Clinical Coagulation Cases
Learning objectives
- LO 1Review how a clot forms, how thrombin, the endothelium and plasmin control it, and how to use the PT and aPTT at the bedside.
- LO 2Recognize hemophilia B, build its differential, and confirm it with the right labs.
- LO 3Compare bleeding in mild and severe hemophilia, justify treatment of severe hemophilia B, and list complications of the disease and its treatment.
- LO 4Work up anemia with low platelets, recite the TTP pentad, and list the differential and key labs.
- LO 5Explain how loss of ADAMTS13 causes TTP and outline treatment.
- LO 6For a long PTT with a normal PT, list the common causes, their classic signs, and the labs you'd expect.
MAPCase strategy: five questions for every bleeding case
LO 1Review: clot formation, control and the lab toolkit
Q1. What are the four steps of hemostasis, and what does the bleeding pattern tell me?
| Step | What happens | Breaks → |
|---|---|---|
| 1 · Vasoconstriction | Endothelin, neural reflex | — |
| 2 · Primary | Platelet plug: vWF–GPIb adhesion, GPIIb/IIIa aggregation | Mucocutaneous bleeding: petechiae, nosebleeds, gums, heavy periods |
| 3 · Secondary | Cascade → thrombin → fibrin mesh | Deep bleeding: joints, muscles, delayed bleeding after surgery |
| 4 · Fibrinolysis | tPA: plasminogen → plasmin → cleaves fibrin → D-dimer | — |
Thrombin builds
- Fibrinogen → fibrin
- Activates V, VIII, XI, XIII; releases VIII from vWF
- Activates platelets (PAR-1)
Thrombin + thrombomodulin brakes
- Activates protein C (+ S) → inactivates Va, VIIIa
- Endothelium adds PGI₂, NO, heparan sulfate (→ antithrombin), TFPI, tPA
High yield
The bleeding pattern names the step: mucocutaneous = platelets / vWF; deep = factors / inhibitors.
Step 1
Plasmin brakes: PAI-1 (blocks tPA), α2-antiplasmin, TAFI. Tranexamic / aminocaproic acid block plasminogen activation: used for mucosal bleeding, heavy periods and dental work.
Q2. What does each screening test measure?
| Test | Measures | Prolonged by |
|---|---|---|
| PT / INR | Extrinsic (VII) + common (X, V, II, fibrinogen) | Warfarin, vitamin K deficiency, liver disease, FVII deficiency |
| aPTT | Intrinsic (XII, XI, IX, VIII) + common | Hemophilia A/B, XI or XII deficiency, vWD (low VIII), heparin, inhibitors |
| Thrombin time | Fibrinogen → fibrin only | Heparin, direct thrombin inhibitors, low/abnormal fibrinogen |
| Platelet count + function | Primary hemostasis | Thrombocytopenia, platelet function defects, vWD |
Memory tool
PT = "Play Tennis outside" → extrinsic (VII). PTT = "Play Table Tennis inside" → intrinsic (XII, XI, IX, VIII: "$12 → $11.98").
Q3. How do I read a mixing study, and which test comes next?
- Normal plasma restores a missing factor to ≈50%, which is enough to normalize the test
- Anti-FVIII antibodies are time- and temperature-dependent: the immediate mix can look corrected, then prolongs after incubation → ask for a mix with prolonged incubation
In-house exam
Mixing rule: corrects = deficiency (lack of a protein); partial or no correction = inhibitor in the patient's plasma.
Analogy — the borrowed cup of sugar
If your recipe failed because you were out of sugar, a neighbor's cup fixes it. If someone keeps eating the sugar, borrowing a cup doesn't help; the thief eats that too.
