DATA interpretation on coagulation

A 44 year old man presents with dyspnoea and is diagnosed as having multiple pulmonary emboli on CTPA. He is commenced on heparin 1000 units/hr after a 5000 unit bolus. During the night his heparin has increased to 1500 units/hr. The blood results are from the next morning:

PT 12, APTT 38.3
Fibrinogen 3.8g/L
D-dimer (latex immunoassay) > 20.0 mgh/ml (normal < 0.5)

1. Give two reasons for the low APTT despite heparin
2. List causes for an increased predisposition to venous thromboembolic disease?

Answer 1
Inadequate heparinisation, AT-III deficiency, increased heparin clearance, increased heparin binding proteins

Note: Heparin resistance is a term used to describe patients who require unusually high doses of heparin (>35,000u/day), and can be attributable to antithrombin deficiency, increased heparin clearance, elevation in heparin-binding proteins, elevation in factor VIII, and elevation of fibrinogen.
Heparin protocols are more effective in achieving goal in anticoagulation than ad hoc approach.

Heparin is a natural gycosaminoglycan that is extracted from procine intestinal mucosa. Intravenous administration results in immediate onset of action with t1/2 of 60secs-90 minutes. Liver and renal disease results in prolonged t1/2. When heparin combine with antithrombin III (heparin cofactor), thrombosis is blocked through inactivation of activated factor II, IX, X, XI and XII. Heparin also binds to platelets, both inhibiting and promoting their function.
Coagulation test findings: increased APTT, mildly increased PT, increased TCT, normal protamine corrected APTT test, normal reptilase time
TCT: thrombin clotting time -   test of the traditional final common pathway of the coagulation cascade which converts fibrinogen to fibrin.
Reptilase time - assist with the differentiation of causes of an increased TCT. Reptilase is a thrombin -like molecule that converts fibrinogen to fibrin but is not inhibited by antithrombin III.
Protamine corrected APTT: the APTT after protamin is added to the patient's blood.


Answer 2
1. anti-thrombin III deficiency
2. protein C and S deficiency
3. Factor V Leiden gene mutation
4. Lupus anticoagulation and anti-cardiolipin
5. malignancy
6. hyperhomocysteinemia

QUESTION 2

A 54 year old man post CABG is bleeding briskly into the chest drains
INR 1.4, PT 16, APTT 55, TT 17, fibrinogen 1.2 and Platelet 65

1. How would you correct this man's coagulation?
Answer: The TT is normal, so coagulopathy is not due to heparin. Consumptive or dilutional coagulopathy and needs platelets, FFP, and cryoprecipitate.

QUESTION 3

A 24 year old woman has the following haematology and coagulation profile post admission to ICU after post partum haemorrhage.
WCC 5.6, Hb 6g/dL, Platelts 30, PT 30.6, APTT > 150, fibrinogen 0.8, D-Dimer > 10 (normal < 0.4)
1. What is the likely cause of these abnormalities?
Answer: DIC
2. In this context list 3 likely causes of this coagulation profile
-preeclampsia, AF embolism, sepsis
-intrauterine fetal death
-massive or mismatched transfusion
3. What does an elevated D-dimer indicate?
Answer: Tests fibrinolysis (breakdown of the X linked fibrin)

QUESTION 4

A 54 year old woman presented to the ED after having been unwell for 4 days. Her FBC report is:
Hb 12.8 g/dL, WBC 56.5, Platelet 347, Hct 41.4%
Neutrophil 96.3%
Lymphocyte 2.8%
Mono 0.7%, Eosin 0.1%, Baso 0.1%
Moderate rouleaux. Marked neutrophilia. Dohle bodies present, toxic granulation present.
1. What likely hematological process is revealed by the abnormal white cell count?
Answer: Acute leukemoid reaction.
-> 50,000 cells, normal baso and eosinophil counts, Dohle bodies, toxic granulation

another DKA patient

Last week, I received a call from my specialist about a man who was admitted 24 hours ago with diabetic ketoacidosis. His metabolic acidosis was severe, pH 6.9 and given bicarbonate therapy. His ketoacidosis improved with insulin therapy but his amylase level was increased. Because of possible acute pancreatitis, I admitted him to ICU for observation.
I reviewed him later in the ICU and noticed that his ABG on admission still showed AG metabolic acidosis (and require insulin for ketoacidosis) but in general he was improving. His Ranson score for initial 24 hours was only 1 and within 48 hours score was less than one. No significant finding on US abdomen/hepatobiliary, but CT scan was not done. He was discharged well the following day.

