CS 1.1: There is a mild leucocytosis and neutrophilia, with a marginally raised ESR.
CS 1.2: The neutrophilia implies a bacterial infection, possibly a response to a chest infection. The sores are swabbed to see if they are infected which may also contribute to the neutrophilia. Another possible problem is of a pulmonary embolism, and this would have prompted the test for d-dimers. The chest X-ray is ordered to exclude fluid in the lungs or other pulmonary disease.
CS 1.3: The raised d-dimer does not make a diagnosis of a VTE, but neither can it be excluded as obesity, arthritis and age may all combine to give a high result. The immobility, obesity and inflammation (due to the arthritis and/or presumed chest infection) would all promote a VTE. The microbiology results suggest the possibility of early septicaemia, justifying the increased antibiotics and blood tests. The presence of these commensal organisms with a normal chest X-ray may point towards the sacral wounds being the source of the infection as opposed to a chest infection. The increases in the neutrophil count and ESR are no-table and also imply a worsening clinical picture.
CS 1.4: The Registrar is concerned of possible septicaemia (with a total white cell count 40% above the top of the reference range on Day 3) and needs to have the blood culture confirmed. The increased thirst and fluid intake (polydipsia) and high urine output (polyuria) may be a response to the high temperature, but equally may indicate diabetes, hence the haemoglobin A1c. Diabetes is a risk factor for increased infections, especially of the skin, as the consequences of the hyperglycaemia include microvascular damage which would impede the neutrophil recruitment needed to fight the local infection.
CS 1.5: The results from day 4 show an increased CRP, which is supportive of an on-going inflammatory process, and so does not add much to the diagnosis or management. The FBC reports a marginal reduction in the total white cell and neutrophils count (possibly reflecting the success of the antibiotics in countering the infection) and a slight reduction in the platelet count, the significance of which is unclear. Overall, the picture suggests an early septicaemia that may be suppressed by the intravenous antibiotics.
CS 1.6: The total white blood cell, neutrophil, monocyte and blasts/atypics have all increased, leading to fears that the infection is still active, hence the increase in antibiotics. The platelet count has fallen for the third day in succession. This is a concern, and will require checking and it is likely to be a real effect. Management will need to be stepped up. The continual discharge and erythema of the sacral wounds and the increased pain supports the worsening infection clinically. ESR is also climbing.
CS 1.7: This is not good. With rising white cells and CRP, the antibiotics are failing to address the septicaemia. A possible cause of the thrombocytopenia is the LMWH (i.e. heparin induced thrombocytopenia). Accordingly, the LMWH will need to be replaced with another anticoagulant, the most likely being a direct thrombin inhibitor such as argatroban. An alternative is one of the direct oral anticoagulants (DOACs) such as dabigatran. However, there is no formal guideline on the use of DOACs in this setting. The blood in the fluid from the sores may be relevant, as may the apparent reduction in production of urine. These may be significant as blood staining may represent impaired coagulation and reduced urine output may be as a result of reduced perfusion pressure due to systemic inflammatory response from her sepsis.
Day 7 (early)
CS 1.8: The increased bloody discharge from the sacral wound may reflect a potential haemorrhage, and the offensive smell a heavy bacterial infection. Thus, the clinical (sweating, temperature) and laboratory signs all point to the development of serious septicaemia. The appearance of metamyelocytes reflects increased granulocytopoiesis in the bone marrow as a consequence of the infection. The fall in platelets is also worrying and puts the patient at risk of haemorrhage. However, with the change in anti-coagulation this may resolve. Both clotting times are at the upper margin of the reference range. The haemoglobin has fallen, but this small drop may not be significant. The worsening markers of renal function may be harbingers of acute renal failure, quite likely secondary to the septicaemia.
Day 7 (late)
CS 1.9: The fall in haemoglobin is likely to reflect an internal haemorrhage, and with the abdominal discomfort this seems a probable site, given the pain. This may be intra-peritoneal or into the lumen of the intestine, and if the latter, may be confirmed by foecal occult blood testing. The coughing reflects increasing pulmonary disturbance (possibly because of an infection), and the nose bleed reflects the thrombocytopenia. Therefore, at increased risk of haemorrhage, anticoagulation is stopped, and the fear of further haemorrhage drives the call for a transfusion of platelets.
