Platelet Disorders
Learning objectives
- LO 1Explain what normal platelets do and walk through the steps of primary hemostasis.
- LO 2Define low and high platelet counts and the ways a count falls.
- LO 3Use the common platelet lab tests and know what each one answers.
- LO 4Compare Bernard-Soulier syndrome and Glanzmann thrombasthenia: defect, smear and bleeding pattern.
- LO 5Recognize immune thrombocytopenia, explain its mechanism, and match each treatment to the step it blocks.
- LO 6Recognize TTP and HUS, recite the diagnostic pentad, and explain how they arise.
MAPBig-picture map of platelet disorders
LO 1Normal platelets and primary hemostasis
Q1. What are platelets, and where do they come from?
- Smallest circulating blood cells: 1–4 µm
- Anucleate (can't make new proteins) but very active
- Lifespan 7–10 days; ≈⅓ sit in the spleen at any time
- Made by megakaryocytes in marrow; adults make 35,000–50,000/µL per day, up to 8× more on demand
- Thrombopoietin (from kidney and liver) drives megakaryocyte production and differentiation
- Main job: stop bleeding after vessel injury. With intact vessels, most platelets never touch the endothelium
Platelets on smear
- Small purple fragments between RBCs
Megakaryocyte
- Huge, lobulated nucleus; sheds platelets
Q2. Which platelet receptors bind which ligands?
| Ligand (in subendothelium/plasma) | Platelet receptor | Step |
|---|---|---|
| von Willebrand factor | GPIb/IX (also GPIIb/IIIa once activated) | Tethering / adhesion |
| Fibrinogen | GPIIb/IIIa (integrin αIIbβ3) | Aggregation (platelet–platelet bridge) |
| Collagen | Listed as GPIIb/IIIa in lecture | Adhesion + activation |
Subendothelial matrix: collagen (most potent: activates platelets and binds vWF), vWF, laminin, fibronectin, thrombospondin.
Trap
GPIb is the only receptor on a resting (non-activated) platelet with real affinity for activated vWF. GPIIb/IIIa only works after activation.
Step 1
Collagen's main direct platelet receptors are GPVI and GPIa/IIa; vWF bridges collagen to GPIb. Remember "Ib = binds vWF; IIb/IIIa = bridges fibrinogen."
Q3. What are the steps of primary hemostasis?
- Activation is a controlled release reaction: granules fuse with the membrane and dump contents → recruits and activates more platelets (amplification)
- The space between aggregating platelets traps ADP and thromboxane A2 → more activation → "inside-out" signaling → irreversible aggregates (fibrinogen, vWF, fibronectin)
Memory tool
"The Red Army Always Fights": Tether, Roll, Activate, Aggregate, Firm adhesion.
Analogy — the velcro and the zip ties
GPIb + vWF is the velcro that catches a passing platelet on the damaged wall. GPIIb/IIIa + fibrinogen are the zip ties that bind platelets to each other.
Q4. What is inside platelet granules?
| Granule | Contents | Role |
|---|---|---|
| Alpha (most abundant) | >280 proteins: chemokines, growth factors, pro- and anti-thrombotic molecules; vWF, fibrinogen; coagulation proteins (FV, FXI, FXIII, prothrombin, HMWK) | Reinforces platelet–platelet binding; supports secondary hemostasis (fibrin stabilizes aggregates) |
| Dense | Fewer molecules: Ca²⁺, histamine, serotonin, ADP | Amplifies aggregation and thrombus formation |
| Lysosomes | Enzymes: serine peptidases, carbohydrases, phosphatases | — |
Gray platelet syndrome
- Alpha granule storage pool disease
- Pale gray platelets; significant bleeding
Step 1
Dense granules = CASH: Ca²⁺, ADP, Serotonin, Histamine.
ApplyLO 1 application questions
A1Which receptor lets a resting platelet catch onto vWF at a site of injury?