Q4. What do the special tests in these cases tell me?
| Test | What it tells you |
|---|---|
| Factor activity | Which intrinsic factor is low and how low (hemophilia severity) |
| Bethesda assay | Inhibitor titer in Bethesda units (BU); 1 BU neutralizes 50% of normal FVIII after 2 h at 37°C |
| dRVVT (dilute Russell viper venom time) | Viper venom activates factor X directly; screens for lupus anticoagulant (below) |
| PTT-LA | aPTT reagent with low phospholipid → very sensitive to lupus anticoagulant |
| Staclot LA | aPTT with vs without extra (hexagonal-phase) phospholipid; a large delta = lupus anticoagulant |
| vWF antigen / activity | How much vWF vs how well it works (ristocetin cofactor) |
| Platelet aggregation | Response to ADP, collagen, epinephrine, arachidonic acid, thrombin, ristocetin |
| ADAMTS13 activity | <10% = TTP |
ApplyLO 1 application questions
A1Day 6 of IV heparin: the aPTT is long, the mix fails, and the thrombin time is very prolonged. Best confirming test?
A2Why does the dRVVT "sure" step shorten in lupus anticoagulant?
LO 2Hemophilia B: presentation, differential and confirmation
Q1. How does hemophilia B present?
- Christmas disease: X-linked recessive deficiency or dysfunction of factor IX (vitamin K–dependent serine protease)
- Boys; carrier mother, affected maternal uncles (≈⅓ new mutations → family history can be negative)
- Deep bleeds: hemarthroses, muscle hematomas, intracranial hemorrhage; delayed bleeding after circumcision, dental work or surgery
- Clinically identical to hemophilia A; no petechiae
Hemarthrosis
- The classic hemophilia bleed
Muscle / soft-tissue bleed
- Large hematoma after minor trauma
X-linked recessive
- Carrier mother → 50% of sons affected
Memory tool
"The boy with the swollen knee." A = 8, B = 9 (B for "Boxing Day": Christmas).
Q2. What else could cause this picture?
| Differential | How to tell it apart |
|---|---|
| Hemophilia A | Identical clinically; ↓ FVIII instead of FIX |
| von Willebrand disease | Mucocutaneous bleeding, either sex, ↓ vWF antigen/activity |
| Factor XI deficiency | Autosomal (Ashkenazi Jewish); bleeding with surgery or trauma only |
| Factor XII deficiency | ↑ aPTT but no bleeding |
| Acquired FVIII inhibitor | Older adult or postpartum, no prior bleeding; mix doesn't correct |
| Heparin | Hospital line or infusion; ↑ thrombin time |
| Non-accidental trauma | Bruises in odd places with normal labs |
Q3. Which labs confirm hemophilia B?
| Test | Hemophilia B result |
|---|---|
| Platelets, bleeding time | Normal |
| PT | Normal |
| aPTT | Prolonged |
| Mixing study | Corrects (deficiency) |
| FIX activity | Low; level sets severity |
| FVIII, vWF | Normal |
| Gene testing | F9 mutation (mostly point mutations; in 14% FIX is present but non-functional) |
Trap
Only a factor assay separates A from B. And newborns normally have low vitamin K–dependent factors (incl. IX), so a borderline FIX in an infant is repeated at ≈6 months.
In-house exam
Exam note: a carrier's factor levels "most resemble" those of the affected relative only if she is extremely lyonized; most carriers have ≈50% and don't bleed.
ApplyLO 2 application questions
A1A 2-year-old boy has a swollen knee after a minor fall; aPTT 75 s, corrected by mixing; PT and platelets normal. Next test?
LO 3Hemophilia severity, treatment and complications
Q1. How does bleeding differ between mild and severe hemophilia?
| Severity | Factor activity | Bleeding (A and B alike) |
|---|---|---|
| Severe | <1% | Spontaneous joint and muscle bleeds from infancy / crawling |
| Moderate | 1–5% | With minor trauma; occasionally spontaneous |
| Mild | >5–40% | Only with surgery or major trauma (may be found as an adult) |
Severity by factor level
- First joint bleed in severe disease ≈18 months
High yield
Severity = factor level, not the type. Severe A and severe B look the same.
Q2. How is severe hemophilia B treated, and why?
