Thrombocytopenia and Thrombotic Microangiopathies

Immune Thrombocytopenic Purpura

Definition and Core Pathophysiology

Immune thrombocytopenic purpura, now more formally called immune thrombocytopenia and abbreviated ITP, is an acquired autoimmune disorder characterized by isolated thrombocytopenia, classically with a platelet count <100,000/µL in the absence of another clear cause. Normal platelet count is approximately 150,000–400,000/µL. The key Step 1 concept is that ITP causes a platelet-type bleeding disorder: mucocutaneous bleeding, petechiae, purpura, epistaxis, gingival bleeding, and menorrhagia, rather than deep tissue hematomas or hemarthroses.

The dominant mechanism is production of IgG autoantibodies against platelet surface glycoproteins, especially GPIIb/IIIa and GPIb-IX. These antibody-coated platelets are opsonized and cleared by splenic macrophages through Fc receptor-mediated phagocytosis. Antibodies may also bind megakaryocytes, impairing platelet production in the bone marrow. Thus, ITP is both a disorder of increased peripheral platelet destruction and inadequate compensatory platelet production. Thrombopoietin levels are usually not as markedly elevated as expected because megakaryocyte mass is often preserved, which explains why thrombopoietin receptor agonists can be effective.

Classification and Clinical Patterns

Classification	Definition	High-Yield Associations
Primary ITP	Autoimmune thrombocytopenia without an identifiable underlying disorder	Most classic exam presentation
Secondary ITP	ITP associated with another condition	SLE, HIV, hepatitis C, H. pylori, CLL, lymphomas, drugs
Newly diagnosed	Duration <3 months	Often post-viral in children
Persistent	Duration 3–12 months	May remit or evolve to chronic ITP
Chronic	Duration >12 months	More typical in adults, especially women

Children often develop abrupt ITP after a viral illness or vaccination; it is commonly self-limited. Adults more often have an insidious, chronic course. In women of childbearing age, ITP may overlap clinically with other autoimmune diseases, especially systemic lupus erythematosus. When autoimmune thrombocytopenia occurs with autoimmune hemolytic anemia, the syndrome is called Evans syndrome.

Laboratory Findings and Diagnosis

ITP is primarily a diagnosis of exclusion. The classic laboratory pattern is isolated thrombocytopenia with otherwise normal coagulation testing. Because the coagulation cascade is intact, PT and PTT are normal. Hemoglobin is usually normal unless bleeding has occurred, and leukocyte count is typically normal. Peripheral smear may show large platelets, reflecting increased marrow release of young platelets. Bone marrow, if examined, shows normal or increased megakaryocytes.

Test	Typical ITP Finding	Reason
Platelet count	<100,000/µL; severe bleeding risk rises especially <10,000–20,000/µL	Immune platelet destruction
PT, INR	Normal	Extrinsic/common coagulation pathways intact
PTT	Normal	Intrinsic/common coagulation pathways intact
Peripheral smear	Large platelets; no schistocytes	Increased platelet turnover; absence of microangiopathic hemolysis
Antiplatelet antibody testing	Not routinely recommended	Limited sensitivity, roughly 50–60%, and imperfect specificity

A key exam distinction is that ITP has no schistocytes and normal PT/PTT, helping separate it from thrombotic microangiopathies and disseminated intravascular coagulation. Evaluation often includes testing for secondary causes such as HIV and hepatitis C, because treating the underlying infection may improve thrombocytopenia.

Treatment Principles and Pharmacology

The goal of treatment is not to normalize the platelet count but to maintain a safe count that prevents clinically significant bleeding, commonly >30,000/µL in stable adults. Current guideline-based practice, including American Society of Hematology recommendations, generally supports observation for adults with platelet counts ≥30,000/µL and no or only minor mucocutaneous bleeding. Adults with platelet counts <30,000/µL are typically treated, especially if bleeding or additional risk factors are present. Many children with no or mild bleeding can be observed even with very low counts because spontaneous remission is common.

