F. A.,
Buxton, R. W. J.
Amer. med. Ass.
1949, 140, 135.
203
This theory has since held the field against all attacks and has recently been confirmed again by SALTZMANin Sweden and SCHWARZ2 in America. Using the dark-ground illumination techniques applied by WALLGREN to ’the study of cytoplasmic structure, SALTZMAN found that the cytoplasm of megakaryocytes and the blood-platelets share some features of arrangement that are found only in these cells, and there are many other points of similarity that occur in few other bone-marrow and blood cells. No signs of life were recognised in the platelets ; the odd protrusions and blisters with granules in brownian movement appear to be quite unchanged by the addition of potassium cyanide to the preparations. SCHWARZ has studied the formation of granules in megakaryocytes. The typical megakaryocyte of bone-marrow, with a uniformly granular cytoplasm, originates from a smaller megakaryoblast that has non-granular cytoplasm. In the megakaryoblast and the next stage-the promegakaryocyte-a relatively pale zone appears in the cytoplasm next to the indentation in the nucleus ; it is within this area that the granules first appear. SCHWARZ calls this pale zone the " functional area," and, by studying many preparations from suitable bone-marrows, he has found that as the megakaryocyte develops, this functional area stains pinkish and the granules become blue; the area spreads as the cell develops until eventually it occupies the whole cytoplasm except3 DE LA FUENTE for a narrow peripheral rim. described a similar development, but he thought that granule formation began in several areas simultaneously. When the megakaryocyte divides, the functional area is not involved and remains unaltered in size and shape ; the nucleus appears to take no The megakaryocyte, part in granule formation. SCHWARZ points out, thus behaves like any other cell ’whose cytoplasm develops a specific functional transformation." It is only when the cytoplasm is fully granular that platelets are formed, by the breaking up of pseudopodia. SCHWARZ also discusses the appearances of the megakaryocyte in thrombocytopenic purpura, which is well known as a primary disease and also occurs as part of other syndromes such as aplastic anaemia. Splenectomy is effective treatment for most, though not all, of the primary cases but is useless in the secondary type. Since the blood-platelets are so much reduced in this form of purpura the megakaryocytes have naturally been carefully studied in the hope of finding a clue to the aetiology of the disease and explaining the occasional failures of Splenectomy.. SCHWARZ finds that the megakaryocytes usually look quite normal ; granule formation in the cytoplasm proceeds in the way described above. There is often hyperplasia of the megakaryocytes, and-exactly as with hyperplasia of other types of marrow cells-early forms are relatively increased. On the other hand, cases have been in which the megakaryocytes were reduced reported or even absent. In another group distinctly abnormal megakaryocytes have been found ; a recent example is the description by DAMESHEK and MILLER4 of odd megakaryocytes with non-granular cytoplasm that
platelets.
"
1. Saltzman, G.-F. Acta med. scand. 1949, 132, suppl. 221. 2. Schwarz, E. Arch. Path. 1948, 45, 333, 342. 3. De la Fuente, V. Arch. intern. Med. 1946, 79, 387. 4. Dameshek, W., Miller, E. B. Blood, 1946, 1, 27.
call " lymphoid forms." Differences of technique make comparison between different reporters difficult, but deficient granule formation is common to all. SCHWARZ examined the marrow from 26 patients with primary thrombocytopenic purpura and found deficient granule formation in only a single case. The early megakaryocytes of this patient had a functional area " that appeared and enlarged as in normal cells, but -no granules developed in the area. There thus seem to be three types of primary thrombocytopenic purpura:e (1) the common type with normal megakaryocytes, (2) a type in which granule formation fails, and (3) one in which the
they
"
megakaryocytes are degenerate or show cytotoxic changes. The second type, in particular, has had undue publicity, but ScgwAtz’s estimate that orilyabout 4% of patients show abnormal marrow pictures will surely be supported by anyone with experience in this difficult field. Consequently statements that splenectomy in thrombocytopenic purpura should if a characteristic marrow only be recommended 5 are is found premature. The knowledge that picture the clinical syndrome of thrombocytopenic purpura has a varied marrow picture may enable us to sort out those whom splenectomy is less likely to benefit, but the evidence has yet to be produced. Annotations ROYAL MEDICAL BENEVOLENT FUND ‘’
Letters of inquiry from medical men which reach the office from time to time lead the Committee to conclude that deserving cases fully entitled to relief fail to be directed to the Fund."
