Pathogenesis and lab investigations in DIC md pathology exam question and robbins based answer
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"disseminated intravascular coagulation" AND laboratory
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Merck Manual disseminated intravascular coagulation diagnosis laboratory findings PT PTT fibrinogen D-dimer
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Disseminated Intravascular Coagulation (DIC)
Definition: DIC is an acquired, secondary thrombohemorrhagic syndrome caused by systemic activation of coagulation. It produces widespread fibrin thrombi in the microcirculation, consumption of platelets and coagulation factors, and secondary activation of fibrinolysis. Thus, it causes both thrombosis/organ ischemia and bleeding.
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 623-625.
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 623-625.
Pathogenesis of DIC
Initiating mechanisms
Robbins describes two major mechanisms:
-
Release of tissue factor or other procoagulants into the circulation
- Obstetric complications: placental tissue, amniotic fluid, retained dead fetus
- Major trauma, burns, extensive surgery: damaged tissue releases tissue factor
- Malignancy: especially mucin-producing adenocarcinomas, in which mucin may activate factor X; acute promyelocytic leukemia is also a classic association.
-
Widespread endothelial injury or activation
- Especially important in sepsis
- Endothelial damage exposes subendothelial matrix, activates platelets and coagulation cascade.
- In sepsis, endotoxin and cytokines, particularly TNF, induce endothelial tissue-factor expression and reduce thrombomodulin expression.
- Reduced thrombomodulin means reduced activation of protein C, so inhibition of factors Va and VIIIa is impaired, favoring coagulation.
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 623-625.
Sequence of events
Underlying disorder
(sepsis / obstetric catastrophe / trauma / malignancy)
↓
Tissue factor release and/or diffuse endothelial injury
↓
Widespread thrombin generation
↓
Fibrin deposition in small vessels + platelet activation
↓
Microvascular thrombi
↓
Tissue ischemia, infarction, multiorgan dysfunction
↓
Consumption of platelets, fibrinogen, and clotting factors
↓
Secondary fibrinolysis with plasmin formation
↓
Fibrin degradation products + depletion of hemostatic factors
↓
Bleeding tendency
Consequences
1. Microvascular thrombosis
- Fibrin thrombi form in small vessels, particularly in the brain, lungs, heart, kidneys, adrenals, spleen, and liver.
- Causes tissue hypoxia, ischemia, infarction, and organ dysfunction.
- Red cells passing through fibrin strands are fragmented, producing microangiopathic hemolytic anemia with schistocytes.
2. Hemorrhagic diathesis
Bleeding occurs because of:
- Consumption of platelets
- Consumption of coagulation factors, including fibrinogen
- Plasmin-mediated degradation of fibrin and factors V and VIII
- Fibrin degradation products that inhibit platelet aggregation, fibrin polymerization, and thrombin activity.
Hence, DIC is also called consumption coagulopathy.
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 624-625.
Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 624-625.
Important causes of DIC
Remember: "Sepsis, Surgery/trauma, Obstetric complications, and Malignancy."
| Category | Examples |
|---|---|
| Sepsis | Gram-negative or gram-positive septicemia, meningococcemia |
| Obstetric causes | Abruptio placentae, amniotic fluid embolism, retained dead fetus, severe preeclampsia/eclampsia |
| Malignancy | Acute promyelocytic leukemia; mucinous adenocarcinoma of pancreas, lung, stomach, colon |
| Tissue injury | Major trauma, burns, extensive surgery, shock |
| Others | Severe pancreatitis, hemolytic transfusion reaction, snake bite, giant hemangioma |
Laboratory Investigations in DIC
DIC is diagnosed by a combination of an appropriate clinical setting and serial coagulation tests. A single normal result does not exclude early or chronic DIC.
| Investigation | Finding in overt DIC | Basis |
|---|---|---|
| Platelet count | Decreased, often progressive thrombocytopenia | Platelet consumption in microthrombi |
| PT/INR | Prolonged | Consumption of extrinsic/common pathway factors |
| aPTT | Usually prolonged | Consumption of intrinsic/common pathway factors |
| Thrombin time (TT) | Prolonged | Hypofibrinogenemia and effect of FDPs |
| Plasma fibrinogen | Decreased | Consumption in fibrin formation |
| D-dimer | Markedly increased | Fibrin formation and degradation |
| Fibrin degradation products (FDPs) | Increased | Secondary fibrinolysis |
| Peripheral smear | Schistocytes/helmet cells may be present | Mechanical fragmentation of RBCs in microthrombi |
| Hemoglobin | May be decreased | Bleeding and microangiopathic hemolysis |
| Factor V and VIII | May be reduced | Consumption and plasmin-mediated degradation |
| Antithrombin | Often reduced | Consumption during excess thrombin generation |
The typical laboratory profile is: thrombocytopenia + prolonged PT/aPTT/TT + low fibrinogen + high D-dimer/FDP.
Tietz Textbook of Laboratory Medicine, p. 3128.
Tietz Textbook of Laboratory Medicine, p. 3128.
Peripheral smear
- May show microangiopathic hemolytic anemia
- Schistocytes and helmet cells support the diagnosis
- Their absence does not exclude DIC.
Important qualification
- In early DIC, aPTT may be normal or even shortened due to circulating activated clotting factors and increased factor VIII as an acute-phase reactant.
- Fibrinogen can be normal in sepsis or chronic DIC because it is an acute-phase protein. Therefore, a falling trend is often more useful than one isolated value.
ISTH scoring system for overt DIC
Use only in a patient with a disorder known to be associated with DIC.
| Variable | Score |
|---|---|
| Platelets >100,000/µL | 0 |
| Platelets <100,000/µL | 1 |
| Platelets <50,000/µL | 2 |
| No increase in fibrin markers | 0 |
| Moderate increase in D-dimer/FDP | 2 |
| Strong increase in D-dimer/FDP | 3 |
| PT prolongation <3 seconds | 0 |
| PT prolongation 3-6 seconds | 1 |
| PT prolongation >6 seconds | 2 |
| Fibrinogen >100 mg/dL | 0 |
| Fibrinogen <100 mg/dL | 1 |
Score ≥5: compatible with overt DIC.
Score <5: possible non-overt DIC; repeat tests after 1-2 days.
Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 954.
Score <5: possible non-overt DIC; repeat tests after 1-2 days.
Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 954.
Exam conclusion
DIC is an acquired systemic coagulopathy in which excessive thrombin formation causes widespread microvascular fibrin thrombi. This leads simultaneously to organ ischemia and consumption of platelets and clotting factors, followed by secondary fibrinolysis and bleeding. The key laboratory findings are falling platelet count, prolonged PT and aPTT, low fibrinogen, and raised D-dimer/FDPs, with schistocytes sometimes seen on smear.
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