Day 8 (early morning)
CS 1.10: Ideally, the platelet transfusion should have corrected the platelet count, and it is very concerning that this has failed to occur, implying the ‘active’ consumption of platelets. The red cell indices continue to fall, and so fuels further fears of an internal haemorrhage. A red cell transfusion is needed and the clinical picture is becoming critical. The failure of the platelet transfusion to restore the platelet count implies they are being consumed, perhaps by the development of disseminated intravascular coagulation (DIC). Of further significance is the purpuric rash, a possible sign of systemic coagulopathy. Reduced consciousness may be the consequence of hypotension (failure to provide the brain with sufficient oxygen) or, at worse, may indicate an intracranial bleed.
Day 8 (afternoon)
CS 1.11: The patient is now seriously ill (falling blood pressure, oedema, increasing pulse rate) with definite septicaemia and other potential pathology. Although the total white cell count has again fallen, the neutrophil count continues to rise. The platelet count has risen marginally, but both clotting times are prolonged, and the level of fibrinogen has fallen below the bottom of the reference range. This is firm evidence of DIC. The rise in CRP and d-dimers are unsurprising and add little to the clinical or laboratory picture. The increased urea implies acute renal failure, unsurprising in view of the clinical picture and the falling urine output, whilst the low serum bicarbonate implies acidosis, which would have been confirmed with blood gas analysis. Prognosis is poor.
Day 8 (evening)
CS 1.12: The afternoon blood samples showed that the neutrophil leucocytosis is profound, and the nucleated red blood cell is simply more evidence of the increased haemopoiesis. The increase in the PT and APTT, and the fall in fibrinogen called for the pro-thrombin complex concentrate as replacement therapy. Similarly, there would probably be a call for additional platelets for transfusion. However, in the evening sample this transfusion has failed to correct the coagulopathy which has worsened. There is little more to be done except crisis management.
CS 2.1: The patient’s initial results show leucocytosis, a reduced haemoglobin accompanied by reduced red cell count, a normal MCH, MCHC and MCV, thus signifying a normocytic, normochromic red cell population. With the symptoms of tiredness this makes the diagnosis of normocytic anaemia, although this is subsequently modified. There is marked thrombocytopenia, and accordingly the sample should be checked for a clot and platelet clumping prior to the release of these results. With the possibility of a clotted sample excluded by macroscopic examination, a blood film would be requested to confirm the blood film findings, per-form a manual differential count and determine the cause of the abnormal FBC results.
CS 2.2: Based upon the findings of an accumulation of blasts and promyelocytes, accompanied by faggot cells and schistocytes, a provisional diagnosis of acute promyelocytic leukaemia should be made. It should be noted that the patient, according to the manual differential count, is neutropenic.
CS 2.3: As the patient has a provisional diagnosis of acute promyelocytic leukaemia (APL), and therefore does have an underlying condition associated with DIC, the ISTH scoring calculator can be applied to this case. According to the results available, the patient should be awarded 2 points for his platelet count, 2 points for his D-Dimer, 1 point for his PT and 1 point for his fibrinogen level. Therefore, with a total of 6 points, he has a diagnosis of overt DIC and should be treated as such.
CS 2.4: When patients develop coagulopathy such as DIC, they bleed profusely as a consequence of a reduced platelet count and consumption of clotting factors. These clotting factors are consumed at a rate exceeding their production, leading to an acquired clotting factor deficiency. In patients with DIC, they bleed readily and rapidly from mucous membranes and sites of tissue dam-age, venepuncture sites – for example, and it can be difficult to control this bleeding. By controlling haemostasis first, the mar-row specimen can be obtained with a reduced risk of bleeding.
CS 2.5: The microbiology results tell us that the GP’s initial suspicions of a Strep pyogenes throat infection was correct and the antibiotics – penicillin – were suitable for this patient’s infection. The recurrent nature of this throat infection was not due to bacterial resistance to the antibiotic, as shown by the zone diameters measured by the microbiology laboratory, rather the patient’s sup-pressed immune system as a response to the patient’s suppressed immune system as a consequence of his acute leukaemia. The fact that this patient was neutropenic (according to his manual differential) provides evidence of his susceptibility to bacterial infection. To compound the problem, many of the patient’s circulating white blood cells are neutrophil precursors yet unable to fully function as phagocytes and so provide little anti-microbial defence.