Mr. R. M.
Handfield-Jones,6 chairman of the committee management of the Royal Medical Benevolent Fund, reports that in spite of the efforts of the central office and the local secretaries, the ladies’ guild, and the British Medical Association, many doctors are still unaware of of
the work and scope of the Fund. How wide this scope is may be judged from the Fund’s " proud tradition for a great many years that no applicant, medical man or woman, wife, widow, or child, is refused assistance if the need is real." Moreover, it is not only subscribers, or the relatives of subscribers, who are entitled to apply for help : the Fund is ready to help the whole profession. At the case-committee meetings none of the members knows whether the applicant has been a subscriber or not. Those who have contributed regularly to the Fund realise this already ; but in order to explain the work of the Fund to the profession at large the annual report is this year being sent to every doctor in England, Scotland, and Wales. Since the little booklet is filled mainly with accounts, it does not take five minutes to glance through the four pages allotted to Mr. HandfieldJones. The information he packs into them has a. personal interest for us all, since as he says " an honourable and learned profession should be able to cope with its own casualties." He foresees many years of necessary work for the Fund, despite national insurance ; for even the most benevolent of national schemes cannot take account of all the ills that flesh is heir to, all the disasters which may overtake a doctor’s family when he is disabled or struck down. Mr. Handfield-Jones quotes two
characteristic of those which came before the aged doctor, infirm with failing vision, is to carry on practice to support an invalid wife ;
cases
Fund :
trying
an
5. Scott, R. B. Brit. med. J. 1949, i, 1063. Obtainable from the secretary, 6. Annual report, 1948. House, Manor Fields, Putney, London, S.W. 15.
1, Balliol
T
Our immediate criticism is not so much of the main difficulty lies in diagnosis. It is curious that all to as the modern advances in the treatment of occlusion exercise some central control of attempt crudity in the present arrangements with their reliance and strangulation-suction drainage, antibiotics, and on the simple rule of uniformity. The hospital services intravenous therapy-are directed to overcoming are vast and complex, and the complexity will have to the late features of the obstruction. There is no need be matched in the arrangements made. If you have for them in the great majority of early occlusions an extensive railway system it is necessary to have and strangulations.. Early diagnosis permits safe and a Bradshaw, and the Bradshaw must take accountspeedy surgery on a patient whose physiology is of the gradients of every little branch line. It is no still nearly normal. It is failure on the part either of use to say " we shall assume that all trains run at the the patient to summon medical aid or of the doctor It is no use to say " we same speed everywhere." to achieve a diagnosis that provides the case in shall leave it to each little line to settle matters for which the correct use of modern aids makes the itself." Nor, where hospitals are concerned, is it difference between life and death. The patient is wise to say " we shall assume that everything that often responsible for delay, but doctors still some. is called a hospital is equal to everything else that is times miss strangulated inguinal hernias because they - called a hospital, and anyone working in one hospital have not looked for them, or, with more excuse, mustbe paid just the same as someone working in internal obstructions because they could feel no another "-just because they happen to be graded to fall lumps. To watch a patient with severe colicky pain into the same categories in discussions which set out in the abdomen and vomiting until he shows dis. to discover minima for the various groups. tension, dehydration, shock, and signs of infection is to wait dangerously long. Any patient in whom the symptoms give reasonable ground for suspecting Obstruction obstruction needs to be in hospital. There, doubts OBSTRUCTION of the small intestine is of three main can often be dispelled by a plain X-ray film of the types, which may to some extent overlap. It may be abdomen to reveal distended coils of bowel which an ileus, where the fault lies in the propulsive mechaare not clinically obvious. nism of the gut and no organic obstruction is present ; The patient reaching hospital with a late obstruction it may be an occlusion of the lumen of the bowel ; offers a pretty problem to the surgeon if the cause is or it may be a strangulation, when cessation of the not clear. If there is a tender irreducible hernia, all blood-supply to a segment of the bowel overshadows is reasonably plain sailing. But if the only abnormal in importance the probable concomitant occlusion is a distended abdomen it is difficult to of the lumen. The distinction between these three physical sign know whether to wait, so that suction and intramain classes of obstruction has become of cardinal venous medication can make-the with a bowel importance in the past few years because continuous occlusion safe for surgery, or patient whether to operate gastro- intestinal suction has been shown to be at once and not prejudice the chances of a patient astonishingly successful in the right type of case with an internal strangulation. Two points are but dangerous in the wrong type. In ileus gastroof some help in these circumstances. Localised intestinal suction is the correct and usually the only tenderness in the abdomen, with rebound tenderness, treatment needed-it goes almost without saying indicates infection and therefore strangulation ; and that the water and chlorides removed