Plasma Transfusion is Ineffective for Correcting Minimally Elevated INR
Wednesday, June 18, 2008

Today, much plasma is ordered prophylactically to correct an elevated protime (PT) prior to an invasive procedure. Physicians performing invasive procedures want to avoid hemorrhagic complications and often regard a mild elevation of a coagulation test result as an indication to order plasma. The decision to prophylactically transfuse plasma is based on three unproven assumptions. (1) Mild prolongation of PT/INR (defined as an INR <1.7) predicts bleeding from an invasive procedure. (2)Pre-procedure transfusion of plasma will correct a prolonged PT/INR. (3) Prophylactic plasma transfusions result in fewer bleeding events.

The evidence clearly contradicts the first assumption. PT and APTT begin to rise above the upper limit of the normal range when coagulation factor levels fall below approximately 70% of normal. When the INR increases to 1.3 - 1.5, vitamin K dependent coagulation factors are still 50% of normal. Even at an INR between 1.8 and 2.0, they remain at 30% of normal, which is still at or above the minimal hemostatic level of 20 -30%. These results explain why a mildly elevated PT/INR is not usually associated with spontaneous hemorrhage and does not increase the risk of bleeding during routine invasive procedures. Studies during the last 20 years in patients undergoing liver biopsies, bronchoscopic biopsies, renal biopsies, central line vein cannulation, thoracentesis and angiography have repeatedly demonstrated that PT and activated plasma thromboplastin time (APTT) are not predictive of hemorrhage. However, it must be remembered that the risk of bleeding is greater if the platelet count is decreased, platelet function is abnormal, or the patient has experienced massive trauma or is undergoing extensive surgery.

Additional evidence clearly disputes assumptions 2 and 3. Prophylactic transfusion of plasma to correct a mildly elevated INR prior to an invasive procedure is often not effective. When the INR is <1.7, transfusion of plasma corrects INR an average of only 0.1 per unit transfused, largely because the INR of plasma itself ranges between 1.0 and 1.3. The difference in coagulation activity between donor plasma and patient plasma is so small that plasma transfusions produce minimal demonstrable effect on the patient’s INR. While a patient with an INR of 1.7 or less may bleed during an invasive procedure, the medical literature clearly demonstrates that the incidence of hemorrhage is not different from that of patients with a normal INR.

In summary, plasma transfusion has minimal effect on normalizing the INR in patients with mildly prolonged INRs for the following reasons. (1) Plasma produced from healthy blood donors can have an INR as high as 1.3. (2) Plasma transfusion to a patient with an INR of less than 1.7 has minimal effect. (3) Plasma transfusion to patients with an INR of less than 1.7 does not decrease the INR more than usual medical care without plasma transfusion.

In view of this information, the common practice of prescribing plasma to correct a mildly elevated INR prior to an invasive procedure needs to be reevaluated. It is not necessary or efficacious to correct an INR below 1.7 to achieve adequate hemostasis.

posted by Fred Plapp @ 7:03 PM, , links to this post


Helicobacter pylori Treatment and Chronic ITP
Saturday, May 10, 2008

A recent study in Blood (2007;10:3833-3841) suggests that eradication of Helicobacter pylori may lead to a significant and persistently increased platelet count in patients with chronic immune thrombocytopenic purpura (ITP). In this study, 75 patients with ITP were screened for infection with H. pylori. Active H. pylori infection was found in 38 (51%) of these patients and effectively eradicated in 34 (89%) patients. The urease breath test was used to assess eradication 4 to 6 weeks following treatment. Platelet counts were then monitored at regular intervals; 2 weeks for the first 2 months, monthly for the next 4 months, and every 6 months thereafter. The average baseline platelet count in H. pylori infected ITP patients was 40.6 x 109/L [± 25.0 x 109/L]. The authors defined platelet responses as follows:
Complete response (CR): normal platelet count for at least 3 months after eradication.
Partial response (PR): platelet count not >149,000 or a doubling of the initial count above 40,000.
No response (NR): platelet count less than or equal to 40,000, even if the initial count doubled.
Five patients without H. pylori but with ITP were also given eradication treatment to act as control subjects.

After a median follow-up time of 60 months post treatment, 23 (68%) of the 34 patients with eradicated H. pylori infection showed a significant and persistent increase in their platelet count. Sixteen (46%) patients achieved CR, 7 (20%) achieved PR and 12 (34%) showed no response. Only 1 patient who was refractory to eradication treatment showed a response during follow-up. No H. pylori-negative patients experienced a platelet response. Overall, 55% of the H. pylori-positive patients with ITP who underwent eradication treatment were disease free at 60 months.