Therapy	Typical Dose	Mechanism and High-Yield Notes
Glucocorticoids	Prednisone 0.5–2 mg/kg/day; or dexamethasone 40 mg/day for 4 days	Decrease autoantibody production and splenic macrophage Fc receptor-mediated clearance
IVIG	1 g/kg/day for 1–2 days; alternative 0.4 g/kg/day for 5 days	Saturates Fc receptors on splenic macrophages; raises platelets rapidly, often within 24–48 hours
Anti-D immune globulin	50–75 µg/kg	For Rh-positive, nonsplenectomized patients; diverts macrophage clearance toward antibody-coated RBCs
Rituximab	375 mg/m2 weekly for 4 weeks	Anti-CD20 monoclonal antibody; depletes B cells producing antiplatelet antibodies
TPO receptor agonists	Romiplostim 1–10 µg/kg weekly; eltrombopag often 50 mg orally daily	Stimulate megakaryocyte platelet production via thrombopoietin receptor signaling

Platelet transfusion is usually ineffective alone because transfused platelets are also rapidly destroyed. It is reserved for life-threatening bleeding, typically combined with IVIG and high-dose corticosteroids. Splenectomy removes the major site of antibody-mediated platelet destruction and antibody production; durable response rates are roughly 60–70%, but it is generally deferred, often for at least 12 months, because spontaneous remission can occur and effective medical options exist.

Classic USMLE Clues

• Child after viral infection with petechiae, isolated thrombocytopenia, normal PT/PTT: acute ITP.
• Adult woman with mucosal bleeding and platelet count far below normal but otherwise normal CBC and coagulation tests: chronic ITP.
• Large platelets on smear indicate increased peripheral destruction with compensatory marrow response.
• No schistocytes distinguishes ITP from TTP, HUS, and DIC.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia is an acquired, drug-induced prothrombotic disorder caused by antibodies that activate platelets after exposure to heparin. The key Step 1 paradox is that HIT causes thrombocytopenia with thrombosis, not primarily bleeding. A normal platelet count is approximately 150,000–450,000/µL; in HIT, the platelet count typically falls by >50% from baseline, often to a nadir of 20,000–100,000/µL.

Heparin Pharmacology and Why HIT Occurs

Heparin is a negatively charged glycosaminoglycan anticoagulant that binds and accelerates antithrombin III, thereby inhibiting thrombin factor IIa and factor Xa. Unfractionated heparin is a heterogeneous mixture of longer polysaccharide chains and is more strongly associated with HIT than low-molecular-weight heparin because longer chains more readily form immunogenic complexes with platelet factor 4.

Drug	Typical Use/Dose Examples	Half-life	Relative HIT Risk
Unfractionated heparin	Prophylaxis: 5,000 units subcutaneously every 8–12 hr; treatment often IV bolus/infusion adjusted by aPTT or anti-Xa	Approximately 30–90 min, dose-dependent	Highest; incidence about 1–5% in high-risk postoperative patients
Low-molecular-weight heparin	Enoxaparin prophylaxis commonly 40 mg subcutaneously daily; treatment commonly 1 mg/kg every 12 hr	Approximately 4–7 hr	Lower; approximately 0.1–1%
Fondaparinux	Factor Xa inhibitor; not heparin, used as a nonheparin option in selected cases	Approximately 17–21 hr	Very low; rare HIT-like reactions reported

Classification: Type I versus Type II HIT

Feature	Type I HIT	Type II HIT
Mechanism	Nonimmune, direct platelet aggregation effect	Immune-mediated IgG against PF4-heparin complexes
Timing	First 1–2 days	Classically days 5–10 after heparin exposure
Severity	Mild platelet fall, usually >100,000/µL	Platelet fall >50%; often 20,000–100,000/µL
Thrombosis risk	Minimal	High; venous and arterial thrombosis
Management implication	Often self-limited	Stop all heparin and anticoagulate with a nonheparin agent

Pathogenesis of Type II HIT

Activated platelets release platelet factor 4, a positively charged chemokine stored in alpha granules. PF4 binds negatively charged heparin, forming PF4-heparin complexes. In susceptible patients, IgG antibodies form against these complexes. The Fc portion of IgG binds platelet FcγRIIa receptors, causing platelet activation, degranulation, and generation of platelet-derived procoagulant microparticles. This produces thrombin generation and endothelial activation. Thus, platelets are consumed, causing thrombocytopenia, while coagulation is amplified, causing thrombosis.

