NR 507 Week 6 TTP Versus DIC Case Analysis Example

Platelets of 14,000, Schistocytes and a Normal INR: Thrombotic Thrombocytopenic Purpura and Disseminated Intravascular Coagulation Given Equal Mechanisms, Then Held Against a 38-Year-Old's Findings

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College of Nursing, Chamberlain University

NR 507: Advanced Pathophysiology

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Month Day, Year

Platelets of 14,000, Schistocytes and a Normal INR: Thrombotic Thrombocytopenic Purpura and Disseminated Intravascular Coagulation Given Equal Mechanisms, Then Held Against a 38-Year-Old's Findings

The Presentation as a Problem

Ms. K., 38, an accountant with no significant history, came to the emergency department with four days of headache and fatigue, a new rash of pinpoint red spots on her legs, and an episode that morning in which she could not find words for about twenty minutes. Temperature was 37.9°C, blood pressure 132/84 mm Hg and heart rate 96. There were petechiae on both shins and no focal deficit on examination.

Her laboratory values were: platelets 14,000/µL, hemoglobin 8.1 g/dL, mean corpuscular volume 88 fL, reticulocytes 6%, lactate dehydrogenase 1,450 U/L, indirect bilirubin 3.2 mg/dL, haptoglobin undetectable and many schistocytes on the blood smear. The direct antiglobulin test was negative. Creatinine was 1.3 mg/dL. Prothrombin time was 12.8 seconds with an INR of 1.0, activated partial thromboplastin time 30 seconds, fibrinogen 310 mg/dL and D-dimer mildly elevated. She had no known cancer, no transplant, was not pregnant and had no source of infection on examination, urinalysis or chest radiograph.

The problem is a microangiopathic hemolytic anemia with severe thrombocytopenia and neurologic symptoms. Two processes can produce red cells fragmented in small vessels and platelets consumed by clotting: thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC). Both deserve a full mechanism before either is chosen.

The First Mechanism: Thrombotic Thrombocytopenic Purpura

Von Willebrand factor is released from endothelial cells as very large multimers, which are especially good at binding platelets under the high shear of small arteries and capillaries. Normally, the plasma enzyme ADAMTS13 cuts these multimers into smaller, less adhesive pieces. In immune TTP, the most common form in adults, an autoantibody inhibits or clears ADAMTS13. The ultra-large multimers persist, platelets stick to them in the microcirculation, and platelet-rich microthrombi form in small vessels throughout the body (Joly et al., 2017).

Each finding follows. Platelets are consumed into the thrombi, so the count falls severely, often below 30,000/µL. Red cells are sheared as they pass partly blocked vessels, producing schistocytes and hemolysis: high LDH, high indirect bilirubin, undetectable haptoglobin and a reticulocyte response. The thrombi reduce flow to organs, and the brain is commonly affected, producing headache, confusion and transient deficits such as her episode of word-finding difficulty. Kidney involvement is usually mild. Importantly, the coagulation cascade is not activated in a widespread way: the thrombi are made of platelets and von Willebrand factor, not fibrin generated by thrombin. The prothrombin time, partial thromboplastin time and fibrinogen are therefore expected to be normal or near normal.

The Second Mechanism, Given Equal Room: Disseminated Intravascular Coagulation

DIC begins with widespread exposure of tissue factor to the blood, usually from sepsis, cancer, trauma or an obstetric complication. Tissue factor activates the extrinsic pathway, generating thrombin throughout the circulation. Thrombin converts fibrinogen to fibrin, activates platelets and forms fibrin-rich microthrombi in small vessels. At the same time, the natural anticoagulant systems are overwhelmed and fibrinolysis breaks down the fibrin, releasing D-dimer.

DIC also produces thrombocytopenia and, in some cases, schistocytes, as red cells are cut on fibrin strands. But its defining feature is consumption of clotting factors. Because thrombin generation uses up fibrinogen and the factors of the cascade, DIC characteristically prolongs the prothrombin time and partial thromboplastin time, lowers fibrinogen and markedly raises D-dimer. It also typically occurs in a patient who is visibly ill from its trigger, most often septic. The international hemostasis society's scoring system, known by its initials as the ISTH score, rates overt DIC using the platelet count, a fibrin-related marker such as D-dimer, prolongation of the prothrombin time and fibrinogen, with a total of 5 or more compatible with overt DIC (Taylor et al., 2001).

Findings That Discriminate

Several findings fit both processes and cannot decide between them: thrombocytopenia, schistocytes, hemolysis and the low-grade fever. The decision rests on the findings that the two mechanisms predict differently.

Table 1

Findings Set Against the Predictions of Each Mechanism

Note. Findings shared by both processes are omitted, since they cannot discriminate.

Scoring the Two

Two published tools formalize the comparison. The PLASMIC score gives one point each for a platelet count below 30,000/µL, evidence of hemolysis, no active cancer, no solid organ or stem cell transplant, a mean corpuscular volume below 90 fL, an INR below 1.5 and a creatinine below 2.0 mg/dL; in its derivation and validation cohorts, scores of 6 or 7 identified patients at high risk of severe ADAMTS13 deficiency (Bendapudi et al., 2017). Ms. K. scores 7. On the ISTH score for overt DIC, her platelet count gives 2 points and a moderately raised D-dimer at most 2, while her prothrombin time and fibrinogen give none, for a total of 4, below the threshold for overt DIC (Taylor et al., 2001). Both tools point the same way.

Scores do not replace the mechanism; they summarize it. The PLASMIC score works because each of its items reflects part of the TTP chain described above, and the ISTH score works because each of its items measures consumption of clotting factors. A patient who scored high on both, which can happen in severe sepsis, would need the mechanisms themselves to sort out which process was driving her illness.

What Would Change the Answer

The conclusion is that immune TTP is by far the more likely process, and it has an immediate consequence: TTP is treated urgently with plasma exchange and immunosuppression, often before the ADAMTS13 result returns, because untreated it is frequently fatal. The conclusion should still be held open to findings that would reverse it. An ADAMTS13 activity above about 10% would make TTP much less likely and send the search toward other thrombotic microangiopathies. A prolonging INR or falling fibrinogen over the next day would raise DIC again and demand a hidden trigger, such as occult infection or malignancy. And a blood culture that grew an organism would change the whole picture. Naming these now makes the diagnosis a claim that the next results can test, rather than a decision already made.

References

Bendapudi, P. K., Hurwitz, S., Fry, A., Marques, M. B., Waldo, S. W., Li, A., Sun, L., Upadhyay, V., Hamdan, A., Brunner, A. M., Gansner, J. M., Viswanathan, S., Kaufman, R. M., Uhl, L., Stowell, C. P., Dzik, W. H., & Makar, R. S. (2017). Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: A cohort study. The Lancet Haematology, 4(4), e157-e164. https://doi.org/10.1016/S2352-3026(17)30026-1

Joly, B. S., Coppo, P., & Veyradier, A. (2017). Thrombotic thrombocytopenic purpura. Blood, 129(21), 2836-2846. https://doi.org/10.1182/blood-2016-10-709857

Taylor, F. B., Jr., Toh, C.-H., Hoots, W. K., Wada, H., & Levi, M. (2001). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thrombosis and Haemostasis, 86(5), 1327-1330. https://doi.org/10.1055/s-0037-1616068