With an average follow-up time of 60 months, the results of this study demonstrated that H. pylori eradication treatment may lead to a sustained improvement in the platelet count and possibly long-term cure in patients with chronic ITP. Therefore, the authors suggest that because the eradication of H. pylori is a simple, safe, effective and inexpensive approach, all patients with ITP should be screened for H. pylori at diagnosis and treated with H. pylori eradication therapy prior to starting or in conjunction with other treatments for ITP.

posted by Fred Plapp @ 9:45 PM, , links to this post


Troponin I Cutoff on Beckman Coulter Analyzers
Saturday, February 09, 2008

Cardiac troponins have become the preferred laboratory tests for the diagnosis of myocardial injury. Clinical and laboratory associations have endorsed the implementation of the 99th percentile reference value for cardiac troponin I for the detection of myocardial ischemia. Elevation of cTnI above the 99th percentile has become the definition of non ST-elevation myocardial infarction. Several recent articles have published the 99th percentile values for second generation cTnI in plasma.

In 2004, Panteghini etal (Clin Chemistry 2004;50:327-32) determined that the 99th percentile for the Beckman Coulter Access Accu TnI on the Access 2 instrument was 0.04 ng/mL (ug/L). This finding was later confirmed by Apple and Murakami in 2007 on a large study of almost 5000 specimens from apparently healthy individuals (Clin Chemistry 2007;53:1558-9).

Our health system has a mixture of Beckman Coulter Access 2 and DxI analyzers, which have very similar performance characteristics. For this reason, our laboratory adopted 0.04 ng/dL as the 99th percentile for cTnI system wide. After almost one year of operation, some interventional cardiologists commented that they were seeing too many with slightly elevated cTnI in patients without discernable ischemic heart disease. A subsequent analysis of cTnI results of healthy individuals participating in an annual health fair revealed that the 99th percentile was actually 0.07 ng/mL. Accordingly, the cutoff point for cTnI was immediately changed from 0.04 to 0.07 ng/mL.

Our experience emphasizes that clinical laboratories definitely need to determine their own 99th percentile for cTnI. Values calculated by carefully controlled research studies may be lower than those obtained by a busy clinical laboratory that does not have as tight of control over specimen collection, transportation and processing.

posted by Fred Plapp @ 1:20 PM, , links to this post


Leukocytosis is a Risk Factor for Thrombosis
Sunday, December 02, 2007

White blood cell count has previously been linked to the incidence of thrombosis in the general population. Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders which are considered hypercoagulable states, due to the high incidence of thrombotic complications, associated with high morbidity and mortality. Ten percent to 30% of patients with these disorders present with major thrombotic complications, and a similar proportion develop a thrombotic complication during their disease course. Arterial thromboses, especially affecting the cerebral or coronary arteries, are more common than venous thromboses. Recent studies on the pathogenesis of thrombosis in myelo-proliferative disorders have suggested a role for leukocyte activation, and leukocyte interaction with platelets and endothelial cells. Two recent studies investigated a possible association between leukocyte count and thrombosis in PV and ET.

In PV, major known risk factors for thrombosis include age over 65 years and previous thrombotic history. A recent study (Blood. 2007;109:2446-2452) analyzed the role of other potential risk factors, including white blood cell count and classic cardiovascular risk factors, in a large database of 1638 patients with PV. Patients with a white blood cell count >15,000/uL had a significant increase in the risk of thrombosis compared with those with a white blood cell count below 10,000/uL, mainly due to an increased risk of myocardial infarction (hazard ratio 2.84). Smoking was also associated with an increased risk of arterial thrombotic events.

In ET, age over 60 years and prior thrombotic events are known independent predictors of vascular complications. These two factors are widely used to stratify thrombotic risk in these patients for cytoreductive drug treatment decisions. A recent study (Blood. 2007;109:2310-2313) of 439 patient with ET investigated whether an increased white blood cell count was associated with thrombosis, and whether this effect could be modulated by cytoreductive therapy. The authors reported that a white blood cell count greater than the median value (8,700/uL) at diagnosis was associated with an increased risk of thrombosis during follow-up (hazard ratio 2.3), and that hydroxyurea-induced lowering of the white blood cell count was associated with a reduction of this thrombogenic risk. The presence of JAK2 mutation was not identified as a risk factor for thrombosis in this study, despite a significant association between the mutation and leukocytosis.

