All the content from the Blood & Clots series can be found here.
CanMEDS Roles addressed: Expert
You are seeing a 56M in your critical care suite who has just arrived as a transfer from a peripheral hospital. The patient has had a recent diagnosis of acute leukemia and was given chemotherapy and a recent stem cell transplant 20 days ago at this hospital. When he started getting sicker, they requested a transfer to your site for further management. The patient had a line inserted during the initial resuscitation at the peripheral hospital. Before you see him, he developed fever and dyspnea on the ward despite being on piperacillin-tazobactam and vancomycin. Eventually, his oxygen requirements had increased to the point where he required intubation/mechanical ventilation and also pressor support, which he is continuing to receive.
Reviewing his records, he has been required multiple daily RBC transfusions to keep his hemoglobin above 70 g/L and platelet transfusions to keep his platelet count above 10 x 109/L. During your assessment, you notice blood is oozing out of his line site. His blood work that morning is as follows:
WBC 0.2 x 109/L, hemoglobin 72 g/L, platelet count 15 x 109/L, creatinine 185, AST 320, ALT 240, blood cultures pending, INR 1.9, PTT 42 seconds.
The nurse informs you of a critical value from the new blood work that was sent upon his arrival. The blood smear that was ordered by your resident demonstrates significant schistocytes. You ask yourself:
- Is my patient bleeding from DIC or liver disease?
- Do the schistocytes suggest TTP or another thrombotic microangiopathy?
- How do I treat my patient?
Differentiating Between Multiple Hematological Clinical Syndromes
Our case represents a difficult clinical scenario where the etiologies of all the different lab abnormalities can be challenging. However, it is worth focusing on the clinical syndromes that are potentially immediately fatal.
The following table outlines some of the features of the differential diagnoses:
|Anemia||Dependent on underlying disease, but also due to bleeding||Often macrocytic anemia (MCV >100)||Hemolytic anemia (increased LDH, haptoglobin, indirect bilirubin)||Dependent on clinical picture, but severe anemia uncommon|
|Thrombocytopenia||Yes, often severe||Yes, but often less severe if due to associated hypersplenism||Yes, often severe||Yes, but severe (<20 x 109/L) uncommon|
|Presence of Schistocytes||Yes||No||Yes||No|
|Coagulation Abnormalities on Testing||All factors decreased (INR, PTT both elevated)||Factor VIII may be normal||Often normal||Often normal|
|D-Dimer||Markedly increased||Normal/mildly elevated||Normal/mildly elevated||Markedly increased|
|Other Clinical Features||Bleeding, often severe clinical picture||Signs of liver failure, hepato-splenomegaly||Often neurological changes or renal failure out of keeping with clinical picture||Recent heparin exposure, evidence of thrombosis|
(DIC: Disseminated intravascular coagulation, TTP: Thrombotic thrombocytopenic purpura, HUS: Hemolytic uremic syndrome, HIT: Heparin-induced thrombocytopenia)
Given the scenario, this is likely most consistent with DIC (bleeding, severe thrombocytopenia, coagulation abnormalities).
Disseminated Intravascular Coagulation (DIC)
DIC occurs when a trigger produces a systemic process leading to abnormally increased clot formation and clot destruction, leading to both thrombosis and hemorrhage (though not necessarily both). It does not occur in isolation, where common triggers include:
- Obstetrical complications
- Severe intravascular hemolysis (such as a hemolytic transfusion reaction or severe malaria)
The most common manifestation is bleeding. Other common features include: organ dysfunction (most commonly renal, but also hepatic and respiratory), shock, thromboembolism, and CNS abnormalities.
Diagnosis of DIC
DIC is a syndrome that should make you ask…What is the underlying diagnosis or trigger?
No single lab finding or marker is diagnostic of DIC, but various DIC scores do exist that provide some guidance of the factors that need to be considered in making the diagnosis. Four scores currently exist (BCSH, JSTH, SISET, ISTH/SSC). There is no clear consensus on which score is superior, but the ISTH/SSC score is used often in Canada.
Factors used in the ISTH/SSC score include 1:
- Thrombocytopenia (especially <50 x 109/L)
- Increase in fibrin makers/fibrin degradation products (D-Dimer is most common)
- Prothrombin Time Prolongation (INR is used at most centres as a surrogate)
- Fibrinogen level
- An inappropriately “normal” level is indicative of DIC as well. Fibrinogen increases as an acute phase reactant, so if the patient is in an inflammatory state and the fibrinogen is not high, consider DIC as a cause.