must be replaced abdominal pain continuing after an hour. or two of intravenously. In occlusion of the bowel lumen gastro-intestinal suction shows that the pain is not due suction is a valuable and often life-saving part of the to colicky contractions of the intestine but to somepreparation for operation ; it may be prolonged and thing else-probably a strangulation. COLLER and occasionally may by itself relieve the occlusion. But BUXTON,2 in reviewing 198 small-bowel obstructions, in strangulation suction is a highly dangerous form contend that even in occlusion operation is indicated of treatment if prolonged for more than the time as soon as possible. They record three cases in which needed to empty the upper reaches of the alimentary suction drainage relieved the symptoms but the tract and so prevent the patient drowning in his bowel perforated at the site of an occluding carcinoma. vomit during induction of the anaesthetic. In in attempts to get a MillerTheir success-rate of strangulation no amount of suction can prevent Abbott tube past the68% will be envied those pylorus organisms and plasma escaping through a dying who have often had to be content with gastricbysuction bowel wall, or stop arterial blood being pumped into because a long tube could not be induced to go a capillary bed from which there is no venous return. further. They found that peritonitis was the comThe sooner this migration of the right things to monest cause of death, and they emphasise again the wrong places is checked by operation the better that early diagnosis is the key to lowered mortality. the patient’s chances. AiRD, who has so lucidly interpreted for surgeons the original work of himself and Platelets and others, has said : " In some quarters the has of IN the early days introduction of suction drainage given a fall haematology almost every in the fatality-rate of occlusion but a rise in that blood-cell was proposed by someone as the mother of strangulation, operation in the latter condition cell of the platelets. In 1906 J. H. WRIGHT contended failure to that sometimes being dangerously delayed by blood-platelets are formed from the cytoplasm it from occlusion." of distinguish megakaryocytes, the giant granular cells of the The principles of treatment for small-bowel obstrucbone-marrow ; he suggested that these cells push tions are easy to understand. Apart from ileus, pseudopodia into the lumen of blood-vessels, and whose cause and presence are usually obvious, the when the pseudopodia break off the fragments form
Small-gut
Megakaryocytes
1
Aird, I.
A
Companion in Surgical Studies. Edinburgh, 1949.
2. Coller, F. A.,
Buxton, R. W. J.
Amer. med. Ass.
1949, 140, 135.
203
This theory has since held the field against all attacks and has recently been confirmed again by SALTZMANin Sweden and SCHWARZ2 in America. Using the dark-ground illumination techniques applied by WALLGREN to ’the study of cytoplasmic structure, SALTZMAN found that the cytoplasm of megakaryocytes and the blood-platelets share some features of arrangement that are found only in these cells, and there are many other points of similarity that occur in few other bone-marrow and blood cells. No signs of life were recognised in the platelets ; the odd protrusions and blisters with granules in brownian movement appear to be quite unchanged by the addition of potassium cyanide to the preparations. SCHWARZ has studied the formation of granules in megakaryocytes. The typical megakaryocyte of bone-marrow, with a uniformly granular cytoplasm, originates from a smaller megakaryoblast that has non-granular cytoplasm. In the megakaryoblast and the next stage-the promegakaryocyte-a relatively pale zone appears in the cytoplasm next to the indentation in the nucleus ; it is within this area that the granules first appear. SCHWARZ calls this pale zone the " functional area," and, by studying many preparations from suitable bone-marrows, he has found that as the megakaryocyte develops, this functional area stains pinkish and the granules become blue; the area spreads as the cell develops until eventually it occupies the whole cytoplasm except3 DE LA FUENTE for a narrow peripheral rim. described a similar development, but he thought that granule formation began in several areas simultaneously. When the megakaryocyte divides, the functional area is not involved and remains unaltered in size and shape ; the nucleus appears to take no The megakaryocyte, part in granule formation. SCHWARZ points out, thus behaves like any other cell ’whose cytoplasm develops a specific functional transformation." It is only when the cytoplasm is fully granular that platelets are formed, by the breaking up of pseudopodia. SCHWARZ also discusses the appearances of the megakaryocyte in thrombocytopenic purpura, which is well known as a primary disease and also occurs as part of other syndromes such as aplastic anaemia. Splenectomy is effective treatment for most, though not all, of the primary cases but is useless in the secondary type. Since the blood-platelets are so much reduced in this form of purpura the megakaryocytes have naturally been carefully studied in the hope of finding a clue to the aetiology of the disease and explaining the occasional failures of Splenectomy.. SCHWARZ finds that the megakaryocytes usually look quite normal ; granule formation in the cytoplasm proceeds in the way described above. There is often hyperplasia of the megakaryocytes, and-exactly as with hyperplasia of other types of marrow cells-early forms are relatively increased. On the other hand, cases have been in which the megakaryocytes were reduced reported or even absent. In another group distinctly abnormal megakaryocytes have been found ; a recent example is the description by DAMESHEK and MILLER4 of odd megakaryocytes with non-granular cytoplasm that
platelets.