Interestingly, neither hematocrit nor platelet count elevations influenced thrombotic risk in either PV or ET. In summary, leukocytosis is a significant risk factor for thrombosis in PV and ET. The authors of these studies suggest that leukocyte count should be considered in defining vascular risk in patients with myeloproliferative disorders, and should be taken into account as an additional factor in cytoreductive treatment decisions. Validation of these findings in prospective studies is indicated.

posted by Fred Plapp @ 6:35 PM, , links to this post


Decreased Nitric Oxide in Banked Blood Associated with Adverse Outcomes

Several studies have shown that blood transfusions increase the risk for myocardial infarction, heart failure, stroke and death. Although differences between banked blood and red blood cells in vivo have been recognized, the mechanisms resulting in these adverse outcomes have not been delineated.

In two studies published online in the Proceedings of the National Academy of Sciences, Duke University Medical Center researchers suggested that shortly after blood is collected, its nitric oxide content becomes depleted leading to impaired vasodilation and decreased tissue perfusion (PNAS.2007;104(43):17058-17068). They further proposed that as a result of banked blood’s inability to dilate small blood vessels, red blood cells may build up and further obstruct larger vessels, resulting in more ischemia. This scenario was suggested as a possible explanation for the adverse outcomes seen in ischemic patients following blood transfusion.

Nitric oxide levels begin to decline rapidly within three hours after collection and are reduced by 70% during the first day of storage. Levels are undetectable by day 21. Based on these findings, the researchers suggested that even “fresh” blood may lead to adverse clinical outcomes. The reduction in nitric oxide directly correlated with stored red blood cell’s inability to promote vasodilation. Nitric oxide depleted blood transfusions led to decreased coronary blood flow in canines. However, when stored red blood cells were replenished with nitric oxide prior to transfusion, coronary perfusion increased. These differences in blood flow were most noticeable during hypoxemic states.

Although adding nitric oxide to stored red blood cells prior to transfusion looks like a promising solution, the authors acknowledged that a large-scale randomized clinical trial in humans is needed to determine whether adding nitric oxide back to stored blood before transfusion or preventing nitric oxide depletion would actually improve patient outcomes. The Duke University studies once again demonstrated that blood transfusions have risks as well as benefits.

posted by Fred Plapp @ 6:32 PM, , links to this post


Lessons Learned from Community Based Thyroid Screening
Sunday, November 04, 2007

A retrospective analysis of the computerized database of a large health medical organization in Tel Aviv, Israel that included 2800 primary care physicians and 2.3 million insured persons, recently revealed some very interesting findings about routine thyroid screening (Arch Intern Med 2007;167(14):1533-38). A total of 422,242 persons aged 21 years and older with no known thyroid disease or previous treatment with thyroid medications, who had at least one TSH measurement during 2002 and were available for follow-up through 2006, were included in the study. The TSH reference range used for this study was 0.35-5.5 mIU/L.

Ninety five percent of the initial TSH concentrations were within normal limits, whereas 3.7% were elevated and 1.2% were decreased. Thirty seven percent of patients with abnormal initial TSH levels were treated with medication and excluded from further analysis. The remaining patients had an average of 3.7 additional TSH measurements during the 5 year follow-up.

Two important conclusions can be drawn from this study. When TSH concentration is normal and there are no new clinical indications of a thyroid disorder, the likelihood of a subsequent abnormal TSH level within 5 years is only 2%. This finding supports recent evidence based recommendations against population based TSH screening. Secondly, more than 50% of patients with abnormal TSH results revert to normal without medical intervention, suggesting that at least two TSH measurements should be obtained before considering treatment.

posted by Fred Plapp @ 8:52 PM, , links to this post


Clostridium difficile becoming more aggressive
Wednesday, October 03, 2007

Clostridium difficile is a Gram-positive, spore-forming, anaerobic bacillus that can cause pseudomembranous colitis. C. difficile-associated disease (CDAD) ranges in severity from mild diarrhea to fulminant colitis. Risk factors for CDAD include antibiotic use within three months prior to symptom onset, and exposure to a health-care setting. Colonization with C. difficile is common in hospitalized patients (20-40%), while only 3% of healthy adults are colonized. Exposure to antibiotics is believed to alter the normal gut flora, resulting in overgrowth of C. difficile. Production of exotoxins A & B by the organism subsequently results in CDAD, and detection of toxin is the basis for diagnostic laboratory tests.

CDC data indicates that the incidence and severity of CDAD has increased since the year 2000. Two recent publications (NEJM 2005; 353:2433-2449) describe an apparently new, more virulent strain of C. difficile that has been responsible for hospital outbreaks in the U.S. and Quebec, Canada. This epidemic strain differs from common strains in that it produces 16 times more toxin A and 23 times more toxin B, which may result from a deletion in the negative regulator gene, tdC. The epidemic strain was also resistant to fluoroquinolones, and prior use of fluoroquinolones was identified in 52% of cases. More severe CDAD is associated with the epidemic strain, including more frequent toxic megacolon, leukemoid reaction, shock, and death, particularly in the elderly.