Comment:
The most common precipitating causes for DKA and HHS are infection and discontinuation of or inadequate insulin therapy. Others are acute illnesses such as CVA, MI and acute pancreatitis. Sometimes I used the pneumonic I GET SMASHED to go through the possible precipitating events.

Serum amylase and lipase are the standard tests to diagnose acute pancreatitis, but are often elevated in patients with DKA who do not have pancreatitis. As a result, the diagnosis of pancreatitis in patients with DKA should be based upon clinical findings and CT scan.  The mechanisms for hyperamylasemia and hyperlipasemia in DKA are not well defined, but the following observations have been made:
1. In 100 consecutive cases of DKA, 11 had acute pancreatitis as confirmed by CT scan. The most common causes were hypertriglyceridemia and alcohol intake. 2 did not have abdominal pain. (Am J gastroenterol 2000)
2. In a review of 134 consecutive episodes of DKA in patients with no CT evidence of acute pancreatitis, elevations of serum amylase and lipase ( 3x or higher) were seen in 17 and 24% respectively. Abdominal pain was present in 19% of the series. (Am J of gastroenterol 2000)
3. The source of these nonspecific amylase elevations is most often salivary though may also be pancreatic. The source of nonspecific lipase elevations is not known.
4. The rise in amylase correlates with pH and plasma osmolality, while the rise in lipase correlates only with plasma osmolality. Peak values are seen within 24 hours of presentation.

Thrombotic Thrombocytopenia Purpura

General principle:
Acute presentation of severe to moderate thrombocytopenia. May present with fever, neurologic signs or symptoms and renal abnormalities. The complete pentad of signs/symptoms (i.e. thrombocytopenia, microangiopathic hemolytic anemia, fever and neurologic and renal abnormalities) is present in fewer than 25% of cases.

Etiology: 1. Autoimmune - may be HIV associated
              2. Congenital

Pathophysiology

1. Deficiency of von Willibrand factor-cleaving enzyme (ADAMTS 13) results in persistence of large multimeric forms and increased platelet adhesion.
a. autoimmune (i.e. idiopathic) TTP: autoantibody forms against ADAMTS 13
b. congenital TTP: Familial decrease in production of functional ADAMTS 13

2. Formation of platelet thrombi in microvasculature leads to tissue ischaemia and end organ disease
3. Intravascular hemolysis by increased shearing forces

Diagnosis
1. Laboratory
a. thrombocytopenia
b. red cell fragnments on peripheral blood film (shistocytes)
c. elevated LDH
d. Indirect bilirubin may be elevated
e. hemostasis parameters otherwise normal
f. creatinine may be increased, hematuria may be present
g. Usefullness of ADAMTS 13 level and antibody for diagnosis controversial

Treatment:
-Medical emergency: more than 90% mortality without treatment
-Institute immediate plasma exchange; replacement fluid must be plasma
-continue daily plasma exchange until LDH and platelet count have normalized for 2-3 days, then begin to taper frequently of plasma exchange
-transfuse FFP (4-6 units in an adult) if plasma exchange delayed
-corticosteroids - role unclear
-Patients with renal failure - hemodialysis
-refractory cases -splenectomy, vincristine, rituximab, immunosuppression

Prognosis
1. 90% mortality without rapid institution of therapy
2. Relapses after reduction/discontinuation of plasma exchange occur in a minority of patients

Hemolytic Uremic Syndrome
Pathophysiology:
1. deposition of platelet thrombi in small and medium sized vessels
2. no deficiency of ADAMTs 13
3. Especially in children, antecedent gastrointestinal illness and exposure to bacterial toxins may precede illness ("endemic HUS")

Treatment
1. Primarily supportive e.g. dialysis
2. Plasma exchange of value in some patients
3. Most cases resolve with supportive care

Data Interpretation

A previously well 54 year-old man presents with confusion. On examination a rash is noted. Temperature 37.1. The initial blood results are provided below.