"
1. Saltzman, G.-F. Acta med. scand. 1949, 132, suppl. 221. 2. Schwarz, E. Arch. Path. 1948, 45, 333, 342. 3. De la Fuente, V. Arch. intern. Med. 1946, 79, 387. 4. Dameshek, W., Miller, E. B. Blood, 1946, 1, 27.
call " lymphoid forms." Differences of technique make comparison between different reporters difficult, but deficient granule formation is common to all. SCHWARZ examined the marrow from 26 patients with primary thrombocytopenic purpura and found deficient granule formation in only a single case. The early megakaryocytes of this patient had a functional area " that appeared and enlarged as in normal cells, but -no granules developed in the area. There thus seem to be three types of primary thrombocytopenic purpura:e (1) the common type with normal megakaryocytes, (2) a type in which granule formation fails, and (3) one in which the
they
"
megakaryocytes are degenerate or show cytotoxic changes. The second type, in particular, has had undue publicity, but ScgwAtz’s estimate that orilyabout 4% of patients show abnormal marrow pictures will surely be supported by anyone with experience in this difficult field. Consequently statements that splenectomy in thrombocytopenic purpura should if a characteristic marrow only be recommended 5 are is found premature. The knowledge that picture the clinical syndrome of thrombocytopenic purpura has a varied marrow picture may enable us to sort out those whom splenectomy is less likely to benefit, but the evidence has yet to be produced. Annotations ROYAL MEDICAL BENEVOLENT FUND ‘’
Letters of inquiry from medical men which reach the office from time to time lead the Committee to conclude that deserving cases fully entitled to relief fail to be directed to the Fund."
Mr. R. M.
Handfield-Jones,6 chairman of the committee management of the Royal Medical Benevolent Fund, reports that in spite of the efforts of the central office and the local secretaries, the ladies’ guild, and the British Medical Association, many doctors are still unaware of of
the work and scope of the Fund. How wide this scope is may be judged from the Fund’s " proud tradition for a great many years that no applicant, medical man or woman, wife, widow, or child, is refused assistance if the need is real." Moreover, it is not only subscribers, or the relatives of subscribers, who are entitled to apply for help : the Fund is ready to help the whole profession. At the case-committee meetings none of the members knows whether the applicant has been a subscriber or not. Those who have contributed regularly to the Fund realise this already ; but in order to explain the work of the Fund to the profession at large the annual report is this year being sent to every doctor in England, Scotland, and Wales. Since the little booklet is filled mainly with accounts, it does not take five minutes to glance through the four pages allotted to Mr. HandfieldJones. The information he packs into them has a. personal interest for us all, since as he says " an honourable and learned profession should be able to cope with its own casualties." He foresees many years of necessary work for the Fund, despite national insurance ; for even the most benevolent of national schemes cannot take account of all the ills that flesh is heir to, all the disasters which may overtake a doctor’s family when he is disabled or struck down. Mr. Handfield-Jones quotes two
characteristic of those which came before the aged doctor, infirm with failing vision, is to carry on practice to support an invalid wife ;
cases
Fund :
trying
an
5. Scott, R. B. Brit. med. J. 1949, i, 1063. Obtainable from the secretary, 6. Annual report, 1948. House, Manor Fields, Putney, London, S.W. 15.
1, Balliol