A2What molecule bridges two activated platelets?
LO 2Low and high platelet counts
Q1. How is thrombocytopenia defined and graded?
| Grade | Platelet count (/µL) |
|---|---|
| Normal | ≥150,000 (to ≈450,000) |
| Mild | 100,000–150,000 |
| Moderate | 50,000–99,000 |
| Severe | <50,000 |
Bleeding risk does not track neatly with the count: it varies with the underlying condition and can be very unpredictable.
Q2. What are the four mechanisms of a low count?
| Mechanism | Examples and clues |
|---|---|
| ↓ Production in marrow | Usually other lines are low too: MDS, infection, B12/folate deficiency; rarely isolated megakaryocyte loss from a drug; alcohol (direct marrow toxicity) |
| Sequestration in spleen | Normal spleen holds ⅓; a big spleen can hold up to 90% → liver disease/cirrhosis, myelofibrosis |
| Antibody-mediated destruction | Antiplatelet antibodies → removal by monocyte/macrophage system: drug-induced, autoimmune disease, primary ITP |
| Consumption | Thrombotic microangiopathy (TTP, HUS), DIC |
Splenomegaly
- Big spleen pools platelets → low count, normal marrow
Memory tool
Low platelets = "Made, Moved, Murdered, or Munched": ↓ production, sequestered, antibody-destroyed, consumed.
Q3. What do I need to know about drug-induced thrombocytopenia?
- Almost any drug can do it; mechanism: drug-dependent platelet-reactive antibody → splenic removal
- Starts 1–2 weeks after daily exposure to a new drug; within hours on re-exposure
- Resolves 5–7 days after stopping; specific therapy rarely needed
- Over-the-counter triggers: quinine-containing beverages (tonic water), herbal preparations, recent vaccinations, acetaminophen, nuts; alcohol (direct marrow toxicity)
Step 1 — heparin-induced thrombocytopenia
HIT type II: 5–10 days after starting heparin, IgG against heparin–PF4 complexes activates platelets → platelets fall >50% and thrombosis (paradoxical clots). Stop all heparin; use a direct thrombin inhibitor (argatroban) or fondaparinux.
Q4. What about a high count (thrombocytosis)?
Thrombocytosis = platelet count above the upper limit of normal (≈450,000/µL).
| Type | Causes |
|---|---|
| Reactive (most common) | Iron deficiency, inflammation/infection, bleeding, malignancy, after splenectomy |
| Clonal | Essential thrombocythemia and other myeloproliferative neoplasms (JAK2, CALR, MPL) |
Trap
Mild thrombocytosis with a microcytic anemia is usually iron deficiency, not a neoplasm.
ApplyLO 2 application questions
A1A man with cirrhosis and a big spleen has platelets of 60,000 and a normal marrow. Mechanism?
A2A patient who drinks tonic water nightly develops sudden petechiae and platelets of 8,000. Likely cause?
LO 3Platelet lab tests
Q1. Which tests measure platelets, and what does each answer?
| Test | Answers | Practical use |
|---|---|---|
| Platelet count (CBC) | How many? | Thrombocytopenia / thrombocytosis |
| Peripheral smear | Size, clumping, other cells | Giant platelets (Bernard-Soulier), large platelets (ITP), schistocytes (TMA), clumps (false low count) |
| Platelet aggregometry | Do they aggregate to each agonist? | Function disorders (BSS, Glanzmann) |
| PT / PTT | Coagulation factors | Normal in platelet disorders; abnormal in DIC |
| ADAMTS13 activity | vWF-cleaving enzyme level | <10% = TTP |
| LDH, haptoglobin, smear | Hemolysis | TMA (↑ LDH, ↓ haptoglobin, schistocytes) |
| Bone marrow | Megakaryocyte number | Only if needed (e.g., suspected ITP over age 60) |
Trap
A very low count in a well patient with no bleeding may be pseudothrombocytopenia: platelets clump in the EDTA tube. Look at the smear or redraw in citrate.