Venous biochemistry
Na 135
K 3.8
Urea 18 mmol/l -*
Creatinine 177 micromol/l-*
Bilirubin 45 micromol/l -*

Hematology:
Hb 99 g/l
WBC 10.8 x 10(9)/L
Platelet 26 x 10(9)/L-*
Blood film: Schistocytes-*

Coagulation
PT 10 s
APTT 29 s
Fibrinogen 3.0 g/L

What is the most likely diagnosis?
Thrombotic thrombocytopenic purpura

What treatment needs to be instituted urgently?
Plasmapheresis

TTP shows a classic pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, and renal and neurological defects. This is thought to be related to an abnormal metalloproteinase (ADAMST 13). The condition is seen with certain infections, drugs (e.g. calcineurin antagonists, clopidogrel), pregnancy, systemic lupus erythematosus and graft versus host disease.
The labarotary findings in this condition are:
-low platelets
-reduced hemoglobin level with polychromasia, shictocytes and spherocytes
-increased reticulocytes
-reduced haptoglobin and increased lactate dehydrogenase levels
-unconjugated hyperbilirubinemia with urinary urobilinogen
-variable neutrophilia
-increased urea and creatinine levels (greater in hemolytic uremic syndrome)

Hematology question

Question 1

A man with fractured ribs following a fall has the following results:

Hb: 10.9 g/dL
PCV: 39%
MCHC: 30g/dL
WBC: 12.8 x 10 (9)/L
Neutrophils: 64%
Lymphocytes: 27%
Monocytes: 3%
Myelocytes: 2%
Metamyelocytes: 4%

Nucleated RBCs, slight poikilocytosis, slight anisocytosis

1. What is this type of blood picture?
A: Leukoerythroblastic picture
leukoerythroblastic picture on blood film can be the bone marrow response to any irritation including marrow infiltration (causing immature red cells). Marrow infiltrative disorders include myelomas, malignancy, myelofibrosis, Gaucher's disease etc. It can also occur as a response to severe critical illness such as trauma, sepsis, massive hemolysis or severe megaloblastic anemia. Leukoerythroblastic change refers to the presence of nucleated red blood cells and primitve white blood cells.

Peripheral blood smear showing the presence of nucleated red blood cells and immature white cells.

2. List four possible underlying causes?Marrow infiltration, overwhelming sepsis, major blood loss and marrow hypoxia

3. What is meant by the terms anisocytosis and poikilocytosis?
Anisocytosis is excessive inequality in the size of red blood cells
Poikilocytosis is increase in number of abnormally shaped red blood cells on film

Question 2

A 78 yr old man presented after a fall resulting in a bruised hip. His Full blood count is the following:

Hb 12.0 g/dL
WBC: 1.9 x 10 (9) --> low
Platelet: 28 x 10 (9) --low
RBC: 3.01 x 10 (9)--low
HCT: 0.358 --low
MCV: 118.9 fL --high
MCH: 39.9 pg --high
MCHC: 335 G/L --normal
Neutrophils 79.6%
Lymphocyte 17.3%
Monocytes 3.1%
Eosinophils 0.0%
Basophils 0.0%

Moderate anisocytosis, marked macrocytosis

List causes for the raised MCV?
Answer:
-B12 deficiency
-folate deficiency
- myeodysplastic syndrome
- therapy with cytotoxics or immunposuppressants
- alcohol
-hypothyroidism
- alcohol and hypothyroidism do not produce such high levels of MCV usually but anwers accepted.

Note: macrocytosis - describe erythrocyte that are larger than normal, typically reported as MCV greater than 100 fL. Because the amount of Hb in the cell increases proportionately with the increase in size, MCHC remains within normal limits.
Causes of macrocytosis are many and range from benign to malignant; thus a complete work up to determine etiology is essential. Macrocytosis can occur at any age, but it is more prevalent in older age groups because the causes of macrocytosis are more prevalent in older persons.