HIT usually appears 5–10 days after starting heparin. If the patient had heparin exposure within the previous approximately 30–100 days, circulating antibodies may cause a rapid platelet fall within hours to 1 day. Thrombosis occurs in about 30–50% of untreated patients. Venous thromboses, especially deep venous thrombosis and pulmonary embolism, are more common than arterial events, but limb ischemia, stroke, myocardial infarction, and skin necrosis can occur.

Clinical Recognition and the 4Ts Score

The 4Ts score estimates pretest probability and is emphasized in current American Society of Hematology guidelines. It prevents overdiagnosis because many hospitalized patients have thrombocytopenia from sepsis, drugs, surgery, dilution, or marrow suppression.

Category	2 Points	1 Point	0 Points
Thrombocytopenia	>50% fall and nadir ≥20,000/µL	30–50% fall or nadir 10,000–19,000/µL	<30% fall or nadir <10,000/µL
Timing	Days 5–10, or ≤1 day with recent exposure	Consistent but unclear, or after day 10	Fall before day 4 without recent exposure
Thrombosis	New thrombosis, skin necrosis, acute systemic reaction after IV heparin bolus	Progressive/recurrent thrombosis or suspected thrombosis	None
Other causes	No other cause evident	Possible other cause	Definite other cause

Total scores: 0–3 low probability, 4–5 intermediate, and 6–8 high. A low 4Ts score has a negative predictive value of approximately >99%, so HIT testing is generally not recommended when the score is low.

Laboratory Diagnosis

Routine coagulation tests such as PT and aPTT are often not diagnostic of HIT itself, although aPTT may be prolonged if the patient is receiving heparin. Diagnosis combines clinical probability with antibody testing.

• PF4-heparin ELISA: highly sensitive, typically >95%, but less specific because it detects nonpathogenic antibodies. Higher optical density values correlate with true HIT.
• Serotonin release assay: functional platelet activation assay and gold standard; specificity usually >95%. Donor platelets release radiolabeled serotonin when exposed to patient serum plus heparin if pathogenic antibodies are present.

Management Principles and High-Yield Pitfalls

If HIT is intermediate or high probability, all heparin must be stopped, including heparin flushes and heparin-coated catheters. Because HIT is strongly prothrombotic, stopping heparin alone is insufficient; a nonheparin anticoagulant is used unless contraindicated. Examples include argatroban, bivalirudin, fondaparinux, and direct oral anticoagulants in selected patients.

Agent	Mechanism	Key Pharmacology
Argatroban	Direct thrombin inhibitor	IV infusion often 2 µg/kg/min initially; hepatic clearance; half-life about 45 min; prolongs aPTT and can elevate INR
Bivalirudin	Direct thrombin inhibitor	Half-life about 25 min; proteolytic and renal clearance; used often in procedural settings
Fondaparinux	Indirect factor Xa inhibitor via antithrombin	Once-daily subcutaneous dosing; renal clearance; long half-life 17–21 hr

Warfarin is contraindicated as initial therapy in acute HIT because early depletion of protein C can worsen the hypercoagulable state, causing venous limb gangrene or skin necrosis. It should generally be delayed until platelet recovery, classically ≥150,000/µL, and overlapped with a nonheparin anticoagulant. Platelet transfusions are avoided unless there is life-threatening bleeding, because adding platelets may theoretically fuel thrombosis.