Q2. How does platelet aggregometry work?
- Make platelet-rich plasma (cloudy)
- Add an agonist: ADP, arachidonic acid, collagen, epinephrine, ristocetin
- Aggregating platelets clump and sink → plasma clears → light transmission rises
- A photometer records the rate and maximum %: 0% = platelet-rich plasma, 100% = platelet-poor plasma
- Two waves: primary (activation) and secondary (irreversible aggregation)
Step 1
Ristocetin makes vWF bind GPIb → tests the vWF–GPIb axis. Abnormal in Bernard-Soulier and von Willebrand disease; corrected by adding normal plasma only in vWD. Bleeding time / PFA-100 is prolonged in platelet function disorders.
ApplyLO 3 application questions
A1A patient with a platelet disorder has normal PT and PTT. Expected?
LO 4Bernard-Soulier vs Glanzmann
Q1. How do the two congenital platelet function disorders compare?
| Bernard-Soulier syndrome | Glanzmann thrombasthenia | |
|---|---|---|
| Defect | GPIb/IX complex | GPIIb/IIIa deficient or dysfunctional |
| Step lost | Adherence to vWF | Aggregation (platelet–platelet) |
| Inheritance | Autosomal recessive; chromosome 17 | Autosomal recessive; chromosome 17 |
| Platelet count / size | Thrombocytopenia with giant platelets | Normal count and size |
| Aggregometry | All agonists normal except ristocetin (abnormal) | All agonists abnormal except ristocetin (normal) |
| Bleeding | Mucocutaneous: epistaxis, easy bruising, heavy menses | Severe mucocutaneous bleeding (gums) |
BSS aggregometry
- Normal to ADP, epinephrine
- Flat to ristocetin
BSS smear
- Giant platelets
Glanzmann aggregometry
- Flat to ADP, collagen, epinephrine
- Normal to ristocetin
Mucocutaneous bleeding
- Gum bleeding (Glanzmann)
High yield
Ristocetin is the mirror: BSS = only ristocetin abnormal; Glanzmann = only ristocetin normal.
Memory tool
Bernard-Soulier = Big platelets, Ib missing, can't Bind vWF. Glanzmann = can't Glue platelets together (IIb/IIIa).
In-house exam
Both are autosomal recessive on chromosome 17. Expect a question that gives aggregometry results and asks you to name the disorder or the missing glycoprotein.
ApplyLO 4 application questions
A1A child with nosebleeds has platelets of 90,000, giant platelets, and no response to ristocetin. Defect?
A2A teen with severe gum bleeding has a normal count; platelets aggregate only with ristocetin. Defect?
LO 5Immune thrombocytopenia (ITP)
Q1. What does ITP look like?
- Isolated thrombocytopenia in an otherwise healthy adult: bruises, petechiae, gum/nose bleeding, heavy menses
- Only the platelet count is low (normal WBC and Hb)
- More common in young adult women; equal sexes in older adults. Incidence ≈3.3/100,000 adults per year
- Associations: HIV, hepatitis C, H. pylori
Case: platelets 1,000
- 32-year-old woman; 3 days of bruises, a non-itchy "rash" on both legs
- No fever, meds or travel; normal WBC and Hb
Easy bruising
- Typical platelet-type bleeding
Q2. What causes ITP?
- Antibody-mediated peripheral destruction of platelets and/or antibody-mediated megakaryocyte destruction
- 60–70% of adults have platelet-specific IgG against GPIIb/IIIa and/or GPIb/IX/V
- Antibody-coated platelets are removed by splenic macrophages (Fc receptors); the spleen is also a major site of antibody production
Analogy — tagged for removal
IgG is a "remove me" sticker on each platelet. Splenic macrophages read the sticker with their Fc receptors and eat the platelet. Every ITP treatment either makes fewer stickers, hides the readers, removes the spleen, or makes more platelets.