Use of Na bicarbonate in diabetic ketoacidosis

On Friday evening after my late afternoon rounds, a new patient arrived in ICU. That time was about 15 minutes to 6 pm. My medical officer told me the diagnosis is diabetic ketoacidosis. She is a young lady, known type 1 diabetes mellitus since she was twelve-year old. There was no appropriate handover since the intern who accompanied the patient only functioned as a  'medical' porter and didn't know what was going on except that his patient has a diagnosis of DKA. This place is very strange and the system is not right. I still not really impressed with the department of emergency in my hospital.
She has a pink cannula (20G) in her right arm. After scrutinizing the case notes (no attached intravenous fluid chart), we concluded that she received the appropriate IV fluid replacement therapy. From the ABG, she had a high AG metabolic acidosis, pH of 7.15. Urine ketone was positive, blood sugar level on admission was 41mmol/l, serum Na 125 and K 4.5. We also noted that IV NaHCO3 was given by medical medical officer to treat the acidosis. Ten units of IV insulin was given but the sliding scale has not been started.

The question is "Is Na bicarbonate therapy is indicated to treat high anion gap acidosis in DKA?"

Let me start with the major effects of metabolic acidosis on the body
Respiratory effects:
1. Hyperventilation (Kussmaul respirations) - as compensatory response
2. Shift of ODC to the right
3. Decreased 2,3 DPG in the red cells (shift the ODC back to the left)

Cardiovascular effects:
1. Depression of myocardial contractility
2. Sympathetic overactivity (include tachycardia, vasoconstriction, decreased arrythmia threshold)
3. Resistance to the effects of catecholamines
4. Peripheral arteriolar vasodilation
5. Venoconstriction of peripheral veins
6. Vasoconstriction of pulmonary arteries
7. Effects of hyperkalemia on heart

The cardiac stimulatory effects of sympathetic activity and release of cathecolamines usually counteract the direct myocardial depression while plasma pH remains above 7.2. At systemic pH values less than this the direct depression of contractility usually predominates. The direct vasodilation is offset by the indirect sympathetically mediated vasoconstriction and cardiac stimulation during a mild acidosis. The venoconstriction shifts blood centrally and this causes pulmonary congestion. Pulmonary artery pressure usually rises during acidosis.

Other effects:
1. Increased bone resorption (chronic acidosis only)
2. Shift of K out of cells causing hyperkalaemia

The effect on K level is variable and indirect effects due to the type of acidosis present are much more important. e.g. hyperkalaemia in renal failure is due to uraemic acidosis rather than the acidosis. In DKA, singnificant K loss due to osmotic diuresis, therefore the K level at presentation is variable although total body K stores are invariably depleted. Treatment with fluid and insulin can cause a prompt and marked fall in plasma K. Hypokalaemia may be than a problem.

Bicarbonate is an anion and cannot be given alone. Its therapeutic use is as a solution of Na bicarbonate. An 8.4% solution is a molar solution ( i.e. contains 1 mmol of HCO3 per ml). Thi solution is very hypertonic and its osmolality is 2,000 mOsm/kg.

The main goal of alkali therapy
1. to counteract the extracellular acidemia with the aim of reversing or avoiding the adverse clinical effects of the acidosis (esp adverse CVS effects).
2. Emergency management of hyperkalemia
3. To promote alkaline diuresis (e.g. to hasten salicylate excretion)

Undesirable effects of bicarbonate administration:
1. Hypernatremia
2. Hyperosmolality
3. Volume overload
4. Rebound or overshoot alkalosis
5. Hypokalaemia
6. Impaired oxygen unloading due to left shift of the ODC
7. Acceleration of lactate production by removal of acidotic inhibition of glycolysis
8. CSF acidosis
9. Hypercapnia

Important points about bicarbonate:
1. Ventilation must be adequate to eliminate the CO2 produced from bicarbonate. If hypercapnia occurs, CO2 crosses the cell membranes easily and intracellular pH may decrease even further with further deterioration of cellular function.
2. Bicarbonate may cause clinical deterioration if tissue hypoxia is present. This is due to increased lactate production (removal of acidotic inhibition of glycolysis) and the impairment of tissue oxygen unloading (left shift of ODC due to increased pH). This means that with lactic acidosis or cardiac arrest then bicarbonate therapy may be dangerous.
3. Bicarbonate is probably not useful in most cases of high anion gap acidosis.
4. The preferred management of metabolic acidosis is to correct the primary cause and to use specific treatment for any potentially dangerous complications.
5. Bicarbonate therapy may be useful for correction of acidemia due to non-organic or mineral acidosis (i.e. normal anion gap acidosis).