Thrombotic Thrombocytopenic Purpura

Core Pathophysiology

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by severe deficiency of ADAMTS13, a plasma metalloprotease that normally cleaves ultra-large von Willebrand factor multimers. In normal hemostasis, endothelial cells release von Willebrand factor (vWF), which binds exposed subendothelial collagen and platelets via glycoprotein Ib. ADAMTS13 cleaves vWF at the A2 domain, specifically the Tyr1605-Met1606 bond, limiting platelet adhesion.

When ADAMTS13 activity is severely reduced, usually to <10% of normal, ultra-large vWF multimers persist and cause widespread platelet adhesion in small arterioles and capillaries. This produces platelet-rich microthrombi, leading to two central findings: thrombocytopenia from platelet consumption and microangiopathic hemolytic anemia (MAHA) from mechanical shearing of erythrocytes across microthrombi. Coagulation factors are not primarily consumed, so PT, PTT, and fibrinogen are typically normal, distinguishing TTP from disseminated intravascular coagulation.

Classification and Triggers

Type	Mechanism	High-Yield Associations
Acquired immune TTP	IgG autoantibody inhibits ADAMTS13 or accelerates its clearance	Most common adult form; associated with autoimmune disease, HIV, pregnancy, malignancy, and drugs such as quinine, ticlopidine, clopidogrel, cyclosporine, and tacrolimus
Congenital TTP / Upshaw-Schulman syndrome	Autosomal recessive ADAMTS13 gene mutations	Recurrent episodes beginning in childhood or triggered by infection, surgery, or pregnancy

Clinical and Laboratory Features

The classic teaching is the pentad: thrombocytopenia, MAHA, neurologic symptoms, renal dysfunction, and fever. However, the complete pentad is present in a minority of patients and should not be required for suspicion. Step 1 emphasizes recognizing thrombocytopenia plus MAHA with normal coagulation studies.

• Platelets: often markedly reduced, commonly <30,000/µL compared with the normal range of approximately 150,000-400,000/µL.
• Peripheral smear: schistocytes, also called helmet cells, reflecting mechanical RBC fragmentation.
• Hemolysis labs: increased LDH, increased indirect bilirubin, increased reticulocytes, low haptoglobin, and a negative direct Coombs test.
• Coagulation tests: PT and PTT usually normal; fibrinogen normal; D-dimer may be normal or mildly increased.
• Organ injury: neurologic findings are prominent, including headache, confusion, seizures, focal deficits, or coma. Renal injury can occur but is usually less severe than in hemolytic uremic syndrome.

Diagnostic Framework and Scoring

The definitive laboratory hallmark is ADAMTS13 activity <10%, often with an inhibitor in acquired disease. Because untreated TTP can deteriorate rapidly, treatment is usually begun before the ADAMTS13 result returns.

The PLASMIC score estimates the probability of severe ADAMTS13 deficiency in suspected TTP. One point is assigned for each feature: platelet count <30,000/µL, hemolysis, no active cancer, no solid-organ or stem-cell transplant, MCV <90 fL, INR <1.5, and creatinine <2.0 mg/dL. Scores of 6-7 indicate high risk; validation studies report approximately 90% sensitivity and 92% specificity for severe ADAMTS13 deficiency, with a high negative predictive value for low scores.

Disorder	Platelets	Hemolysis	PT/PTT	Key Distinction
TTP	Low	MAHA with schistocytes	Usually normal	Severe ADAMTS13 deficiency; neurologic symptoms prominent
DIC	Low	MAHA possible	Prolonged	Consumption of coagulation factors; low fibrinogen and high D-dimer
HUS	Low	MAHA	Usually normal	Renal failure prominent; often follows Shiga toxin-producing infection

Treatment Principles and Pharmacology

Untreated TTP has mortality exceeding 90%. With prompt therapy, mortality falls to approximately 10-20%. Current guideline-based therapy for immune TTP includes plasma exchange, immunosuppression, and increasingly anti-vWF therapy.