CS 3.1: The patient had been feeling tired an appeared a little pale so the FBC was to check for anaemia. The headaches could a consequence of temporal arteritis, although they were probably not sufficiently severe, but ESR is often used as a general health indicator. The biochemistry profile could give clues to any bone pathology possibly responsible for the low back pain.
CS 3.2: From table 18.6, the FBC revealed a normocytic, normochromic anaemia arising from reduced red cell numbers. The markedly elevated ESR would be partly due to the anaemia, but the marked rouleaux and background staining suggest an additional pathology. The calcium level is elevated, which could indicate bone involvement/degradation, although the ALP is normal, albeit at the high end of normal. The urea and creatinine levels are slightly elevated, which is likely to reflect slight renal impairment.
CS 3.3: The patient was only mildly anaemic but the red cell indices and blood film appearances were not suggestive of nutritional deficiency and there was no evidence of increased red cell destruction. The reticulocyte count is low normal, suggesting the bone marrow was not responding to the anaemia and was in some way compromised. Despite the normal white cell count and appearances, and normal platelet count, the high ESR, marked rouleaux and background staining, and suggestion of bone pathology, suggested the possibility of a more serious haematological disorder, multiple myeloma.
CS 3.4: The bone marrow plasma cells of >30% excludes monoclonal gammopathy of unknown significance (MGUS), and symptomatic bone lesions exclude smouldering myeloma. The presence of paraprotein excludes non-secretory myeloma. The lack of plasma cells in peripheral blood excludes plasma-cell leukaemia. The patient did not have osteosclerotic myeloma, which is a component of the rare POEMS syndrome, with symptoms of Polyneuropathy Organomegaly Endocrinopathy Monoclonal gammopathy Skin changes. Solitary plasmacytoma of bone involves a single tumour in the bone and not the presence of abnormal cells throughout the bone marrow. Similarly, extraosseous/extramedullary plasmacytoma does not involve bone marrow infiltration of plasma cells.
The patient’s results (table 18.7) revealed an IgG-kappa paraprotein. The total serum protein was markedly higher than the albumin level, due to the increased IgG, which was accompanied by a typical reduction in IgM and IgA. The presence of the paraprotein caused the elevated ESR and plasma viscosity, rouleaux and background staining on the blood film. The >30% plasma cells in the bone marrow was highly suggestive of multiple myeloma, accompanied by the t(11;14)(q13;q32), which is the most com-mon translocation seen in multiple myeloma. The elevated calcium level evidenced the typical bone degradation seen in multiple myeloma, which was a likely cause of the patient’s back pain. The elevations in urea and creatinine suggest that his renal function was beginning to show impairment, possibly because of the elevated calcium and/or hyperproteinaemia, although it can occur for other reasons. Plasma cell infiltration of the bone marrow had affected red cell production, leading to his anaemia. β2 microglobulin was elevated as it is secreted by myeloma cells. Elevated LDH can be seen in active myeloma.
CS 3.5: The red cell indices are mildly reduced, but the white cell count is normal. Although the platelet count was now slightly reduced, it was not low enough to be the sole cause of bleeding. Fibrinogen was normal and the normal thrombin time excluded interference by unfractionated heparin or a direct thrombin inhibitor. In any case, the patient was not receiving therapeutic anticoagulation. Both PT and APTT were prolonged, suggesting an abnormality in the ‘common pathway’, and clotting times for both tests in their mixing tests were only slightly shorter and nowhere near normal, indicating the presence of an inhibitor, which was most likely to be the cause of the bleeding. The normal liver function tests and albumin (18.6) effectively rule out liver damage as a cause of reduced levels of coagulation factors and so the abnormal PT and APTT.
(i) All coagulation factors in table 18.10 were normal except for FX, which was undetectable, suggesting that the inhibitor had FX specificity.
(ii) Reduced FX alone will elevate both DRVVT and DAPTT but both assays revealed inhibition in their mixing tests. Lupus anticoagulants are phospholipid-dependent inhibitors, so if a lupus anticoagulant was the cause, the confirmatory test ratios would have been significantly lower than the screening tests ratios, but they were not.
(iii) Screening tests indicated the presence of an inhibitor and factor assays indicated that the only factor apparently affected was FX, so a Bethesda assay based on inhibition of FX was necessary to confirm and quantify the inhibitor.
CS 3.7: FX Bethesda: 30 BU/mL