Q3. How is ITP diagnosed?
- Clinical, presumptive diagnosis after a full history and exam rule out other causes
- Age <60: no further testing, no bone marrow needed
- Age >60: marrow to look at megakaryocytes (rule out MDS)
- If done, marrow shows normal or ↑ megakaryocytes; smear may show large platelets (young platelets)
Q4. How does each treatment interfere with the disease?
| Treatment | Step it blocks |
|---|---|
| Corticosteroids (first line) | ↓ Antibody production and ↓ macrophage clearance of coated platelets |
| IVIG | Saturates/blocks Fc receptors on splenic macrophages → fast rise |
| Anti-D (Rh+ patients) | Coats RBCs that compete for Fc receptors |
| Rituximab (anti-CD20) | Depletes B cells → ↓ antibody |
| TPO receptor agonists (romiplostim, eltrombopag) | ↑ Production by megakaryocytes |
| Splenectomy | Removes the main site of destruction and antibody production |
| Platelet transfusion | Only for life-threatening bleeding; transfused platelets are coated and destroyed too |
Step 1
- Children: acute ITP 1–3 weeks after a viral infection; usually self-limited.
- Adults: chronic ITP, women of reproductive age; maternal IgG can cross the placenta → neonatal thrombocytopenia.
- Splenomegaly is absent in ITP; a big spleen suggests another cause.
In-house exam
Stem: heavy menses, petechiae, platelets 15,000 with enlarged platelets, no organomegaly; transfused HLA-matched platelets don't raise the count → destruction of antibody-coated platelets by the spleen.
ApplyLO 5 application questions
A1A 9-year-old has bruises 3 weeks after an RSV infection; platelets 11,000; other counts normal; improves with steroids. Cause?
A2Why does IVIG raise the platelet count within days?
LO 6Thrombotic microangiopathy: TTP and HUS
Q1. What is a thrombotic microangiopathy (TMA)?
By definition: microvascular thrombosis + thrombocytopenia + hemolytic anemia + RBC fragmentation. Endothelial injury → platelet-rich microthrombi consume platelets; RBCs passing the clots are sliced → schistocytes; the clots damage organs.
| Criterion | Definition |
|---|---|
| Thrombocytopenia | <150,000 or a 25% drop from baseline |
| Microangiopathic hemolysis | ↑ LDH, ↓ haptoglobin, fragmented cells, microspherocytes, schistocytes; >2 fragments per HPF (≈1% of RBCs) is significant |
| End-organ damage | Renal, neurologic, cardiac, hepatic, GI, skin |
Schistocytes
- RBC fragments from fibrin/platelet strands
TTP smear
- Schistocytes, very few platelets
Hereditary TMA
- Young children
- Complement, metabolic or coagulation defects
- Inherited ADAMTS13 deficiency
Acquired TMA
- Adults
- Anti-ADAMTS13 antibodies (TTP)
- Shiga toxin (HUS), drugs, acquired complement defects
Q2. Why does TTP happen?
- ADAMTS13 = metalloprotease that keeps vWF multimers at normal size
- Acquired TTP: adults, autoantibodies against ADAMTS13
- Diagnosis: ADAMTS13 activity and antigen; activity must be <10%
- Fatal if untreated; recognize and treat promptly
- Treatment: plasma exchange + immunosuppression (removes antibody, replaces ADAMTS13)
High yield — the pentad (will be tested)
- Thrombocytopenia
- Microangiopathic hemolytic anemia
- Neurologic abnormalities
- Renal insufficiency
- Fever
The pentad actually applies to any TMA, not just TTP.
Memory tool
"FAT RN": Fever, Anemia (MAHA), Thrombocytopenia, Renal, Neuro.
Step 1
TTP: normal PT/PTT (vs DIC). Don't transfuse platelets ("fuel on the fire"). Add-on: caplacizumab (anti-vWF), rituximab.