A blood smear will also demonstrate schistocytes (cell fragments). The most common differential diagnoses for schistocytes includes:
- Thrombotic Microangiopathies (TTP, HUS)
- Heart valve hemolysis
Treatment Options for DIC
- Treat the underlying disorder
- Actively treating the DIC occurs when DIC is clinically relevant (ie “prophylactic” treatment is not routinely recommended)
- Bleeding complications
- Thrombotic complications
Otherwise, supportive care individualized for the patient including hemodynamic/ventilatory support.
DIC with Bleeding Being Predominant
- Red Blood Cell Transfusions
- One unit at a time with a restrictive threshold (<70-80 g/L) if possible
- Frozen Plasma (10-15cc/kg; often 3-4 units)
- Only when clinical bleeding and/or urgent/emergent surgery is occurring AND INR > 1.7
- Patients with increased INR and no bleeding should not receive plasma
- Platelets (1 adult dose; each dose typically increases platelet count by 15-30 x 109/L – but may be lower with platelet consumption in DIC)
- Likely indicated if platelet count is <50 x 109/L AND severe bleeding
- Likely indicated if platelet count is <20 x 109/L prophylactically (based on consensus evidence)
- Fibrinogen replacement (cryoprecipitate [10 units is a standard adult dose] or fibrinogen concentrate [4 grams is a standard adult dose])
- Definitely indicated if fibrinogen levels < 1 g/L and bleeding
- Likely indicated if fibrinogen levels < 1.5 g/L and expected to decrease further (fulminant DIC, massive hemorrhage, acute promyelocytic leukemia)
Other options may include:
- Transfusions guided by point-of-care coagulation testing (ie ROTEM, TEG)
- Tranexamic acid
- Generally contraindicated in patients at elevated risk of thrombosis but may be considered in patients with disorders of excessive fibrinolysis (ie acute promyelocytic leukemia, trauma)
Prothrombin complex concentrates, recombinant factor VIIa, and antithrombin III concentrates lack evidence of efficacy and are not recommended.
DIC with Thrombosis Being Predominant
Prophylactic anticoagulation is generally not recommended, but may be considered based on individual patient circumstances. Warfarin is not recommended.
If anticoagulation is considered, using APTT to guide anticoagulation may be misleading due to elevation from DIC/underlying disease(known as PTT confounding). This should be discussed with a hematologist and institution-specific guidelines should be consulted, but options include measurement of anti-Xa levels or using a weight-based dosing nomogram (rather than relying on APTT for guidance) 2.
Treatment Options for Other Disorders Discussed
Other specific resources should be consulted, but some general guidelines include:
- Liver Disease – Supportive care. Frozen plasma transfusion if INR >1.7 and bleeding and/or surgery required. Red blood cell, platelet, and fibrinogen transfusions are based on general indications. Treatment of the underlying disorder and consultation with a gastroenterologist.
- TTP/HUS – Supportive care and plasma exchange to begin. Hematologist consultation.
- HIT – Stop the heparin and initiate a non-heparin anticoagulant in those without bleeding (but not warfarin to begin with). The 4Ts score can be used to determine the likelihood of HIT 3. Hematologist consultation should occur and the diagnosis should be confirmed with laboratory testing.
You suspect the patient has line-related sepsis leading to DIC given the coagulation abnormalities. Given the patient has clinical bleeding, you transfuse packed red blood cells, plasma, platelets, and cryoprecipitate. A pre-transfusion fibrinogen level comes back at 0.6 g/L. The patient continues to bleed, require transfusions, and increases in pressor support. Renal insufficiency and repeated transfusions lead to fluid overload making further transfusions problematic. The patient’s hematologist is consulted who notifies you that the patient had not reached complete remission despite induction chemotherapy and re-induction, where the family wished to proceed with the bone marrow transplantation regardless. You hold a family meeting to discuss goals of care with the hematologist present and they opt to discontinue active therapy and provide comfort care. The patient passes away the next day.
- DIC presents with both clotting and bleeding, but should be thought of as a syndrome in which there is an underlying cause.
- No single lab test or clinical finding leads to a diagnosis of DIC, but a panel including CBC, blood smear, INR, APTT, fibrinogen level, and D-dimer provide a starting point.
- Active treatment should depend on clinical evidence of bleeding or thrombosis.
All the content from the Blood & Clots series can be found here.