• Therapeutic plasma exchange: performed daily, typically exchanging 1.0-1.5 plasma volumes. It removes anti-ADAMTS13 autoantibody and supplies functional ADAMTS13.
• Glucocorticoids: commonly prednisone 1 mg/kg/day or intravenous methylprednisolone in severe disease; reduce autoantibody production and immune activation.
• Rituximab: anti-CD20 monoclonal antibody, often 375 mg/m² weekly for 4 doses; depletes B cells that produce anti-ADAMTS13 antibodies.
• Caplacizumab: nanobody against the vWF A1 domain, blocking vWF-platelet glycoprotein Ib interaction. Dose is 10 mg IV before plasma exchange, then 10 mg subcutaneously daily after exchange, continued for at least 30 days after plasma exchange. The HERCULES trial showed faster platelet normalization and reduced composite TTP-related adverse outcomes, but increased mucocutaneous bleeding risk.

A key exam point is that platelet transfusion is generally avoided unless there is life-threatening bleeding, because adding platelets can worsen microvascular thrombosis. For Step 1, the unifying concept is: ADAMTS13 deficiency → ultra-large vWF multimers → platelet microthrombi → thrombocytopenia + MAHA + normal PT/PTT.

Haemolytic Uraemic Syndrome

Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy defined by the triad of microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, and acute kidney injury. The core pathologic event is endothelial injury in small vessels, especially renal arterioles and glomerular capillaries, causing platelet-rich microthrombi. Red blood cells are mechanically fragmented as they traverse narrowed, fibrin- and platelet-lined vessels, producing schistocytes on peripheral smear and a Coombs-negative haemolytic anaemia.

Classification and Pathogenesis

Type	Typical trigger	Mechanism	Classic patient	Key Step 1 association
Typical HUS	Shiga toxin–producing organisms, especially E. coli O157:H7 and Shigella dysenteriae	Shiga toxin endothelial injury, especially in renal microvasculature	Child after bloody diarrhoea	Undercooked beef, unpasteurised juice, petting zoo exposure
Atypical HUS	Complement dysregulation; may be triggered by infection, pregnancy, surgery, drugs	Uncontrolled alternative complement pathway activation injures endothelium	Child or adult; recurrent disease	Mutations in factor H, factor I, MCP/CD46, C3, or factor B
Pneumococcal-associated HUS	Streptococcus pneumoniae infection	Neuraminidase exposes the Thomsen-Friedenreich antigen on RBCs, platelets, and endothelium	Child with pneumonia or meningitis	May have positive direct Coombs test, unlike most HUS

In typical HUS, Shiga toxin is absorbed from the gut after invasive colitis. It binds the globotriaosylceramide receptor (Gb3), highly expressed on renal endothelial cells. The toxin’s A subunit inactivates the 60S ribosomal subunit by depurinating 28S rRNA, thereby inhibiting protein synthesis. Endothelial injury promotes release of von Willebrand factor, platelet adhesion, and formation of microvascular thrombi. Unlike disseminated intravascular coagulation, coagulation factors are not globally consumed, so PT and PTT are usually normal.

Typical HUS occurs most often in children and classically appears 5–10 days after onset of diarrhoea, often bloody. Approximately 5–15% of children infected with Shiga toxin–producing E. coli O157:H7 develop HUS. Fever is not prominent compared with invasive bacterial dysentery, and antibiotics or antimotility agents may increase toxin exposure and are generally avoided in suspected STEC infection.

Clinical and Laboratory Features

• MAHA: fatigue, pallor, jaundice; low haemoglobin, elevated LDH, elevated indirect bilirubin, low haptoglobin, and schistocytes.
• Thrombocytopenia: platelet count typically below the normal range of 150,000–400,000/µL, often 20,000–100,000/µL; purpura may occur, but severe spontaneous bleeding is less common than in immune thrombocytopenic purpura.
• Renal injury: oliguria, haematuria, proteinuria, rising BUN and creatinine; hypertension may occur from renal parenchymal injury and salt/water retention.
• Coagulation studies: PT approximately 11–13.5 seconds and PTT approximately 25–35 seconds are usually normal, helping distinguish HUS/TTP from DIC.