Equally alarming, community-acquired cases of severe CDAD in individuals with minimal risk factors have been reported recently (MMWR 2005;54:1201-1205). Analysis of the organism responsible for two of these infections showed they were not caused by the epidemic strain. Another report suggests that use of proton pump inhibitors increases the risk of community-acquired CDAD by 2-3 times (JAMA 2005; 294:2989-2995).

Hand hygiene is of particular importance in reducing the incidence of CDAD. Of note is that hand-washing with soap and water is necessary for C. difficile eradication, as its spores are resistant to alcohol-gel based preparations. In light of the apparent changing epidemiology of CDAD, the CDC has stressed the importance of judicious antibiotic use, and the need for a high index of suspicion for community-acquired CDAD in patient with severe diarrhea.

The newest diagnostic tests for CDAD are enzyme immunoassays (EIA), which detect 100 to 1000 pg of cytotoxin A & B. The sensitivity and specificity of the test are 95% and 97% respectively. A positive test indicates the presence of Clostridium difficile. Normal stools are negative for toxins.

posted by Fred Plapp @ 6:53 PM, , links to this post


Case Study of Progressive Weakness & Sensory Loss
Sunday, September 02, 2007

An 80 year old man has a 6 month history of progressive weakness and seonsory loss in both legs. Serum total protein is 6.5 g/dL. Serum protein electrophoresis detected an IgM kappa monoclonal antibody at a concentration of 0.5 g/dL. Bone marrow aspirate did not detect a lymphoproliferative disorder, but flow cytometry detected a mino clonal population of B cells with monotypic kappa light chains. What is the patient's most likely diagnosis and how does it explain his neurological symptoms? What additional testing would you order to confirm your diagnosis?

posted by Fred Plapp @ 7:26 PM, , links to this post


PSA Threshold for Prostate Biopsy

One of the most difficult dilemmas that has arisen after widespread PSA testing is deciding the optimal PSA threshold at which prostate biopsy should be performed in asymptomatic patients. Using a PSA value that is too low results in unnecessary biopsies and detects indolent cancers, while using a threshold that is too high misses aggressive tumors. Traditionally, a PSA of 4.0 ng/mL has been recognized as the lower limit for biopsy consideration. Approximately 35% of men with a PSA level between 4 and 10 ng/mL have cancer. However, more recent studies have suggested that a cutoff of 4.0 is too high of a threshold for biopsy because 25% of men with PSA levels in the range of 2.5 to 4.0 have clinically significant cancer. Lowering the threshold to 2.6 would nearly double the rate of detecting cancer in men younger than 60 years old with little loss of specificity.

A recent study published in BJU International (2007;99:1427-31) examined the performance of the five most commonly used methods to measure PSA concentration. The study was comprised of 596 untreated Caucasian males referred to a urology clinic. Of this total, 314 men had histologically confirmed prostate cancer while 282 did not have detectable cancer in 8 to 12 biopsy cores. The median age of men with cancer was 66 years and the median age of the men without cancer was 63 years. The median PSA concentration in men with cancer was 6.2 ng/mL (range 5.8-6.6) compared to a median value of 3.8 ng/mL (range 3.1-4.5) in men without cancer.
The performance of the Beckman Coulter PSA assay in detecting prostate cancer at a threshold of 4.0 and 2.5 is shown below.

Another way to look at this data is to realize that 68 out of 314 men with prostate cancer (22%) had PSA values less than 4.0 ng/mL and would not have been referred for biopsy using this threshold. In contrast, only 26 men with prostate cancer (8%) were missed, when the PSA threshold was lowered to 2.5 ng/mL. Clearly, lowering the PSA threshold detects significantly more cancer cases.

However, the trade off for increased sensitivity is decreased specificity. When a PSA threshold of 4.0 ng/mL was used, 139 of 282 men without cancer (49%) had elevated PSA values, but the number of false positives increased to 187 (66%) when the threshold was lowered to 2.5 ng/mL. Thus, lowering the PSA threshold to 2.5 ng/mL, meant that almost two thirds of men referred for biopsy did not have detectable cancer.

The National Comprehensive Cancer Network guidelines recommend biopsy for men with a PSA higher than 2.5 ng/mL.

posted by Fred Plapp @ 7:08 PM, , links to this post