Diabetes Ketoacidosis - summary of events in pathophysiology of DKA:
1. A precipitating event occurs which results in insulin deficiency (absolute or relative) and usually an excess of stress hormones (particularly glucagon)
2. Hyperglycemia occurs due to decreased gluconse uptake in fat and muscle cells due to insulin deficiency
3. Lipolysis in fat cells now occurs promoted by the insulin deficiency releasing FFA into the blood
4. Elevated FFA levels provide substrate to the liver
5. A switch in hepatic lipid metabolism occurs due to the insulin deficiency and glucagon excess, so the excess FFA is metabolised resulting in excess production of acetyl CoA
6. The excess hepatic acetyl CoA is converted to acetoacetate which is released into the blood
7. Ketoacidosis and hyperglycemia both occur due to the lack of insulin and the increase in glucagon and most of the clinical effects follow from these two factors
8. Other acid-base and electrolyte disorders may develop as a consequence and complicate the clinical condition.

Oher acid base disorders may be present: Possible complicating acid base disorders are
1. Lactic acidosis due to hypoperfusion and anaerobic muscle metabolism
2. Metabolic alkalosis secondary to excessive vomiting
3. Respiratory alkalosis with sepsis
4. Respiratory acidosis due to pneumonia or mental obtundation
5. Renal tubular acidosis type 4 - the syndrome known as hyporeninemic hypoaldosteronism occurs in some elderly diabetics who have pre-existing moderate renal insufficiency by is not a common problem in acute DKA.


Correction of acidosis in DKA
This occurs more slowly than the correction of blood glucose but the use of bicarbonate in DKA remains controversial (Viallon CCM 1999) . In most studies the use of bicarbonate fails to provide any hemodynamic benefit that could not be attributed purely to osmotic load of sodium administered (Cooper ICM 1994). Therefore the evidence of benefits are lacking (Latif KA Diabetes care 2002). In a randomized trial of 24 DKA patients with admission arterial pH between 6.9 and 7.4 bicarbonate therapy did not change morbidity of mortality (Morris LR Ann inter med 1986). The study was small, limited to arterial pH 6.9 and above. There was no difference in the rate of rise in the arterial pH and serum bicarbonate and placebo groups. No prospective trial in DKA with pH values less than 6.9. Below pH 6.9 most authorities would recommend the use of bicarbonate to correct the pH partially.

There is no doubt that blood pH can be improved, but at the expense of worsening intracellular acidosis (Forsythe Chest 2000). Neurologic deterioration has been reported due to paradoxical fall in cerebral pH (Narins RG Ann Intern Med 1987). Other side effects of bicarbonate are listed above.

In the context of DKA, sodium bicarbonate also delays the clearance of ketones and may further enhance hepatic production even when insulin and glucose are being delivered (Okuda J Clin Endocrinol Metab 1996). This may slow the rate of recovery of the ketosis. At pH of > 7.0 insulin will block lipolysis and ketoacid production.

Selected patients who may benefit from cautious alkali therapy (Narins RG Ann Intern Med 1987):
1. Patients with an arterial pH of 7.0 in whom decreased cardiac contractality and vasodilation can further impair tissue perfusion. At an arterial pH above 7.00 most experts agree that bicarbonate thrapy is not necessary since insulin therapy alone will result in resolution of most of the metabolic acidosis.
2. Patiens with potentially life threatening hyperkalemia, since bicarbonate therapy in acidemic patients drives potassium into cells, thereby lowering the serum potassium concentration.

The conclusion is administering bicarbonate therapy is recommended if the pH is less than 6.9. Give 100mls of 8.4% of Na bicarbonate (can be added into 400mls of D5%)  together with 20mmol of KCl if the serum K is less than 5.3 mmol/l and administered over two hours.