Comparison with Other Thrombotic Microangiopathies

Feature	HUS	TTP	DIC
Dominant organ involvement	Kidney	Brain more prominent	Systemic bleeding and thrombosis
Typical patient	Child after bloody diarrhoea	Adult with neurologic findings	Sepsis, trauma, obstetric catastrophe, malignancy
ADAMTS13 activity	Usually normal or mildly reduced	Severely reduced, classically <10%	Not primary abnormality
PT/PTT	Normal	Normal	Prolonged
Fibrinogen	Normal	Normal	Decreased
D-dimer	Normal or mildly elevated	Normal or mildly elevated	Markedly elevated

Management Principles and Pharmacology

For USMLE Step 1, the most important management concept is mechanism-based: typical STEC-HUS is treated supportively. Support includes careful fluid and electrolyte management, red blood cell transfusion if severe symptomatic anaemia, blood pressure control, and dialysis when indicated for severe acute kidney injury, refractory hyperkalaemia, acidosis, or volume overload. Platelet transfusion is generally avoided unless there is life-threatening bleeding or an urgent invasive procedure, because platelets may fuel microthrombus formation.

Antibiotics and antimotility agents are generally avoided in suspected STEC diarrhoea. The rationale is that bacterial lysis or prolonged intestinal toxin contact may increase Shiga toxin release or absorption. This is a high-yield exam contrast with invasive bacterial diarrhoea, where antibiotics may be appropriate depending on organism and severity.

In atypical HUS, the key pharmacologic therapy is terminal complement blockade. Eculizumab is a monoclonal antibody against complement protein C5, preventing cleavage into C5a and C5b and thereby blocking membrane attack complex formation. A commonly used adult aHUS regimen is 900 mg IV weekly for 4 weeks, then 1,200 mg IV at week 5, then 1,200 mg every 2 weeks. Its half-life is approximately 11 days. Ravulizumab is a longer-acting anti-C5 antibody with a half-life of about 50 days, allowing maintenance dosing about every 8 weeks in adults after loading.

Because terminal complement blockade impairs killing of encapsulated organisms, especially Neisseria meningitidis, patients should receive meningococcal vaccination ideally at least 2 weeks before therapy when feasible; urgent treatment may require antibiotic prophylaxis. This association is high-yield: C5–C9 deficiency or blockade predisposes to recurrent Neisseria infection.

Prognosis differs by subtype. Typical HUS in children has mortality below 5% with modern supportive care, but approximately 20–30% may later develop hypertension, proteinuria, or chronic kidney disease. Atypical HUS has a higher recurrence risk and historically worse renal outcomes without complement inhibition.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is an acquired, systemic activation of coagulation that produces widespread microvascular fibrin thrombi with simultaneous consumption of platelets and clotting factors. The key Step 1 concept is paradoxical: patients may clot and bleed at the same time. Unlike TTP/HUS, in which platelet-rich microthrombi occur with usually normal PT and aPTT, DIC is a consumptive coagulopathy with abnormal coagulation studies.

Pathophysiology

DIC begins when an underlying disorder exposes or induces tissue factor, activating the extrinsic pathway: tissue factor binds factor VIIa, generating factor Xa, thrombin, and fibrin. Thrombin converts fibrinogen to fibrin and activates platelets, factors V, VIII, XI, and XIII. Simultaneously, physiologic anticoagulants such as antithrombin, protein C, and protein S are depleted or overwhelmed. Plasmin-mediated fibrinolysis increases, producing fibrin degradation products including D-dimer, a marker of cross-linked fibrin breakdown.

The result is microangiopathic hemolytic anemia from red cell shearing across fibrin strands, producing schistocytes, elevated LDH, decreased haptoglobin, and indirect hyperbilirubinemia. At the same time, consumption of platelets, fibrinogen, prothrombin, and other clotting factors causes mucosal bleeding, venipuncture-site oozing, ecchymoses, hematuria, gastrointestinal bleeding, and postpartum hemorrhage. Severe microthrombosis may cause renal failure, respiratory failure, digital ischemia, or shock.