- Prophylactic FIX concentrate (recombinant, extended half-life) → keeps trough levels above ≈1%, turning "severe" into "moderate" and preventing joint damage
- On-demand FIX for acute bleeds; antifibrinolytics (tranexamic acid) for mucosal or dental bleeding
- Gene therapy (AAV-delivered F9) for selected adults
- Avoid IM injections, aspirin, NSAIDs
- Desmopressin does nothing in B: it releases stored vWF + FVIII, not FIX
Trap
DDAVP works only for mild hemophilia A and type 1 vWD. Never in hemophilia B, and avoid it in vWD type 2B.
Step 1
Emicizumab (bridges IXa and X) is for hemophilia A, with or without inhibitors.
Q3. What are the complications of the disease and of treatment?
Disease
- Hemophilic arthropathy ("target joints")
- Muscle bleeds: iliopsoas → femoral nerve palsy; compartment syndrome
- Intracranial hemorrhage (leading cause of death)
Treatment
- Inhibitors (alloantibodies): ≈25–30% severe A, 3–5% B
- In B: anaphylaxis + nephrotic syndrome with FIX in inhibitor patients
- Thrombosis with bypassing agents
- Older plasma products → HIV, HCV
ApplyLO 3 application questions
A1A boy with severe hemophilia B on FIX prophylaxis suddenly stops responding, and the aPTT no longer corrects on mixing. What happened, and which test?
A2Why won't desmopressin help a patient with mild hemophilia B?
LO 4Working up anemia with low platelets: TTP
Q1. How do I work up anemia with a low platelet count?
| Step | Question | TTP result |
|---|---|---|
| Reticulocytes | Is the marrow responding? | ↑ (6.3% in Case 5) → destruction, not production |
| Hemolysis labs | Are RBCs being destroyed? | ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin |
| DAT (Coombs) | Immune? | Negative |
| Smear | Mechanical? | Schistocytes → MAHA |
| PT / aPTT / fibrinogen | Cascade consumed? | Normal (vs DIC) |
| ADAMTS13 activity | Confirms | <10%; inhibitor antibody |
Case 5 smear
- Schistocytes (helmet cells, fragments), few platelets
Trap
The smear is what confirms MAHA. LDH is non-specific (any rapid cell turnover).
Q2. What is the TTP pentad?
| Letter | Feature | Case 5 |
|---|---|---|
| F | Fever | 6 hours of fever |
| A | Anemia: microangiopathic hemolytic (schistocytes) | Hb 6.7, retics 6.3%, LDH 762 |
| T | Thrombocytopenia | Platelets 5,000 |
| R | Renal insufficiency | BUN 57, creatinine 2.8 |
| N | Neurologic symptoms (headache, confusion, stroke, coma) | 24 hours of worsening headache |
Memory tool
FAT RN: the "fat registered nurse." The full pentad is seen in a minority; MAHA + low platelets is enough to act.
In-house exam
The pentad of TTP is flagged high yield in-house. Know all five.
Q3. What else causes MAHA with low platelets?
| Look-alike | Clue |
|---|---|
| HUS | Child, bloody diarrhea (Shiga toxin), severe kidney injury |
| DIC | ↑ PT and aPTT, ↓ fibrinogen, ↑ D-dimer; sepsis, trauma, obstetric |
| HELLP | Pregnant, ↑ liver enzymes |
| Evans syndrome | AIHA + ITP: DAT positive, spherocytes not schistocytes |
| ITP | Isolated low platelets; no anemia, no schistocytes |
| Malignant hypertension | Very high BP |
Trap
Case 5's creatinine (2.8) is higher than typical for TTP; renal injury in TTP is usually mild. Severe kidney failure pushes toward HUS.
ApplyLO 4 application question
A1A 6-year-old has bloody diarrhea, then petechiae, oliguria and schistocytes. Best test?
LO 5ADAMTS13 and TTP treatment
Q1. How does losing ADAMTS13 cause TTP?
- ADAMTS13 = metalloprotease that keeps vWF multimers at a normal size
- Hereditary form (Upshaw-Schulman) = inherited ADAMTS13 deficiency in children
- Diagnose by ADAMTS13 activity and antigen: activity must be <10%
- PT and aPTT stay normal: the cascade isn't consumed (unlike DIC)
Analogy — the hedge trimmer
ADAMTS13 is the hedge trimmer for vWF. Without it, the vWF strands grow into a bramble that snags every platelet floating by, and red cells get shredded pushing through.