Q3. How is HUS different?
- Usually children
- Triad: MAHA + acute renal insufficiency + thrombocytopenia
- Follows infection with verotoxin (Shiga toxin)-producing bacteria: E. coli O157, Shigella, Salmonella
- Toxin damages endothelium (especially kidney) → platelet plugs → hemolysis and organ damage
- No direct therapy: supportive care, transfusion, dialysis
| TTP | HUS | DIC | |
|---|---|---|---|
| Who | Adults | Children after bloody diarrhea | Very sick: sepsis, trauma, malignancy, abruption |
| Cause | ↓ ADAMTS13 | Shiga toxin | Widespread coagulation activation |
| Dominant organ | Brain (neuro) | Kidney | Bleeding + clotting everywhere |
| PT/PTT | Normal | Normal | Prolonged; ↓ fibrinogen, ↑ D-dimer |
| Treatment | Plasma exchange | Supportive | Treat cause |
Trap
Don't give antibiotics reflexively for O157:H7 diarrhea in children; they can increase toxin release and HUS risk.
ApplyLO 6 application questions
A1A 40-year-old woman has confusion, fever, platelets 12,000, schistocytes, ↑ creatinine, normal PT/PTT. Test to confirm and treatment?
A2A 4-year-old has bloody diarrhea after a petting zoo, then pallor and low urine output. Diagnosis?
IDImage ID
Image 1 — marrow
Image 2 — smear
Image 3 — tracing
Image 4 — tracing
Image 5 — skin
Image 6 — smear
Image 7 — smear
Image 8 — abdomen
MCQExam-style questions
1A 37-year-old woman has 6 months of heavy menses and new petechiae. No organomegaly. Hb 14.2, WBC normal, platelets 15,000 with enlarged platelets. HLA-matched platelet transfusion does not raise her count. Basis of her bleeding?
2A 9-year-old has bruises 3 weeks after RSV pneumonia. Platelets 11,300; other counts normal. He improves with corticosteroids. Cause?
3A 21-year-old with protein C deficiency starts anticoagulation for PE. Two weeks later she has a left MCA stroke; platelets 65,400; PTT 51. Which drug caused this?
4A child with recurrent nosebleeds has platelets 85,000 with giant platelets. Aggregation is normal with ADP, collagen and epinephrine but absent with ristocetin. Deficient protein?
5A teenager has severe gum bleeding and a normal platelet count and size. Platelets fail to aggregate to ADP, collagen and epinephrine but aggregate with ristocetin. Diagnosis?
6Which receptor on a resting platelet captures activated vWF at a site of injury?
7A 35-year-old woman has fever, confusion, platelets 14,000, schistocytes, ↑ LDH, ↑ creatinine, and normal PT/PTT. What is the best next treatment?
8In TTP, the deficient ADAMTS13 normally does what?
9A 5-year-old develops pallor, low platelets and acute kidney injury a week after bloody diarrhea. Most likely trigger?
10Which ITP treatment works mainly by blocking Fc receptors on splenic macrophages?
11A 30-year-old has isolated thrombocytopenia (20,000), no symptoms other than petechiae, normal exam and normal other counts. What is required for the diagnosis of ITP?
12Which granule contents are released to amplify aggregation?
!Numbers that differ between in-house and Step 1
| Item | In-house | Step 1 / board review |
|---|---|---|
| Platelet lifespan | 7–10 days | 8–10 days |
| TPO source | Kidney and liver | Mainly liver |
| Collagen receptor | Table lists GPIIb/IIIa | GPVI and GPIa/IIa (vWF bridges collagen to GPIb) |
| Platelet size | 1–4 µm | 2–3 µm |
| TTP pentad | Applies to any TMA | Often taught as TTP-specific; full pentad seen in a minority |
| ITP marrow | Needed only if >60 years old | ↑ megakaryocytes if done |