Common Triggers and Clinical Patterns

• Sepsis: especially gram-negative endotoxin, but also gram-positive and fungal sepsis. Endotoxin and cytokines such as TNF-α and IL-1 induce tissue factor on monocytes and endothelium.
• Obstetric complications: placental abruption, amniotic fluid embolism, retained dead fetus, septic abortion, severe preeclampsia/HELLP.
• Malignancy: acute promyelocytic leukemia is classic; mucin-producing adenocarcinomas may cause chronic DIC with thrombosis.
• Major trauma, burns, pancreatitis, heat stroke, and massive transfusion.
• Severe infections causing purpura fulminans: classically Neisseria meningitidis; bilateral adrenal hemorrhage is Waterhouse-Friderichsen syndrome.

Acute DIC is rapidly progressive, often dominated by bleeding and shock. Chronic DIC is more compensated, often malignancy-associated, and may present with venous or arterial thrombosis because the liver and marrow partially replace consumed factors and platelets.

High-Yield Laboratory Findings

Test	Typical DIC Finding	Mechanism / Normal Reference
Platelet count	Decreased, often <100,000/µL	Consumption in thrombi; normal about 150,000-400,000/µL
PT / INR	Prolonged	Consumption of extrinsic/common pathway factors; PT normally about 11-13.5 seconds
aPTT	Prolonged	Consumption of intrinsic/common pathway factors; normal about 25-35 seconds
Fibrinogen	Decreased, often <150 mg/dL in overt DIC	Converted to fibrin and degraded; normal about 200-400 mg/dL
D-dimer / FDPs	Increased	Plasmin breakdown of cross-linked fibrin
Peripheral smear	Schistocytes	Microangiopathic hemolysis from fibrin strands

ISTH Overt DIC Scoring

The International Society on Thrombosis and Haemostasis (ISTH) score is a commonly tested framework. It is intended for patients with a compatible underlying disorder. A score ≥5 supports overt DIC and should be trended, often daily. Scores <5 suggest non-overt or evolving DIC and may be repeated in 1-2 days. Validation studies generally show high specificity, approximately 95%-97%, with sensitivity around 90%, though performance varies by population.

Parameter	Points
Platelets >100,000/µL; 50,000-100,000/µL; <50,000/µL	0; 1; 2
Elevated fibrin marker, e.g., D-dimer: none; moderate; strong	0; 2; 3
Prolonged PT: <3 sec; 3-6 sec; >6 sec above control	0; 1; 2
Fibrinogen >100 mg/dL; <100 mg/dL	0; 1

Distinguishing DIC from Other Thrombocytopenic Disorders

Disorder	Platelets	PT/aPTT	Key Clue
DIC	Low	Both prolonged	Low fibrinogen, high D-dimer, bleeding plus thrombosis
TTP/HUS	Low	Usually normal	Platelet microthrombi; ADAMTS13 deficiency in TTP or Shiga toxin in HUS
Immune thrombocytopenia	Low	Normal	Isolated thrombocytopenia, usually no schistocytes
Heparin-induced thrombocytopenia	Low	Usually normal PT	Thrombosis 5-10 days after heparin; anti-PF4 antibodies

Principles of Treatment

The most important intervention is treatment of the underlying cause, such as antibiotics and source control for sepsis, delivery for obstetric catastrophe, or all-trans retinoic acid for acute promyelocytic leukemia. Supportive replacement is guided by bleeding risk rather than laboratory abnormalities alone. Common guideline thresholds include platelet transfusion for active bleeding or procedures when platelets are <50,000/µL, and for severe nonbleeding thrombocytopenia around <10,000-20,000/µL. Fresh frozen plasma is typically dosed 10-15 mL/kg for bleeding with prolonged PT/aPTT. Cryoprecipitate contains fibrinogen, factor VIII, factor XIII, and von Willebrand factor; about 10 units in an adult can raise fibrinogen roughly 50-100 mg/dL, with targets often >150 mg/dL in bleeding DIC. Heparin is not routine for acute bleeding DIC but may be considered in chronic DIC with predominant thrombosis.