Q2. How is TTP treated?
- Plasma exchange: removes the antibody and ultra-large vWF, replaces ADAMTS13
- Plus immunosuppression: steroids ± rituximab
- Start immediately on clinical suspicion; don't wait for the ADAMTS13 result
- Avoid platelet transfusion (feeds the microthrombi)
High yield
TTP = emergency: recognize the signs, start plasma exchange + immunosuppression. Untreated mortality is ≈90%.
Step 1
Caplacizumab (anti-vWF nanobody) blocks vWF–GPIb binding and is added to plasma exchange.
ApplyLO 5 application question
A1A 45-year-old woman with confusion, fever, platelets 28,000, schistocytes and creatinine 3.1. Underlying cause?
LO 6Long PTT, normal PT: the differential
Q1. What are the common causes, and how does each present?
| Disorder | Classic picture | Mix | Confirming labs | Treatment |
|---|---|---|---|---|
| Hemophilia A / B | Boy; hemarthroses, muscle bleeds; X-linked family history | Corrects | ↓ FVIII or FIX; vWF normal | Factor replacement; DDAVP for mild A |
| vWD | Mucocutaneous bleeding, heavy periods, dental bleeding; AD | Corrects | ↓ vWF antigen + activity, ± ↓ FVIII; ↓ ristocetin | DDAVP (type 1); vWF concentrate; TXA |
| Factor XI deficiency | Bleeding after surgery or trauma; Ashkenazi Jewish | Corrects | ↓ FXI | Plasma, antifibrinolytics |
| Factor XII deficiency | No bleeding; found on pre-op labs | Corrects | ↓ FXII | None |
| Acquired FVIII inhibitor | Older adult or postpartum; sudden extensive bruises, muscle and GI bleeds; no prior history | Doesn't (time-dependent) | FVIII very low; Bethesda titer | Bypassing agents / porcine FVIII + immunosuppression |
| Lupus anticoagulant | Thrombosis (stroke, DVT), pregnancy loss; usually no bleeding | Doesn't (immediate) | dRVVT, PTT-LA, Staclot; FVIII normal | Anticoagulate if thrombosis |
| Heparin | Hospitalized; IV infusion or line flush | Doesn't | ↑ thrombin time; anti-Xa | Stop / protamine |
Memory tool
Bleeds deep = hemophilia · mucocutaneous = vWD · surgical = XI · none = XII · clots = lupus anticoagulant · hospital line = heparin · grandpa with new bruises = acquired inhibitor.
Trap
A prolonged PTT with no bleeding = lupus anticoagulant or FXII deficiency. Neither needs bleeding precautions before surgery.
Q2. What makes acquired hemophilia A so dangerous?
- Autoantibodies neutralize FVIII in people with no hemophilia: 1–4 per million per year
- Older adults, postpartum women, autoimmune disease, cancer, drugs; about half idiopathic
- Severe bleeds in up to 90%; mortality 8–22%
- Treatment is two-pronged: (1) control bleeding (bypassing agents, porcine FVIII that the antibody doesn't recognize); (2) eradicate the inhibitor (immunosuppression)
High yield
Older adult + new extensive bruising + isolated ↑ PTT that doesn't correct + very low FVIII = acquired FVIII inhibitor. Liver disease would prolong the PT too.
Q3. Why does a "lupus anticoagulant" cause clots?
- Heterogeneous autoantibodies against phospholipid-binding proteins (β2-glycoprotein I, prothrombin)
- In the tube: they block tests that use a limited supply of phospholipid → ↑ aPTT (± PT)
- In the body: prothrombotic → stroke, DVT/PE, recurrent miscarriage
- Has nothing to do with lupus for most patients; it was first found in lupus patients
| # | ISTH criteria for lupus anticoagulant |
|---|---|
| 1 | At least one abnormal screening test (PTT-LA, dRVVT) |
| 2 | No correction on mixing |
| 3 | Shortening with excess phospholipid |
| 4 | Exclusion of a specific factor inhibitor |
Trap
Prolonged clotting time ≠ bleeding risk. A surgeon sees a long PTT, but this patient needs clot prevention, not plasma.
Step 1
Antiphospholipid syndrome = clot or pregnancy event + persistent antibody (lupus anticoagulant, anticardiolipin, anti-β2GPI) on 2 tests ≥12 weeks apart → long-term warfarin. Can cause a false-positive VDRL.
ApplyLO 6 application questions
A1A 50-year-old has an aPTT of 85 s on pre-op labs but had no bleeding after a tonsillectomy. Likely cause?
A2Six weeks postpartum, a woman has thigh hematomas; the aPTT mix corrects at first, then prolongs after 2 hours of incubation. Tests?
CASEThe five lecture cases
Case 1. An 82-year-old man with new, deep bruises
No prior bleeding. For 3 weeks: very extensive, deep ecchymoses on the forearms with minimal trauma. Hypertension, otherwise well.
| Lab | Result | Reads as |
|---|---|---|
| Hb · WBC · platelets | 9.9 g/dL · 9 · 343 | Mild anemia; platelets normal |
| PT | 11 s (10.7–13.0) | Normal → extrinsic fine |
| PTT | 83 s (25–38) | Intrinsic problem |
| PTT mix | 60.4 s | Doesn't correct → inhibitor |
| PTT-LA · Staclot delta | 131.4 · 19.9 | Can look falsely abnormal |
| Thrombin time | 15.3 s | Normal → not heparin |
| FVIII activity · inhibitor | <1% · 64 BU | High-titer anti-FVIII |
1aWorking diagnosis?
1bThe three most useful tests for his long PTT?
Case 2. A 10-year-old boy with nosebleeds and bruises
3 weeks of nosebleeds and easy bruising; his older brother is similar. Nasal and gingival bleeding; ecchymoses in various stages of healing.
| Lab | Result | Reads as |
|---|---|---|
| Platelets · morphology | 300,000 · normal | Count and size fine |
| PT · aPTT | Normal | Factors fine |
| Ristocetin | Normal | vWF–GPIb adhesion fine |
| Thrombin (and ADP, collagen, epi) | No aggregation | Aggregation step broken |
Glanzmann aggregation
- Flat for ADP, collagen, epinephrine; only ristocetin rises
2Defect? (A) Factor VII (B) Fibrinogen (C) GPIIb-IIIa (D) Granule storage pool (E) vWF
Case 3. A 43-year-old man with an ischemic stroke
Hypertension; no surgeries, negative family history, multivitamins only.
| Lab | Result | Reads as |
|---|---|---|
| Platelets | 287 | Normal |
| PT · INR | 25.0 s · 2.3 | Prolonged |
| Prothrombin activity | 6% | Very low prothrombin |
| PTT · mix | 62.0 · 42.0 s | Only partial correction → inhibitor |
| PTT-LA · Staclot delta | 113.0 · 61.5 | Strongly positive LA screens |
| Thrombin time | 17.0 s | Not heparin |
| dRVVT check · sure · ratio | 99.2 · 70.2 · 1.4 | Corrects with excess phospholipid |
| FVIII activity · inhibitor | 85% · none | No specific factor inhibitor |
3Diagnosis? (a) FVIII inhibitor (b) Bernard-Soulier (c) Not enough information (d) Lupus anticoagulant
Case 4. A 24-year-old woman with easy bruising and heavy periods
A "few" nosebleeds as a child. Periods last 7 days; 5–7 tampons a day for the first 3 days. No surgeries, no medications.
| Lab | Result | Reads as |
|---|---|---|
| PT · INR | 12 s · 1.0 | Normal |
| aPTT | 31 s | Normal / borderline |
| Platelets | 275,000 | Normal |
| Follow-up: vWF antigen · activity | 35% · 40% | Both low, in proportion → type 1 |
| Aggregation | Normal except ristocetin | vWF problem |
Mucocutaneous bleeding
- Nosebleeds, bruising, heavy periods
4Most helpful? (a) FVIII (b) Mixing study (c) vWF activity (d) vWF antigen (e) Platelet aggregation (f) c, d and e
In-house exam
In vWD, FVIII is slightly decreased (vWF protects it). Mild vWD → DDAVP. Type 2B: give vWF concentrate and avoid DDAVP (rapid thrombocytopenia).
Memory tool
Antigen ≈ activity → type 1 (or 3 if undetectable). Activity < antigen → type 2 (enough protein, broken function).
Case 5. A 45-year-old woman with headache and fever
24 hours of worsening headache, fever for 6 hours. No prior illness, medications or travel.
| Lab | Result | Reads as |
|---|---|---|
| WBC | 10.2 | Minimally ↑ |
| Hb · Hct | 6.7 · 21.5 | Severe anemia |
| Platelets | 5,000 | Severe thrombocytopenia |
| Na · K | 145 · 5.5 | K mildly ↑ |
| BUN · creatinine | 57 · 2.8 | Acute kidney injury |
| LDH | 762 | Hemolysis / cell turnover |
| Retic count | 6.3% | Marrow responding |
| Smear | Schistocytes | MAHA |
5Test most likely to give the diagnosis? (a) aPTT (b) PT (c) Bleeding time (d) ADAMTS13 activity
IDImage ID
Image 1 — smear
Image 2 — tracing
Image 3 — knee
Image 4 — face
Image 5 — mouth
Image 6 — back
MCQExam-style questions
1An 82-year-old man with no bleeding history has 3 weeks of extensive deep forearm bruises. Platelets 343,000; PT 11 s; PTT 83 s; mixing study 60 s; thrombin time normal. Most likely diagnosis?
2A 10-year-old boy has nosebleeds and gum bleeding; his brother is similar. Platelets 300,000 with normal morphology; PT and aPTT normal. Aggregation is normal to ristocetin but absent to thrombin. Defect?
3A 43-year-old man has an ischemic stroke. PT 25 s, PTT 62 s, PTT mix 42 s (partial correction), dRVVT check/sure ratio 1.4, FVIII 85% with no inhibitor. Diagnosis?
4A 24-year-old woman has easy bruising, 7-day heavy periods and childhood nosebleeds. PT 12 s, aPTT 31 s, platelets 275,000. Which workup is best?
5A 45-year-old woman has headache and fever. Hb 6.7, platelets 5,000, creatinine 2.8, LDH 762, retics 6.3%, schistocytes on smear. Test most likely to yield the diagnosis?
6A boy with factor IX activity of 0.5% asks how his bleeding will behave without treatment. Best answer?
7Which therapy has no role in hemophilia B?
8In TTP, the deficient enzyme normally does which of the following?
9A patient with suspected TTP has platelets of 8,000. Which step should be avoided?
10A 50-year-old's pre-op aPTT is 85 s and corrects on mixing. He had no bleeding after a tonsillectomy or dental extractions. Most likely?
11A woman has two second-trimester losses and a DVT. aPTT is prolonged and doesn't correct on mixing. Best next test?
12An acquired FVIII inhibitor is confirmed. Why is porcine FVIII useful?
!Numbers that differ between in-house and Step 1
| Item | In-house | Step 1 / board review |
|---|---|---|
| Case 1 answer: factor assays | Lists VIII, IX, X and XII as intrinsic | X is common pathway (would prolong the PT) |
| Case 1 hemoglobin | "Hb 99" | 99 g/L = 9.9 g/dL |
| Case 4 aPTT 31 s | Called "slightly prolonged" in class notes | Normal against a 25–38 s range; vWD often has a normal aPTT |
| vWD type 2 labs | Class notes tie "antigen > activity" to 2B | Activity < antigen applies to all type 2 (2A, 2B, 2M) |
| Hemophilia severity | <1 / 1–5 / >5–40% | Same; one practice explanation lists mild 1–5%, moderate 5–75%; use the standard |
| Hemophilia B frequency | ≈1:100,000 males (HEM08) | ≈1:25,000–30,000 male births |
| TTP kidney injury | Case 5 creatinine 2.8 | Usually mild in TTP; severe renal failure → think HUS |